Introduction

The microtubule (MT)-targeted, tubulin-polymerizing agents (MTPAs) have been demonstrated to exert a high level of clinical activity, represented by clinical remissions in advanced ovarian, breast and the upper aerodigestive tract cancers (Rowinsky and Donehower, 1995; Miller and Sledge, 1999). The central role of these agents in the therapy of the common epithelial cancers is further highlighted by their ability to induce remissions in patients with anthracycline or cis-platinum-resistant epithelial cancers (Rowinsky and Donehower, 2001). This favorable clinical activity profile was established over the past decade, following the introduction into the clinic and FDA approval of the prototypes of MTPAs, that is, the taxanes, paclitaxel and taxotere. Newer nontaxane MTPAs such as epothilone B and discodermolide, which may have superior antitumor activity than paclitaxel, are undergoing clinical testing (Kowalski et al., 1997; Lee et al., 2001; Stachel et al., 2001). Following intracellular uptake, MTPAs bind to -tubulin and promote tubulin polymerization, which interferes with the function of the mitotic spindle resulting in mitotic arrest at the metaphase/anaphase junction (Jordan, 2002). Treatment with MTPAs also activates p34cdc kinase, which promotes G2/M transition (Donaldson et al., 1994; Ibrado et al., 1998). It appears that the resulting MTPA-induced mitotic arrest triggers the mitotic spindle checkpoint, which somehow induces the mitochondrial permeability transition, release of prodeath molecules into the cytosol, and caspase-dependent apoptosis of neoplastic cells (Bhalla et al., 1993; Ibrado et al., 1996; Jordan et al., 1996; Rudner and Murray, 1996; Wang et al., 2000c) (Figure 1). Therefore, so far, most published reports indicate that the molecular ordering of the events following MTPA treatment involves first the anti-MT effects and mitotic arrest, and then the engagement of the mitochondrial pathway of apoptosis (Ibrado et al., 1998; Wang et al., 2000c; Jordan, 2002). How MTPA-induced cell cycle perturbation is linked to the initiation of apoptosis remains to be completely understood. Nevertheless, the distinct temporal association of MTPA-induced cell cycle and apoptosis-associated events suggests that the targeted manipulation of each of these events can modulate MTPA-induced apoptosis of cancer cells. The focus of the ensuing review is to discuss the salient aspects of the mechanistic basis of MTPA-induced mitotic arrest and apoptosis, as well as to illuminate the potential strategies that have been conceived and tested to enhance the antitumor activity of these agents.

Figure 1.

Schematic representation of MTPA-induced mitochondrial pathway of apoptosis and its regulation by bcl-2 and IAP family of proteins

Full figure and legend (120K)

Dynamics of the MT ends in mitosis

The mitotic arrest caused by anticancer MTPAs is due to their effects on the mitotic spindle. MTs are polymers of - and -tubulin peptide dimers, and are in unstable equilibrium with the pool of soluble tubulin dimers (Mitchison and Kirschner, 1984). There are six isotypes each of - and -tubulins. Post-translational modifications of tubulin include phosphorylation, acetylation, detyrosylation and glutamylation, which may affect the polymerization of the tubulin dimers (Rowinsky and Donehower, 1995; Haggarty et al., 2003). To assemble the polarized arrays of MTs, - and -tubulin dimer polymerization occurs more rapidly at the plus than the minus end, creating the polarity to the growth of the MTs (Sammak and Borisy, 1988). The minus end is anchored at the centrosome that contains -tubulin, which is involved in the nucleation of the MTs (Tassin and Bornens, 1999). Following nucleation, the MTs grow out by further polymerization of the tubulin dimers at the plus end, switching between phases of slow growth and rapid shrinkage, called 'the dynamic instability' (Belmont et al., 1990). During mitosis, this process allows the MTs to grow and assemble into the mitotic spindle, where the plus end of the MT attaches to the chromosomes via the kinetochore (Reider and Salmon, 1998; Karsenti and Vernos, 2001). As the kinetochore-attached MTs grow and shrink, the chromosomes are pushed or pulled toward the polar centrosomes where the minus end of the MT is attached (Inoue and Salmon, 1995). The polarized arrays of MTs also provide the tracks for the transport of the organelles. Recent studies have shown that the plus end of an MT is a molecular machine that converts chemical energy into mechanical work, and the MT dynamics can generate high force (Mitchison, 1993; Dogterom and Yurke, 1997). GTP hydrolysis provides the energy for the MT dynamics, and tubulin is really a GTPase that polymerizes in the presence of nonhydrolysable GTP to form stable MTs (Erickson and O'Brien, 1992). Although -tubulin can bind GTP, it is the -tubulin that triggers GTP hydrolysis (Nogales et al., 1999). Since GDP MTs are very unstable, GTP hydrolysis is coupled to the polymerization process at the plus end of the MT (Desai and Mitchison, 1997). Proteins that modulate the dynamics at the ends of the MTs are known as the MT-associated proteins (MAPs) (Andersen, 2000). It is now clear that the polymerization of the tubulin dimers is influenced by several factors, including the concentrations of the tubulin isotypes GTP (promotes assembly) and Ca²⁺ (inhibits assembly). The nature of the ends of the MTs and the control of their dynamics is critical for the creation and function of the mitotic spindle during mitosis (Derry et al., 1998; Howard and Hyman, 2003).

Modulation of interaction between MTs and MPTAs

Taxanes have been shown to bind to the N-terminal 31 amino acids of the -tubulin subunit in the tubulin oligomers or polymers (Rao et al., 1994). Photoaffinity labeling of MT with a taxane analogue has defined the site of interaction as Arg 282 (Rao et al., 1999). Electron crystallography of the structure of the -tubulin N-terminus indicates that His 227 and Asp 224 are critical for the binding of the C2 benzoyl side chain of paclitaxel (Nogales et al., 1999). Epothilones also occupy the same binding site on -tubulin (He et al., 2001). This binding shifts the dynamic equilibrium between tubulin dimers and MT toward MT assembly and stabilization (Jordan et al., 1996). However, at substoichiometric concentrations, taxanes have been shown to suppress MT dynamics without significantly affecting the MT polymer mass (Derry et al., 1995). Recent studies have also shown that treatment with MTPAs can produce aneuploidy in cancer cells due to aberrant mitosis, since multipolar spindles are induced by the MTPAs (Chen and Horwitz, 2002). The specificity of the activity of MTPAs on the mitotic spindle and mitosis may be because the mitotic MTs are more dynamic than the interphase MTs (Desai and Mitchison, 1997). Regardless of the precise effect on the MTs, MTPAs induce mitotic arrest and the mitochondrial pathway of apoptosis.

Several studies have focused on determining the influence of the composition of tubulin isotypes, mutations and post-translational modifications, as well as of the MT dynamics, on the mitotic arrest and the lethal effects induced by MTPAs (Table 1). In vitro studies showed that cancer cells resistant to MTPAs contained alterations in the tubulin content, tubulin polymerization or the tubulin isotype content (Dumontet and Sikic, 1999). For example, resistance to taxanes in a leukemia cell type was shown to be associated with increased expression of the class IVa tubulin isotype. In separate reports on other MTPA-resistant cell lines, reduced amount of total tubulin, a higher percentage of polymerized tubulin and a higher content of the other tubulin isotypes were observed (Ohta et al., 1993; Kavallaris et al., 1997; Dumontet and Sikic, 1999). Paclitaxel-treated tumors have been shown to display significant increases in class I, III and IVa isotypes of -tubulin (Kavallaris et al., 1997). Additionally, in lung cancer cells resistant to paclitaxel, a reduction in the expression of the class III -tubulin expression following treatment with antisense oligonucleotides to class III -tubulin was shown to increase the sensitivity to paclitaxel (Kavallaris et al., 1999). In contrast, no correlation could be demonstrated between isotype expression and paclitaxel sensitivity in a human sarcoma cell line or ovarian cancer xenografts (Dumontet et al., 1996; Nicoletti et al., 2001). Cells containing hypostable MTs, which possess a spontaneous tendency to undergo depolymerization, were also shown to be resistant to the antimitotic and lethal effects of MTPAs (Minotti et al., 1991). In a more recent study, decreased taxane sensitivity of the lung cancer cells was shown to be due to increased dynamic instability of the MTs (Gonçalves et al., 2001). These findings explain why some taxane-dependent cells are unable to grow in the absence of taxanes in the culture medium.

Table 1 - Molecular determinants of antimicrotubule (MT) and cell cycle effects of MT-targeted tubulin-polymerizing agents (MTPAs).

Full table

Mutations in -tubulin resulting in decreased MT assembly and resistance to MTPAs have been described in cancer cells resistant to paclitaxel or Epothilone B (Giannakakou et al., 1997, 2000; He et al., 2001). Mutations in -tubulin confer resistance to MTPAs by altering MT dynamics, and not by interfering with the binding of MTPAs to MT. In addition, the presence of -tubulin mutations has also been correlated with poor outcome in patients with lung cancer (Monzo et al., 1999). Conversely, several reports have failed to demonstrate mutations in -tubulin to be a clinically relevant cause of paclitaxel resistance in breast and ovarian cancers (ale et al., 2002; Lamendola et al., 2003; Maeno et al., 2003). Recently, in a paclitaxel-resistant/-dependent lung cancer cell line, -tubulin mutation was shown to be associated with increased MT instability (Martello et al., 2003). In these cells, elevated levels of MT-destabilizing factors were also noted. These included the active phosphorylated form of stathmin and the inactive phosphorylated form of MAP4. The tumor suppressor p53 transcriptionally represses MAP4 and stathmin, which are known to affect MT polymerization and paclitaxel sensitivity (Murphy et al., 1996; Zhang et al., 1998; Ahn et al., 1999; Gigant et al., 2000). Breast cancer cells harboring mutant p53 have been shown to express high levels of stathmin, decreased polymerization of MTs and binding to paclitaxel, as well as resistance to paclitaxel (Alli et al., 2002). Conversely, antisense inhibition of stathmin expression sensitized leukemia cells to the cytotoxic effect of paclitaxel (Iancu et al., 2000). Increased intracellular levels of MAP4 were also shown to be associated with increased MT polymerization, enhanced binding of paclitaxel to MT and greater sensitivity to paclitaxel (Zhang et al., 1998). Conversely, the MT-stabilizing function of MAP4 is inhibited by phosphorylation, as was seen in the paclitaxel-resistant lung cancer cells with a mutation in -tubulin. Although these preclinical findings indicate that alterations in MT polymerization due to alteration in tubulin or the MT-interacting proteins affect the cytotoxic effects of MTAPs (Table 1), the clinical relevance of these observations has yet to be established.

Modulation of MTPA-induced mitotic arrests and ensuing apoptosis: role of aurora-2 kinase, survivin, BRCA1, p53 and Her-2

Aurora 2 kinase (A2K)

Also known as Aurora A, STK15 or BTAK (breast tumor-amplified kinase), A2K is a centrosome-associated serine/threonine kinase, which is localized to chromosome 20q13, a region that is commonly amplified in a variety of human epithelial cancers (Sen et al., 1997; Zhou et al., 1998; Giet and Prigent, 1999). A2K function is involved in centrosome separation, bipolar spindle formation and chromosomal kinetochore attachment to the mitotic spindle (Bischoff and Plowman, 1999; Dutertre et al., 2002). Amplification and overexpression of A2K leads to centrosome amplification, chromosomal instability and transformation in epithelial cancers. A2K is also considered to be a MAP, and it binds in vitro to paclitaxel-stabilized MTs (Roghi et al., 1998). A2K RNA, protein and catalytic activity are cell cycle regulated, with levels peaking in the G2-M phase of the cell cycle (Bischoff and Plowman, 1999). A2K is regulated by phosphorylation on threonine 288, which is in the activation loop of the catalytic domain of the kinase (Walter et al., 2000; Cheetham et al., 2002). Elevated A2K levels and activity have been recently demonstrated to override the mitotic assembly checkpoint and induce resistance to paclitaxel-induced apoptosis (Anand et al., 2003). This suggests that the primary role of A2K could be in regulating the kinetochore-MT dynamics targeted by MTPAs. It also raises the possibility that A2K could be a potential target for selective inhibitory molecules that would block cell proliferation and sensitize cancer cells to MTPA-induced apoptosis.

Survivin

Survivin is a 16 kDa member of the inhibitor of apoptosis (IAP) family of proteins that contains a single BIR domain (Deveraux et al., 1999). This is followed by a long -helical region in the C-terminus that is required for its binding to the MTs in the mitotic spindle (Li et al., 1998; Deveraux et al., 1999; Reed and Bischoff, 2000). Survivin is expressed in cancer but not in normal terminally differentiated adult tissues (Li et al., 1998). Survivin expression increases during the G2/M phase of the cell cycle, and survivin is phosphorylated on Thr34 by CDK1-cyclin B1. This may be required to preserve cell viability at cell division (Li et al., 1998; O'Connor et al., 2000; Altieri, 2001). The crystal structure of survivin has revealed that it has a unique dimeric configuration (Muchmore et al., 2000). The dimer-related C-terminal helices form an extended negatively charged surface surrounding residue Asp-71 that is critical for the dual function of survivin in apoptosis control and preservation of ploidy (Muchmore et al., 2000). Survivin is overexpressed in most human cancers (Ambrosini et al., 1997; Altieri, 2001). Overexpression of survivin inhibits caspase activity and apoptosis induced by anticancer drugs. Abrogation of the expression/function of survivin causes increased caspase-3 activity at G2/M and apoptosis, as well as results in the dysregulation of mitosis progression, with supernumerary centrosomes, aberrant mitotic spindles and polyploidy (Li et al., 1999; Chen et al., 2000). Repression of survivin by antisense oligonucleotides has also been shown to sensitize cancer cells to chemotherapeutic agents, especially MTPAs (Olie et al., 2000; Wittmann et al., 2003). Recently, treatment with flavopiridol, a multiple cyclin-dependent kinase inhibitor, was shown to suppress survivin phosphorylation on Thr 34 and downregulate the levels of survivin, as well as sensitize breast cancer cells to MTPA-induced apoptosis (Wall et al., 2003; Wittmann and Bhalla, 2003). Taken together, these studies indicate that targeted knockdown of survivin and A2K may induce mitotic catastrophe and enhance MTPA-induced apoptosis of cancer cells (Table 1).

BRCA1

BRCA1 is a tumor-suppressor gene, which is involved in hereditary breast and ovarian cancers and has been implicated in maintaining genomic stability through DNA repair (Rosen et al., 2003). Recent studies have also shown that BRCA1 is located in the centrosome and binds to -tubulin (Deng, 2002). Targeted disruption of BRCA1 results in centrosome amplification, suggesting that BRCA1 may be a negative regulator for centrosome duplication. BRCA1 has been shown to play a role in cellular resistance to paclitaxel in ovarian cancer cells (Zhou et al., 2003). Recently, the expression of the dominant-negative BRCA1 truncation mutant was shown to confer resistance against paclitaxel (Thangaraju et al., 2000; Fedier et al., 2003). Also, in BRCA1 defective breast cancer HCC1937 cells, the resistance to paclitaxel was restored by the reconstituted expression of the full-length BRCA1 protein (Tassone et al., 2003). Conversely, the inducible expression of BRCA1 was shown to enhance paclitaxel-induced apoptosis (Mullan et al., 2001).

p53

Unlike mutations in BRCA1, the mutational loss of function of the p53 tumor suppressor does not confer resistance against MTPAs as it does against the DNA-damaging anticancer agents (Vasey et al., 1996; Wahl et al., 1996). A lack of p53 dependence on paclitaxel-induced apoptosis was also demonstrated in the NCI anticancer drug screen, since no correlation was observed between p53 status and the sensitivity to paclitaxel (O'Connor et al., 1997). Additionally, cells lacking wild-type p53 have been demonstrated to display increased sensitivity to paclitaxel (Hawkins et al., 1996; Blagosklonny and Fojo, 1999; Cassinelli et al., 2001). Also, cells from p53-null mice were shown to have increased sensitivity to paclitaxel. Although the precise mechanism(s) underlying this sensitization has not been elucidated, the potential role of MAP4 and stathmin has been investigated, as was noted above. In a recent report, the suppression of MT dynamic instability by low concentrations of MTPAs enhanced the nuclear accumulation of p53 and induction of proapoptotic p53-upregulated modulator of apoptosis (PUMA) (Giannakakou et al., 2002). This may represent a p53-dependent mechanism of MTPA-induced apoptosis in cells that harbor functional p53 (Woods et al., 1995).

Her-2

Her-2 is a member of the EGFR subfamily of transmembrane receptor tyrosine kinases, which is amplified and overexpressed in approximately 30% of breast cancers (Slamon et al., 1989; Harari and Yarden, 2000). Her-2 overexpression was demonstrated to confer resistance against paclitaxel, and the downregulation of Her-2 by the anti-Her-2 antibody Herceptin was demonstrated to sensitize breast cancer cells to MTPAs (Yu et al., 1996; Lee et al., 2002) (Table 1). Overexpression of Her-2 transcriptionally upregulates p21, which associates with CDK1. This inhibits MTPA-induced activation of CDK1 (Yu et al., 1998). CDK1 inhibition may block MTPA-mediated entry into mitosis and apoptosis. Importantly, p21 may participate in the G2/M checkpoint that contributes to resistance to MTPA-induced apoptosis. Her-2 has also been shown to bind to CDK1 and induce the inhibitory phosphorylation on Y15 of CDK1 (Tan et al., 2002). This delays M-phase entry and confers resistance to MTPA-induced apoptosis. Thus, Her-2 overexpression can inhibit CDK1 either by inducing p21 or by directly phosphorylating CDK1 on Y15.

Potential links between MTPA-induced mitotic arrest and apoptosis

Several reports have indicated the temporal ordering of MTPA-induced tubulin polymerization, CDK1 activation, mitotic arrest and the engagement of the intrinsic mitochondrial pathway of apoptosis (Donaldson et al., 1994; Ibrado et al., 1998; Scatena et al., 1998). Different mechanisms have also been highlighted that can link MTPA-induced mitotic arrest to the initiating event in the mitochondrial pathway of apoptosis (Table 2). These initiating events have included either the direct inactivation of the antiapoptotic Bcl-2 by phosphorylation or through the activation of the pro-death molecules Bax and Bad, which in turn inactivate Bcl-2 or Bcl-x_L (Blagosklonny, 2001; Konishi et al., 2002; Yamaguchi et al., 2002). For example, treatment with Epothilone B has been shown to induce the activating Bax conformational change, which translocates Bax to the mitochondria, where it can independently or through its interaction with Bcl-2 and Bcl-x_L trigger the mitochondrial pathway of apoptosis (Yamaguchi et al., 2002). Bad is a BH3 domain-only containing the proapoptotic protein, which is phosphorylated on serine (S) residues: at S112 by protein kinase A and S136 by AKT and p70S6 kinase (Datta et al., 1997, 2000b; del Peso et al., 1997; Chao and Korsmeyer, 1998; Harada et al., 1999). Bad phosphorylated on S112 and S136 is sequestered in an inactive state bound to 14-3-3 and away from Bcl-x_L and Bcl-2, which are then free to inhibit apoptosis (Zha et al., 1996; Chao and Korsmeyer, 1998). The unphosphorylated and active Bad hetrodimerizes with and inactivates Bcl-x_L and Bcl-2 to promote cell death (Figure 1). Recently, CDK1 activation was shown to phosphorylate pro-death BH3 domain-only Bad on serine 128 (Konishi et al., 2002). This promotes the apoptotic effect of Bad by inhibiting the growth factor-mediated S112 and S136 phosphorylation and inactivation of Bad (Datta et al., 1997; del Peso et al., 1997; Blume-Jensen et al., 1998; Bonni et al., 1999; Konishi et al., 2002). It should be noted that Bax and Bad-dependent mechanisms downstream to the MTPA-induced mitotic arrest may depend on the cellular context, and may also not be mutually exclusive.

Table 2 - Mechanisms linking MTPA-induced mitotic arrest to apoptosis.

Full table

Phosphorylation of Bcl-2

The significance of the role of Bcl-2 phosphorylation in facilitating MTPA-induced apoptosis had generated some controversy, since it was also shown to occur downstream to IL-3-mediated survival signaling in myeloid cells (May et al., 1994; Ito et al., 1997). At the outset, it should be noted that, although the sites phosphorylated due to IL-3 signaling may overlap with those seen following treatments with MTPAs, the cellular context created by mitosis versus mitogen stimulation are quite dissimilar, and are likely to yield dissimilar outcome and are not comparable (Blagosklonny, 2001). Several reports have demonstrated that MTPA-induced mitotic arrest induces the phosphorylation of Bcl-2 on its serine (S) and threonine (T) residues S70, S87 and T69 in its 'loop' domain (Haldar et al., 1995, 1998; Blagosklonny et al., 1996; Ling et al., 1998; Scatena et al., 1998) (Table 2). This was proposed to inactivate Bcl-2 as an antiapoptotic protein and to promote MTPA-induced apoptosis (Haldar et al., 1995, 1998). Support for this has come from studies demonstrating that the expression of mutant Bcl-2 in which S70, S87 and T69 had been changed to alanine enhanced the antiapoptotic activity of Bcl-2 against MTPA-induced apoptosis (Yamamoto et al., 1999). Ectopic expression of Bcl-2 from which the 'loop domain' had been deleted (Bcl-232-90) produced discrepant results with respect to the sensitivity to paclitaxel of HL-60 versus U937 myeloid leukemia or breast cancer cells (Fang et al., 1998; Srivastava et al., 1999; Wang et al., 1999a). This may have been due to the differences in the cellular context in the cell types, related to the levels and phosphorylation status of Bcl-2 and the other antiapoptotic family members, Bcl-x_L and Mcl-1, which have also been shown to undergo phosphorylation (Poruchynsky et al., 1998; Domina et al., 2000). So far, no study has addressed the issue as to what influence the residual unphosphorylated Bcl-2 (or Bcl-x_L and Mcl-1) relative to the phosphorylated Bcl-2 has on MTPA-induced apoptosis. A variety of different kinases have been implicated in the MTPA-induced phosphorylation of Bcl-2, including JNK, c-Raf, ERK1/2, CDK1 and cAMP-dependent PKA and PKC (Blagosklonny et al., 1996; Ito et al., 1997; Ling et al., 1998; Yamamoto et al., 1999; Blagosklonny, 2001). However, except for JNK, the role of the other kinases in MTPA-induced Bcl-2 phosphorylation is controversial (Blagosklonny, 2001). The precise mechanism of the inactivation of Bcl-2 by phosphorylation also remains to be elucidated. It is noteworthy that Bcl-2 phosphorylation also occurs during regular mitosis in untreated cells (Schandl et al., 1996; Yamamoto et al., 1999). Consequently, Bcl-2 phosphorylation has been proposed as a marker of the M-phase events and not as a determinant of apoptosis (Ling et al., 1998; Scatena et al., 1998). Although its significance remains unclear, paclitaxel has also been shown to bind to the 'loop domain' of Bcl-2 (Rodi et al., 1999). Taken together, the published evidence does not support a pre-eminent role for MTPA-induced Bcl-2 phosphorylation in mediating MTPA-induced apoptosis in all cancer types, although its role in a specific cellular context cannot be refuted.

Modulations of apoptosis signaling by pro- or antiapoptotic regulators: role in MTPA-induced apoptosis

Apoptosis signaling and Bcl-2 family members

Cleavage of a wide range of cellular protein targets by effector caspases, for example, caspase-3, -6 and -7, results in apoptosis (Hengartner, 2000; Strasser et al., 2000) (Figure 1). There are two main pathways to apoptosis, that is, extrinsic and mitochondrial pathways (Strasser et al., 2000). The extrinsic pathway of apoptosis is triggered by death ligands, for example, tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL, also known as Apo-2L). Apo-2L/TRAIL binds and induces oligomerization of its agonistic cell-membrane death receptors DR4 and DR5. The ligation and oligomerization of DR4 and DR5 result in the recruitment and assembly of the adaptor protein FADD and caspase-8 into a death-inducing signaling complex (DISC). This results in the processing and activation of caspase-8. Active caspase-8 either directly or through the recruitment of the mitochondria-based death machinery induces the processing and activity of the downstream effector caspases and apoptosis. An intracellular protein c-FLIP competes with caspase-8 for binding to FADD and inhibits caspase-8 activation in the DISC and the resulting apoptosis (Strasser et al., 2000). Active caspase-8 cleaves the cytosolic p22BID into the BH3-only domain-containing, proapoptotic, truncated p15 tBID fragment (Hengartner, 2000). tBID targets the mitochondria, where it binds to its mitochondrial proapoptotic partner Bax or Bak to trigger the loss a number of prodeath molecules from the mitochondria into the cytosol (Wang, 2001). Accordingly, BID may serve to amplify and link the extrinsic pathway to the mitochondrial events, mediating triggering the intrinsic pathway of apoptosis. As noted above, MTPA-induced mitotic arrest leads to mitochondrial permeability transition with the loss from the mitochondria of multiple pro-death molecules, including cytochrome (cyt) c, second mitochondria-derived activator of caspases (Smac), Omi/HtrA2, apoptosis-inducing factor (AIF) and endonuclease G (Kroemer and Reed, 2000; Wang, 2001) (Figure 1). In the cytosol, released cyt c and dATP bind to the adaptor molecule Apaf-1 (Zou et al., 1998). This causes multimerization of Apaf-1, allowing the recruitment of procaspase-9 and -3 into an Apaf-1 assembled 'apoptosome', resulting in the processing and activation of caspase-9 and -3 (Srinivasula et al., 1998; Zou et al., 1998). Among the growing list of genes that regulate apoptosis is the bcl-2 family of genes (Adams and Cory, 1998; Gross et al., 1999). The Bcl-2 family of proteins is divided into three subfamilies. The members of the subfamily that includes Bcl-2, Bcl-x_L and Mcl-1 inhibit apoptosis (Adams and Cory, 1998; Gross et al., 1999). The Bax subfamily members Bax and Bak that promote apoptosis share three of the four Bcl-2 homology domains, BH1–BH3, with Bcl-2 (Adams and Cory, 1998; Gross et al., 1999). These proteins also have a C-terminus hydrophobic tail, which localizes the proteins to the outer membranes of the mitochondria and endoplasmic reticulum. The third BH3-only subfamily, including Bid, Bim and Bad, also promote apoptosis (Huang and Strasser, 2000) (Figure 1). Most of these BH3-only proapoptotic proteins appear to function essentially as transdominant inhibitors by binding to antiapoptotic Bcl-2 family members and neutralizing their cell survival activity. The structure of Bcl-x_L and Bcl-xL/Bak-BH3 peptide complex has revealed that the BH1, BH2 and BH3 domains together form a hydrophobic pocket located on the surface of the Bcl-x_L protein (Fesik, 2000). The exposed hydrophobic face of the BH3 domain represents the counter structure on the BH3-only proapoptotic proteins, which, similar to a peptide ligand, inserts into the surface pocket (similar to a receptor) created by the combination of BH1, BH2 and BH3 domains of the dimerization partners (Sattler et al., 1997; Fesik, 2000). In fact, the cell-permeable Bcl-2-binding peptides, or small molecule inhibitors that block BH3 domain-mediated heterodimerization between Bcl-2 family members, have been shown to induce apoptosis (Degterev et al., 2001; Wang et al., 2000a,2000b). However, recent studies have shown that BH3-only proteins require Bax and Bak to trigger mitochondrial apoptotic signaling for apoptosis (Wei et al., 2000, 2001; Zong et al., 2001). The antiapoptotic Bcl-2 family members, in part, inhibit apoptosis by blocking the release of pro-death molecules into the cytosol (Yang et al., 1997; Gross et al., 1999). Bcl-2 and its antiapoptotic homologs also inhibit the loss of mitochondrial membrane potential and the generation of reactive oxygen species (ROS) associated with mitochondrial permeability transition (Kim et al., 1997). Heterodimerization between the pro- and antiapoptotic Bcl-2 family members that share BH1–BH3 domains determines the release of the death-promoting factors from the mitochondria (Kroemer and Reed, 2000; Wang, 2001). Mitochondrial leakiness induced by proapoptotic Bax and Bak may either be due to their interaction with Bcl-2 and Bcl-x_L, or with the permeability transition pore complex (PTPC) made up of voltage-dependent anion channel (VDAC) and adenine-nucleotide translocator (ANT) (Gross et al., 1999; Vander Heiden and Thompson, 1999).

Modulations of MTPA-induced apoptosis by pro- or anti-apoptotic regulators

Several studies have demonstrated that the ectopic overexpression of Bcl-2 or Bcl-x_L confers resistance against apoptosis due to chemotherapeutic agents including MTPAs (Tang et al., 1994; Huang et al., 1997; Ibrado et al., 1997; Yamaguchi et al., 2002). In the cells isolated in the continuous selection pressure of paclitaxel, the resistance to paclitaxel was associated with up to 2.5–3-fold increase in Bcl-2 or Bcl-x_L (Huang et al., 1997). In contrast, higher levels of the ectopic overexpressions of Bcl-2 or Bcl-x_L were necessary to confer resistance against paclitaxel-induced apoptosis (Ibrado et al., 1997). In the estrogen receptor expressing human breast cancer MCF-7 cells, exposure to estrogen increased bcl-2 levels and conferred resistance to paclitaxel-induced apoptosis, while treatment with an antiestrogen lowered Bcl-2 levels and restored sensitivity to paclitaxel (Huang et al., 1997). The effect of Bcl-2 and Bcl-x_L on paclitaxel-induced upstream events leading to mitotic arrest, as well as on the downstream engagement of the mitochondrial pathway of apoptosis, was investigated (Ibrado et al., 1998). Following S-phase arrest, the cells were released to progress through the cell cycle in a synchronized manner in the presence or absence of paclitaxel. Neither the cellular uptake, interaction with tubulin, MT polymerization and CDK1 activation, nor the mitotic arrest induced by paclitaxel, was significantly inhibited by the overexpression of Bcl-2 or Bcl-x_L. In contrast, Bcl-2 or Bcl-x_L overexpression inhibited the downstream paclitaxel-induced mitochondrial release of cyt c into the cytosol, and the activation of caspases and apoptosis. Conversely, the inhibition of Bcl-2 or Bcl-x_L expression by antisense deoxyoligonucleotides has been demonstrated to enhance apoptosis induced by MTPAs (Jansen et al., 1998; Zangemeister-Wittke et al., 2000; Benimetskaya et al., 2001). An antisense approach to downmodulate Bcl-x_L was also shown to inhibit cell cycle progression in prostate cancer cells and confer resistance to MTPAs (Vilenchik et al., 2002). Blocking the antiapoptotic function of Bcl-2 by the nonpeptidyl small-molecule Bcl-2 antagonist HA14-1 was shown to sensitize breast cancer cells to MTPA-induced apoptosis (Wang et al., 2000b; Yamaguchi et al., 2002). At the level of the apoptosome, loss of Apaf-1 expression in Apaf-/- cells has been shown to confer resistance to apoptosis due to paclitaxel (Perkins et al., 2000). In contrast, the ectopic overexpression of Apaf-1 sensitized leukemia cells to paclitaxel-induced apoptosis (Perkins et al., 1998, 2000). Taken together, these studies indicate that modulating the threshold for apoptosis set by the levels and activity of the Bcl-2 and IAP family members, as well as the levels of Apaf-1, can significantly modulate MTPA-induced apoptosis of cancer cells (Table 3).

Table 3 - Strategies to enhance MTPA-induced apoptotic signaling.

Full table

Consistent with its ability to heterodimerize with and antagonize with Bcl-2 and Bcl-x_L, as well as directly induce mitochondrial permeability transition, the ectopic overexpression of the pro-death Bax has also been shown to induce apoptosis and confer paclitaxel sensitivity in ovarian cancer cells (Strobel et al., 1996; Tai et al., 1999). Cotreatment with the cell-permeable Bak-BH3 peptide, homologous to the BH3 domain of Bak, has been demonstrated to sensitize and overcome resistance of Bcl-2-overexpressing breast cancer cells to MTPA-induced apoptosis (Yamaguchi et al., 2002). As noted above, the unphosphorylated and active Bad hetrodimerizes with and inactivates Bcl-x_L and Bcl-2 to promote cell death (Chao and Korsmeyer, 1998). Consistent with this, the ectopic overexpression of Bad has been shown to enhance paclitaxel-induced apoptosis of ovarian cancer cells (Strobel et al., 1998). In addition, cotreatment with a cell-permeable Bad-BH3 peptide has also been demonstrated to sensitize breast cancer cells to apoptosis induced by chemotherapeutic agents including MTPAs (Wang and Bhalla, 2003). Bim is also a BH3 domain-only proapoptotic protein, which interacts with and antagonizes the antiapoptotic Bcl-2 family members (O'Connor et al., 1998; Huang and Strasser, 2000; Yamaguchi and Wang, 2002). The proapoptotic function of Bim is regulated at the transcriptional levels downstream of Jun N-terminal kinase (JNK), PI-3K and Ras-mitogen activated protein kinase (MAPK) pathways (Dijkers et al., 2000; Putcha et al., 2001; Shinjyo et al., 2001; Stahl et al., 2002). Recently, Erk1/2 activated by the survival signaling initiated by cytokines and growth factors induced serine phosphorylation of Bim (Bouillet et al., 1999). Whether a similar phosphorylation induced by MTPAs plays a role in MTPA-induced apoptosis has yet to be established. Alternatively, UV radiation-activated JNK has also been shown to phosphorylate Bim, causing the release of Bim from the dynein and myosin V motor complexes, and allowing it to trigger the mitochondrial pathway of apoptosis (Lei and Davis, 2003). Bim-null lymphocytes have been reported to be relatively resistant to apoptosis induced by paclitaxel (Bouillet et al., 1999). Consistent with this, recent studies from our laboratory have shown that knockdown of Bim by siRNA confers resistance to apoptosis induced by MTPAs on breast cancer cells (Bali and Bhalla, 2003). Conversely, a cell-permeable Bim-BH3 domain peptide has been shown to sensitize breast cancer cells to MTPA-induced apoptosis (Yamaguchi and Wang, 2002; Bali and Bhalla, 2003). How Bim phosphorylation affects its pro-death function during MTPA-induced apoptosis remains to be determined.

Regulation of caspase activity and apoptosis by IAP proteins

In the mitochondrial and common effector pathway of apoptosis, the processing and proteolytic activity of caspase-9, followed by caspase-3 and -7, are inhibited by the IAP family of proteins (Deveraux and Reed, 1997) (Figure 1). This family includes XIAP, cIAP1, cIAP2 and survivin (Deveraux et al., 1998). All IAPs contain at least one BIR domain, although some contain three (Deveraux and Reed, 1997). Another region, the RING domain, has ubiquitin ligase activity and promotes the self-degradation of IAPs through the proteasomes in response to some apoptotic stimuli (Yang et al., 2000). Furthermore, during Fas death receptor-mediated apoptosis, XIAP is cleaved by activated caspase-3 into the amino-terminal BIR1-2 and BIR3-RING finger fragments (Deveraux et al., 1999). The latter specifically inhibits caspase-9. Recently, the crystal structure of caspase-3 or -7 complexed with XIAP has been elucidated (Chai et al., 2001; Huang et al., 2001; Riedl et al., 2001). This has revealed that the N-terminus linker peptide of the BIR2 domain of XIAP makes the most contact with the catalytic, substrate-binding cleft of these caspases, and sterically hinders its substrate binding, while the BIR2 domain is required only to align and stabilize this inhibitory interaction between the linker peptide and the catalytic cleft (Huang et al., 2001). Overexpression of XIAP inhibits anticancer drug (including TPA)-induced caspase activity and apoptosis (Datta et al., 2000a). In contrast, downregulation of XIAP sensitizes cancer cells to apoptosis induced by chemotherapeutic drugs (Sasaki et al., 2000). The antiapoptotic activity of NFB mediates its antiapoptotic activity by inducing IAPs and Bcl-x_L, and the down-modulation of NFB can sensitize breast cancer cells to paclitaxel (Wang et al., 1998a; Huang et al., 2000).

Neutralization of IAPs and potentiation of MTPA-induced caspase-9 and -3 activities by Smac and Omi

During apoptosis, along with cyt c, Smac and Omi are also released from the mitochondria into the cytosol (Du et al., 2000; Hegde et al., 2001). Smac and Omi relieve the inhibition of caspase-9 by XIAP, by disrupting the interaction between the BIR3 domain of XIAP and the N-terminus four residues of the linker peptide on the small subunit of caspase-9 (Liu et al., 2000; Srinivasula et al., 2001). These residues share homology with the N-terminal tetrapeptide in Smac and Omi, which can also bind to BIR3. Thus, binding to BIR3 by two conserved peptides, one from Smac or Omi and one from caspase-9, is mutually exclusive and has an opposing effect on caspase-9 activity and apoptosis. Smac also promotes the proteolytic activation of procaspase-3 and the enzymatic activity of mature caspase-3 (Chai et al., 2000; Srinivasula et al., 2000). Omi is also a serine protease and has been recently shown to process XIAP (Srinivasula et al., 2003; Yang et al., 2003). During MTPA-induced apoptosis, Smac is released from the mitochondria into the cytosol, where it neutralizes the inhibitory effect of XIAP on caspase-9 (Guo et al., 2002). A seven- or four-residue peptide derived from the amino terminus of Smac has been shown to promote procaspase-3 activation (Guo et al., 2002). These findings also suggest that the cytosolic Smac or Omi, or their N-terminus peptide, should bypass Bcl-2 or Bcl-x_L inhibition and promote caspase-3 activation by MTPA (Srinivasula et al., 2000; Guo et al., 2002).

Role of Erk1/2, JNK, NFB and AKT activity in modulating the threshold of MTPA-induced apoptosis

Erk1/2

The MAPKs are a family of serine–threonine kinases that can be activated by divers stimuli (Widmann et al., 1999; Dent and Grant, 2001). Among these, the extracellular signal-regulated kinases (Erk1/2), the c-JNKs and the p38 kinase are the three major types. Recent studies have indicated that treatment with MTPAs can induce the activities of Erk1/2 and the downstream transcription factor Elk-1 (McDaid and Horwitz, 2001; Seidman et al., 2001; Yu et al., 2001). Sequential or cotreatment with paclitaxel and MAPK kinase inhibitor has also been shown to enhance paclitaxel-induced apoptosis (MacKeigan et al., 2000; McDaid and Horwitz, 2001; Yu et al., 2001). This effect was most evident in tumor cells that expressed high activity of Erk1/2 (McDaid and Horwitz, 2001).

JNK

Paclitaxel has also been shown to activate JNK in cancer cells, which may occur through the activation of Ras and/or ASK1 (Wang et al., 1998b; Lee et al., 1998; Yamamoto et al., 1999). Paclitaxel-induced JNK activity was shown to be involved in phosphorylation of Bcl-2, although paclitaxel-induced apoptosis was shown to be mediated by JNK-dependent and independent manner (Wang et al., 1999b; Yamamoto et al., 1999).

NFB

The transcription factor NFB is activated in many types of cancer and is involved in transactivating genes, which promote cell proliferation, angiogenesis, metastasis and suppression of apoptosis (Baldwin, 2001). Inhibition of NFB has been shown as a rational strategy against some hematologic malignancies, and is being investigated as an adjuvant approach in combination with chemotherapy against epithelial cancers (Orlowski and Baldwin, 2002). Treatment with paclitaxel has also been shown to downregulate IB through upregulation of the key subunit of IB kinase (IKK) complex, IKK , which phosphorylates and downregulates IB, thus activating NFB (Huang et al., 2000; Huang and Fan, 2002). This suggests that activation of NFB may determine the susceptibility of tumor cells to paclitaxel (Huang et al., 2002). Consistent with this, inhibition of NFB has been shown to enhance paclitaxel-induced apoptosis (Patel et al., 2000).

AKT

The serine–threonine kinase AKT is a downstream target of the phosphoinositide 3-kinase (PI3K), which recruits it to the cell membrane, where it is phosphorylated and activated by phosphoinositide 3-phosphate-dependent kinase (PDK) 1 and 2 (Chang et al., 2003; Paez and Sellers, 2003). Several targets of the PI3K/AKT signaling pathway have been described that are known to inhibit apoptosis and promote survival and growth in cancer cells (Datta et al., 1999; Vivanco and Sawyers, 2002; Chang et al., 2003). Constitutively active PI3K/AKT pathway has been described in a variety of malignancies and may lead to multidrug resistance, including resistance to MTPAs (Clark et al., 2002; Knuefermann et al., 2003). Consistent with this, inhibition of PI3K/AKT-mediated signaling has been shown in vitro and in vivo to sensitize cancer cells to MTPA-induced apoptosis (Hu et al., 2002; Shingu et al., 2003). Geldanamycin analogues that target heat shock protein (hsp)-90 and its chaperone association with AKT, c-Raf and Her-2 promote proteasomal degradation and downregulation of these signaling kinases (Neckers, 2002; Isaacs et al., 2003). Consequently, Geldanamycin analogue 17-allylamino-demethoxy Geldanamycin (17-AAG) has been demonstrated to sensitize tumors to paclitaxel-induced apoptosis (Nguyen et al., 1999; Solit et al., 2003) (Table 3). More recently, treatment with the histone deacetylase inhibitor LAQ824 has been shown to acetylate and inhibit the chaperone function of hsp-90, which also results in downregulation of c-Raf, AKT and Her-2 and sensitizes cancer cells to MTPA-induced apoptosis (Fuino et al., 2003).

In summary, this review has highlighted the current basis for our understanding of the intracellular determinants of the events that begin with the binding of MTPAs to -tubulin and culminate with the execution of apoptosis of cancer cells. The levels and activities of these molecular determinants set the threshold for the sensitivity/resistance of cancer cells to MTPA-induced anti-MT effects, mitotic arrest and apoptosis. This threshold in various cancer cell types is cellular context dependent, which is likely to be dictated by the unique molecular genotype and phenotype of the cancer cell type. As our understanding of the molecular and structural biology of the determinants evolves, novel concepts and strategies are likely to emerge, that will refine our use of the MTPA in the treatment of human cancers.

References

1. Adams JM and Cory S. (1998). Science, 281, 1322–1326. | Article | PubMed | ISI | ChemPort |
2. Ahn J, Murphy M, Kratowicz S, Wang A, Levine AJ and George DL. (1999). Oncogene, 18, 5954–5958. | Article | PubMed | ISI | ChemPort |
3. Alli E, Bash-Babula J, Yang JM and Hait WN. (2002). Cancer Res., 62, 6864–6869. | PubMed | ISI | ChemPort |
4. Altieri DC. (2001). Trends Mol. Med., 7, 542–547. | Article | PubMed | ISI | ChemPort |
5. Ambrosini G, Adida C and Altieri D. (1997). Nat. Med., 3, 917–921. | Article | PubMed | ISI | ChemPort |
6. Anand S, Penrhyn-Lowe S and Venkitaraman AR. (2003). Cancer Cell, 3, 51–62. | Article | PubMed | ISI | ChemPort |
7. Andersen SS. (2000). Trends Cell Biol., 10, 261–267. | Article | PubMed | ISI | ChemPort |
8. Baldwin AS. (2001). J. Clin. Invest., 107, 241–246. | PubMed | ISI | ChemPort |
9. Bali P and Bhalla K. (2003). Personal communication.
10. Belmont LD, Hyman AA, Sawin KE and Mitchison TJ. (1990). Cell, 62, 579–589. | Article | PubMed | ISI | ChemPort |
11. Benimetskaya L, Miller P, Benimetsky S, Maciaszek A, Guga P, Beaucage SL, Wilk A, Grajkowski A, Halperin AL and Stein CA. (2001). Mol. Pharmacol., 60, 1296–1307. | PubMed |
12. Bhalla K, Ibrado AM, Tourkina E, Tang CQ, Mahoney ME and Huang Y. (1993). Leukemia, 7, 563–568. | PubMed | ISI | ChemPort |
13. Bischoff JR and Plowman GD. (1999). Cell Biol., 9, 454–459.
14. Blagosklonny MV. (2001). Leukemia, 15, 869–874. | Article | PubMed | ChemPort |
15. Blagosklonny MV and Fojo T. (1999). Int. J. Cancer, 83, 151–156. | Article | PubMed | ISI | ChemPort |
16. Blagosklonny MV, Schulte TW, Nguyen P, Trepel J and Neckers L. (1996). Cancer Res., 56, 1851–1854. | PubMed | ISI | ChemPort |
17. Blume-Jensen P, Janknecht R and Hunter T. (1998). Curr. Biol., 8, 779–782. | Article | PubMed | ISI | ChemPort |
18. Bonni A, Brunet A, West A, Datta SR, Takasu M and Greenberg ME. (1999). Science, 286, 1358–1362. | Article | PubMed | ISI | ChemPort |
19. Bouillet P, Metcalf D, Huang DC, Tarlinton DM, Kay TW, Kontgen F, Adams JM and Strasser A. (1999). Science, 286, 1735–1738. | Article | PubMed | ISI | ChemPort |
20. Cassinelli G, Supino R, Perego P, Polizzi D, Lanzi C, Pratesi G and Zunino F. (2001). Int. J. Cancer, 92, 738–747. | Article | PubMed | ISI | ChemPort |
21. Chai J, Du C, Wu J, Kyin S, Wang X and Shi Y. (2000). Nature, 406, 855–862. | Article | PubMed | ISI | ChemPort |
22. Chai J, Shiozaki E, Srinivasula S, Wu Q, Datta P, Alnemri E and Shi Y. (2001). Cell, 104, 769–780. | Article | PubMed | ISI | ChemPort |
23. Chang F, Lee JT, Navolanic PM, Steelman LS, Shelton JG, Blalock WL, Franklin RA and McCubrey JA. (2003). Leukemia, 17, 590–603. | Article | PubMed | ISI | ChemPort |
24. Chao DT and Korsmeyer SJ. (1998). Annu. Rev. Immunol., 16, 395–419. | Article | PubMed | ISI | ChemPort |
25. Cheetham GMT, Knegtel RMA, Coll JT, Renwick SB, Swenson L, Weber P, Lippke JA and Austen DA. (2002). J. Biol. Chem., 277, 42419–42422. | Article | PubMed | ISI | ChemPort |
26. Chen J, Wu W, Tahir SK, Kroeger PE, Rosenberg SH, Cowsert LM, Bennett F, Krajewski S, Krajewska M, Welsh K, Reed J and Ng SC. (2000). Blood, 2, 235–241.
27. Chen JG and Horwitz SB. (2002). Cancer Res., 62, 1935–1938. | PubMed | ISI | ChemPort |
28. Clark AS, West K, Streicher S and Dennis PA. (2002). Mol. Cancer Ther., 1, 707–717. | PubMed | ISI | ChemPort |
29. Datta R, Oki E, Endo K, Biedermann V, Ren J and Kufe D. (2000a). J. Biol. Chem., 275, 31733–31738. | Article | PubMed | ISI | ChemPort |
30. Datta SR, Brunet A and Greenberg ME. (1999). Genes Dev., 13, 2905–2927. | Article | PubMed | ISI | ChemPort |
31. Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y and Greenberg ME. (1997). Cell, 91, 231–241. | Article | PubMed | ISI | ChemPort |
32. Datta SR, Katsov A, Hu L, Petros A, Fesik SW, Yaffe MB and Greenberg ME. (2000b). Mol. Cell, 6, 41–51. | Article | PubMed | ISI | ChemPort |
33. Degterev A, Lugovskoy A, Cardone M, Mulley B, Wagner G, Mitchison T and Yuan J. (2001). Nat. Cell Biol., 3, 173–182. | Article | PubMed | ISI | ChemPort |
34. del Peso L, Gonzalez-Garcia M, Page C, Herrera R and Nunez G. (1997). Science, 278, 687–689. | Article | PubMed | ChemPort |
35. Deng CX. (2002). Oncogene, 21, 6222–6227. | Article | PubMed | ISI | ChemPort |
36. Dent P and Grant S. (2001). Clin. Cancer Res., 7, 775–783. | PubMed | ChemPort |
37. Derry WB, Wilson L and Jordan MA. (1995). Biochemistry, 34, 2203–2211. | Article | PubMed | ISI | ChemPort |
38. Derry WB, Wilson L and Jordan MA. (1998). Cancer Res., 58, 1177–1184. | PubMed |
39. Desai A and Mitchison TJ. (1997). Annu. Rev. Cell Dev. Biol., 13, 83–117. | Article | PubMed | ISI | ChemPort |
40. Deveraux Q, Leo E, Stennicke H, Welsh K, Salvesen G and Reed J. (1999). EMBO J., 18, 5242–5251. | Article | PubMed | ISI | ChemPort |
41. Deveraux Q and Reed JC. (1997). Genes Dev., 13, 239–252.
42. Deveraux Q, Roy N, Stennicke HR, Van Arsdale T, Zhou Q, Srinivasula SM, Alnemri ES, Salvesen GS and Reed JC. (1998). EMBO J., 17, 2215–2223. | Article | PubMed | ISI | ChemPort |
43. Dijkers PF, Medema RH, Lammers JW, Koenderman L and Coffer PJ. (2000). Curr. Biol., 10, 1201–1204. | Article | PubMed | ISI | ChemPort |
44. Dogterom M and Yurke B. (1997). Science, 278, 856–860. | Article | PubMed | ISI | ChemPort |
45. Domina AM, Smith JH and Craig RW. (2000). J. Biol. Chem., 275, 21688–21694. | Article | PubMed | ISI | ChemPort |
46. Donaldson KL, Goolsby GL, Kiener PA and Wahl AF. (1994). Cell Growth Differ., 5, 1041–1050. | PubMed |
47. Du C, Fang M, Li Y, Li L and Wang X. (2000). Cell, 102, 33–42. | Article | PubMed | ISI | ChemPort |
48. Dumontet C, Duran GE, Steger KA, Beketic-Oreskovic L and Sikic BI. (1996). Cancer Res., 56, 1091–1097. | PubMed | ISI | ChemPort |
49. Dumontet C and Sikic BI. (1999). J. Clin. Oncol., 17, 1061–1070. | PubMed | ISI | ChemPort |
50. Dutertre S, Descamps S and Prigent C. (2002). Oncogene, 21, 6175–6183. | Article | PubMed | ChemPort |
51. Erickson HP and O'Brien ET. (1992). Annu. Rev. Biophys. Biol. Struct., 21, 145–166.
52. Fang G, Chang BS, Kim CN, Perkins C, Thompson CB and Bhalla K. (1998). Cancer Res., 58, 3202–3208. | PubMed | ISI | ChemPort |
53. Fedier A, Steiner RA, Schwartz VA, Lenherr L, Haller U and Fink D. (2003). Int. J. Oncol., 22, 1169–1173. | PubMed | ISI | ChemPort |
54. Fesik S. (2000). Cell, 103, 273–282. | Article | PubMed | ISI | ChemPort |
55. Fuino L, Bali P, Wittmann S, Donapaty S, Guo F, Yamaguchi H, Wang HG, Atadja P and Bhalla K. (2003). Mol. Cancer Ther., 10, 971–984.
56. Giannakakou P, Gussio R, Nogales E, Downing K, Zaharevitz D, Bollbuck B, Poy G, Sackett D, Nicolaou KC and Fojo T. (2000). Proc. Natl. Acad. Sci. USA, 97, 2904–2909. | Article | PubMed | ChemPort |
57. Giannakakou P, Nakano M, Nicolaou KC, O'Brate A, Yu J, Blagosklonny MV, Greber UF and Fojo T. (2002). Proc. Natl. Acad. Sci. USA, 99, 10855–10860. | Article | PubMed | ChemPort |
58. Giannakakou P, Sackett D, Kang YK, Zhan Z, Butters J, Fojo T and Poruchynsky M. (1997). J. Biol. Chem., 272, 17118–17125. | Article | PubMed | ISI | ChemPort |
59. Giet R and Prigent C. (1999). J. Cell Sci., 112, 3591–3601. | PubMed | ISI | ChemPort |
60. Gigant B, Curmi PA, Martin-Barbey C, Charbaut E, Lachkar S, Lebeau L, Siavoshian S, Sobel A and Knossow M. (2000). Cell, 120, 809–816.
61. Gonçalves A, Braguer D, Kamath K, Martello L, Briand C, Horwitz S, Wilson L and Jordan MA. (2001). Proc. Natl. Acad. Sci. USA, 98, 11737–11741. | Article | PubMed | ISI | ChemPort |
62. Gross A, McDonnell J and Korsmeyer S. (1999). Genes Dev., 13, 1899–1911. | PubMed | ISI | ChemPort |
63. Guo F, Nimmanapalli R, Paranawithana S, Wittman S, Griffin D, Bali P, O'Bryan E, Fumero C and Bhalla K. (2002). Blood, 99, 3419–3426. | Article | PubMed | ISI | ChemPort |
64. Haggarty SJ, Koeller KM, Wong JC, Grozinger CM and Schreiber SL. (2003). Proc. Natl. Acad. Sci. USA, 100, 4389–4394. | Article | PubMed | ChemPort |
65. Haldar S, Basu A and Croce CM. (1998). Cancer Res., 58, 1609–1615. | PubMed | ISI | ChemPort |
66. Haldar S, Jena N and Croce DM. (1995). Proc. Natl. Acad. Sci. USA, 92, 4507–4511. | Article | PubMed | ChemPort |
67. Harada H, Becknell B, Wilm M, Mann M, Huang LJ, Taylor SS, Scott JD and Korsmeyer SJ. (1999). Mol. Cell, 3, 413–422. | Article | PubMed | ISI | ChemPort |
68. Harari D and Yarden Y. (2000). Oncogene, 19, 6102–6114. | Article | PubMed | ISI | ChemPort |
69. Hawkins DS, Demers GW and Galloway DA. (1996). Cancer Res., 56, 892–898. | PubMed | ISI | ChemPort |
70. He L, Huang Yang CP and Horwitz SB. (2001). Mol. Cancer Ther., 1, 3–10. | PubMed |
71. Hegde R, Srinivasula S, Zhang Z, Wassell R, Mukattash R, Cilenti L, DuBois G, Lazebnik Y, Zervos A, Fernandes-Alnemri and Alnemri E. (2001). J. Biol. Chem., 277, 432–438. | Article | PubMed | ISI | ChemPort |
72. Hengartner M. (2000). Nature, 407, 770–775. | Article | PubMed | ISI | ChemPort |
73. Howard J and Hyman AA. (2003). Nature, 422, 753–758. | Article | PubMed | ISI | ChemPort |
74. Hu L, Hofmann J, Lu Y, Mills GB and Jaffe RB. (2002). Cancer Res., 62, 1087–1092. | PubMed | ISI | ChemPort |
75. Huang D and Strasser A. (2000). Cell, 103, 839–842. | Article | PubMed | ISI | ChemPort |
76. Huang Y and Fan W. (2002). Mol. Pharmacol., 61, 105–113. | Article | PubMed | ISI | ChemPort |
77. Huang Y, Fang Y, Dziadyk JM, Norris JS and Fan W. (2002). Oncol. Res., 13, 113–122. | PubMed |
78. Huang Y, Johnson KR, Norris JS and Fan W. (2000). Cancer Res., 60, 4426–4432. | PubMed | ISI | ChemPort |
79. Huang Y, Park Y, Rich R, Segal D, Myszka D and Wu H. (2001). Cell, 104, 781–790. | PubMed | ISI | ChemPort |
80. Huang Y, Ray S, Reed JC, Ibrado AM, Tang C, Nawabi A and Bhalla K. (1997). Breast Cancer Res. Treatment, 42, 73–81.
81. Iancu C, Mistry SJ, Arkin S and Atweh GF. (2000). Cancer Res., 60, 3537–3541. | PubMed | ISI | ChemPort |
82. Ibrado AM, Huang Y, Fang G and Bhalla K. (1996). Cell Growth Differ., 7, 1087–1094. | PubMed |
83. Ibrado AM, Kim CN and Bhalla K. (1998).
84. Ibrado AM, Liu L and Bhalla K. (1997). Cancer Res., 57, 1109–1115. | PubMed | ISI | ChemPort |
85. Inoue S and Salmon ED. (1995). Mol. Biol. Cell, 6, 1619–1640. | PubMed | ISI | ChemPort |
86. Isaacs JS, Wanping X and Neckers L. (2003). Cancer Cell, 3, 213–217. | Article | PubMed | ISI | ChemPort |
87. Ito T, Deng X, Carr B and May WS. (1997). J. Biol. Chem., 272, 11671–11673. | Article | PubMed | ISI | ChemPort |
88. Jansen B, Schlagbauer-Wadl H, Brown B, Bryan R, van Elsas A, Muller M, Wolff K, Eicher H and Pehamberger H. (1998). Nat. Med., 4, 232–234. | Article | PubMed | ISI | ChemPort |
89. Jordan MA. (2002). Curr. Med. Chem. Anti-Cancer Agents, 2, 1–17. | ChemPort |
90. Jordan MA, Wendell K, Gardiner S, Derry WB, Copp H and Wilson L. (1996). Cancer Res., 56, 816–825. | PubMed | ISI | ChemPort |
91. Karsenti E and Vernos I. (2001). Science, 294, 543–547. | Article | PubMed | ISI | ChemPort |
92. Kavallaris M, Burkhart CA and Horwtiz SB. (1999). Br. J. Cancer, 80, 1020–1025. | Article | PubMed | ISI | ChemPort |
93. Kavallaris M, Kuo DY-S, Burkhart CA, Regl DL, Norris MD, Haber M and Horwitz SB. (1997). J. Clin. Invest., 100, 1282–1293. | PubMed | ISI | ChemPort |
94. Kim CN, Wang X, Huang Y, Ibrado AM, Liu L, Fang G and Bhalla K. (1997). Cancer Res., 57, 3115–3120. | PubMed | ISI | ChemPort |
95. Knuefermann C, Lu Y, Liu B, Jin W, Liang K, Wu L, Schmidt M, Mills GB, Mendelsohn J and Fran Z. (2003). Oncogene, 22, 3205–3212. | Article | PubMed | ISI | ChemPort |
96. Konishi Y, Lehtinen M, Donovan N and Bonni A. (2002). Mol. Cell, 9, 1005–1015. | Article | PubMed | ISI | ChemPort |
97. Kowalski R, Giannakakou P and Hamel E. (1997). J. Biol. Chem., 272, 2534–2541. | PubMed | ChemPort |
98. Kroemer G and Reed J. (2000). Nat. Med., 6, 513–519. | Article | PubMed | ISI | ChemPort |
99. Lamendola DE, Duan Z, Penson RT, Oliva E and Seiden MV. (2003). Anticancer Res., 23, 681–686. | PubMed | ISI | ChemPort |
100. Lee FYF, Borzilleri R, Fairchild CR, Kim SH, Long BH, Reventos-Suarez C, Vite GD, Rose WC and Kramer RA. (2001). Clin. Cancer Res., 7, 1429–1437. | PubMed | ISI | ChemPort |
101. Lee LF, Li G, Templeton DJ and Ting JP. (1998). J. Biol. Chem., 273, 28253–28260. | Article | PubMed | ISI | ChemPort |
102. Lee S, Yang W, Lan KH, Sellappan S, Klos K, Hortobagyi G, Hung MC and Yu D. (2002). Cancer Res., 62, 5703–5710. | PubMed | ISI | ChemPort |
103. Lei K and Davis RJ. (2003). Proc. Natl. Acad. Sci. USA, 100, 2432–2437. | Article | PubMed | ChemPort |
104. Li F, Ackermann E, Bennett CF, Rothermel AL, Plescia J, Tognin S, Villa A, Marchisio PC and Altieri DC. (1999). Nat. Cell Biol., 1, 461–466. | Article | PubMed | ISI | ChemPort |
105. Li F, Ambrosini G, Chu EY, Plescia J, Tognin S, Marchisio PC and Altieri DC. (1998). Nature, 396, 580–584. | Article | PubMed | ISI | ChemPort |
106. Ling Y-H, Tornos C and Perez-Soler R. (1998). J. Biol. Chem., 273, 18984–18991. | Article | PubMed | ISI | ChemPort |
107. Liu Z, Sun C, Olejniczak E, Meadows RP, Betz SF, Oost T, Herrmann J, Wu JC and Fesik SW. (2000). Nature, 408, 1004–1012. | Article | PubMed | ISI | ChemPort |
108. MacKeigan JP, Collins TS and Ting JP. (2000). J. Biol. Chem., 275, 38953–38956. | Article | PubMed | ISI | ChemPort |
109. Maeno K, Ito K, Hama Y, Shingu K, Kimura M, Sano Nakagomi H, Tsuchiya S and Fujimori M. (2003). Cancer Lett., 198, 89–97. | Article | PubMed |
110. Martello LA, Verdier-Pinard P, Shen H-J, He L, Torres K, Orr GA and Horwitz SB. (2003). Cancer Res., 63, 1207–1213. | PubMed | ISI | ChemPort |
111. May WS, Tyler PG, Ito T, Armstrong DK, Qatasha KA and Davidson NE. (1994). J. Biol. Chem., 269, 26865–26870. | PubMed | ISI | ChemPort |
112. McDaid HM and Horwitz SB. (2001). Mol. Pharmacol., 60, 290–301. | PubMed | ChemPort |
113. Miller KD and Sledge Jr GW. (1999). Cancer Invest., 17, 121–136. | PubMed |
114. Minotti AM, Barlow SB and Cabral F. (1991). J. Biol. Chem., 266, 3987–3994. | PubMed | ISI | ChemPort |
115. Mitchison T and Kirschner M. (1984). Nature, 312, 237–242. | Article | PubMed | ISI | ChemPort |
116. Mitchison TJ. (1993). Science, 261, 1044–1047. | PubMed | ISI | ChemPort |
117. Monzo M, Rosell R, Sanchez JJ, Lee JS, O'Brate A, Gonzalez-Larriba JL, Alberola V, Lorenzo JC, Nunez L, Ro JY and Martin C. (1999). J. Clin. Oncol., 17, 1786–1793. | PubMed |
118. Muchmore S, Chen J, Jakob C, Zakula D, Mayayoshi E, Wu W, Zhang H, Li F, Ng SC and Altieri D. (2000). Mol. Cell, 6, 173–182. | Article | PubMed | ISI | ChemPort |
119. Mullan PB, Quinn JE, Gilmore PM, McWilliams S, Andrews H, Gervin C, McCabe N, McKenna S, White P, Song YH, Maheswaran S, Liu E, Haber DA, Johnston PG and Harkin DP. (2001). Oncogene, 20, 6123–6131. | Article | PubMed | ISI | ChemPort |
120. Murphy M, Hinman A and Levine AJ. (1996). Genes Dev., 10, 2971–2980. | Article | PubMed | ISI | ChemPort |
121. Neckers L. (2002). Trends Mol. Med., 8, 55–61.
122. Nguyen DM, Chen A, Mixon A and Schrump DS. (1999). J. Thorac. Cardiovasc. Surg., 118, 908–915. | PubMed |
123. Nicoletti MI, Valoti G, Giannakakou P, Zhan Z, Kim JH, Lucchini V, Landoni F, Mayo JG, Giavazzi R and Fojo T. (2001). Clin. Cancer Res., 7, 2912–2922. | PubMed |
124. Nogales E, Whittaker M, Milligan RA and Downing KH. (1999). Cell, 96, 79–88. | Article | PubMed | ISI | ChemPort |
125. O'Connor D, Grossman D, Plescia J, Li F, Zhang H, Villa A, Tognin S, Marchisio P and Altieri D. (2000). Proc. Natl. Acad. Sci. USA, 97, 13103–13107. | Article | PubMed | ChemPort |
126. O'Connor L, Strasser A, O'Reilly LA, Hausmann G, Adams JM, Cory S and Huang DC. (1998). EMBO J., 17, 384–395. | Article | PubMed | ISI | ChemPort |
127. O'Connor PM, Jackman J, Bae I, Myers TG, Fan S, Mutoh M, Scudiero DA, Monks A, Sausville EA, Weinstein JN, Friend S, Fornace Jr AJ and Kohn KW. (1997). Cancer Res., 57, 4285–4300. | PubMed | ChemPort |
128. Ohta S, Nishio K, Ohmori T, Kubota N, Takeda Y, Kanzawa F, Takahashi T and Saijo N. (1993). The Mechanism and New Approach to Drug Resistance of Cancer Cells, Miyazaki T, Takaku F and Sakurada K (eds) Elsevier Science: New York, pp. 209–212.
129. Olie R, Simões-Wüst AP, Baumann B, Leech SH, Fabbro D, Stahel RA and Zangemeister-Wittke U. (2000). Cancer Res., 60, 2805–2809. | PubMed | ISI | ChemPort |
130. Orlowski RZ and Baldwin Jr AS. (2002). Trends Mol. Med., 8, 385–389. | Article | PubMed | ISI | ChemPort |
131. Paez J and Sellers WR. (2003). Cancer Treat. Res., 115, 145–167. | PubMed | ChemPort |
132. Patel NM, Nozaki S, Shortle NH, Bhat-Nakshatri P, Newton TR, Rice S, Gelfanov V, Boswell SH, Goulet Jr RJ, Sledge Jr GW and Nakshatri H. (2000). Oncogene, 19, 4159–4169. | Article | PubMed | ISI | ChemPort |
133. Perkins C, Fang G, Kim C and Bhalla K. (2000). Cancer Res., 60, 1645–1653. | PubMed | ISI | ChemPort |
134. Perkins C, Kim CN, Fang G and Bhalla K. (1998). Cancer Res., 58, 4561–4566. | PubMed | ISI | ChemPort |
135. Poruchynsky MS, Wang EW, Rudin CM and Blagosklonny MV. (1998). Cancer Res., 58, 3331–3338. | PubMed | ISI | ChemPort |
136. Putcha GV, Moulder KL, Golden JP, Bouillet P, Adams JA, Strasser A and Johnson EM. (2001). Neuron, 29, 615–628. | Article | PubMed | ISI | ChemPort |
137. Rao S, He L, Chakravarty S, Ojima I, Orr GA and Horwitz SB. (1999). J. Biol. Chem., 274, 37990–37994. | PubMed |
138. Rao S, Krauss NW, Heerding JM, Swindell CS, Ringel I, Orr G and Horwitz SB. (1994). J. Biol. Chem., 269, 3132–3134. | PubMed | ISI | ChemPort |
139. Reed F and Bischoff J. (2000). Cell, 102, 545–548. | Article | PubMed | ISI | ChemPort |
140. Reider CL and Salmon ED. (1998). Trends Cell Biol., 8, 310–318. | Article | PubMed | ISI | ChemPort |
141. Riedl S, Renatus M, Schwarzenbacher R, Zhou Q, Sun C, Fesik S, Liddington R and Salvesen G. (2001). Cell, 104, 791–800. | Article | PubMed | ISI | ChemPort |
142. Rodi DJ, Janes RW, Sanganee HJ, Holton RA, Wallace BA and Makowski L. (1999). J. Mol. Biol., 285, 197–203. | Article | PubMed | ISI | ChemPort |
143. Roghi C, Giet R, Uzbekov R, Morin N, Chartrain I, Le Guellec R, Couturier A, Doree M, Philippe M and Prigent C. (1998). J. Cell Sci., 111, 557–572. | PubMed | ISI | ChemPort |
144. Rosen EM, Fan S, Pestell RG and Goldberg ID. (2003). J. Cell. Physiol., 196, 19–41. | Article | PubMed | ISI | ChemPort |
145. Rowinsky EK and Donehower RC. (1995). N. Engl. J. Med., 332, 1004–1014. | Article | PubMed | ISI | ChemPort |
146. Rowinsky EK and Donehower RC. (2001). Cancer Chemotherapy & Biotherapy: Principles and Practice, Chabner BA and Longo DL (eds) Lippincott Williams & Wilkins: Philadelphia, pp. 329–372.
147. Rudner AD and Murray AW. (1996). Curr. Opin. Cell Biol., 8, 773–780. | Article | PubMed | ISI | ChemPort |
148. ale S, Sung R, Shen P, Yu K, Wang Y, Duran GE, Kim JH, Fojo T, Oefner PJ and Sikic BI. (2002). Mol. Cancer Ther., 1, 215–225. | PubMed | ISI | ChemPort |
149. Sammak PJ and Borisy GG. (1988). Nature, 332, 724–726. | Article | PubMed | ISI | ChemPort |
150. Sasaki H, Sheng Y, Kotsuji F and Tsang B. (2000). Cancer Res., 60, 565–566.
151. Sattler M, Liang H, Nettesheim D, Meadows RP, Harlan JE, Eberstadt M, Yoon HS, Shuker SB, Chang BS, Minn AJ, Thompson CB and Fesik SW. (1997). Science, 275, 983–986. | Article | PubMed | ISI | ChemPort |
152. Scatena CD, Stewart ZA, Mays D, Tang LJ, Keefer CJ, Leach SD and Pietenpol JA. (1998). J. Biol. Chem., 273, 30777–30784. | Article | PubMed | ISI | ChemPort |
153. Schandl CA, Priest DG and Willingham MC. (1996). Cell. Pharmacol., 3, 367–372.
154. Seidman R, Gitelman I, Sagi O, Horwitz SB and Wolfson M. (2001). Exp. Cell Res., 268, 84–92. | Article | PubMed | ISI | ChemPort |
155. Sen S, Zhou H and White RA. (1997). Oncogene, 14, 2195–2200. | Article | PubMed | ISI | ChemPort |
156. Shingu T, Yamada K, Hara N, Moritake K, Osago H and Terashima M. (2003). Cancer Res., 63, 4044–4047. | PubMed | ISI | ChemPort |
157. Shinjyo T, Kuribara R, Inukai T, Hosoi H, Kinoshita T, Miyajima A, Houghton PJ, Look AT, Ozawa K and Inaba T. (2001). Mol. Cell. Biol., 21, 854–864. | Article | PubMed | ISI | ChemPort |
158. Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A and McGuire WL. (1989). Science, 244, 707–712. | Article | PubMed | ISI | ChemPort |
159. Solit DB, Basso AD, Olshen AB, Scher HI and Rosen N. (2003). Cancer Res., 63, 2139–2144. | PubMed | ISI | ChemPort |
160. Srinivasula S, Datta P, Fan X, Fernances-Alnemri T, Huang Z and Alnemri E. (2000). J. Biol. Chem., 275, 36152–36157. | Article | PubMed | ISI | ChemPort |
161. Srinivasula S, Hegde R, Saleh A, Datta P, Shiozaki E, Chai J, Lee R, Robbins P, Fernandes-Alnemri T, Shi Y and Alnemri E. (2001). Nature, 410, 112–116. | Article | PubMed | ISI | ChemPort |
162. Srinivasula SM, Ahmad M, Fernandes-Almenri T and Almenri ES. (1998).
163. Srinivasula SM, Gupta S, Datta P, Zhang Z, Hegde R, Cheong N, Fernandes-Alnemri T and Alnemri ES. (2003). J. Biol. Chem., 34, 31469–31472.
164. Srivastava RK, Mi Q-S, Hardwick JM and Longo DL. (1999). Proc. Natl. Acad. Sci. USA, 96, 3775–3780. | Article | PubMed | ChemPort |
165. Stachel SJ, Biswas K and Danishefsky SJ. (2001). Curr. Pharm. Des., 7, 1277–1290. | PubMed |
166. Stahl M, Dijkers PF, Kops GJ, Lens SM, Coffer PJ, Burgering BM and Medema RH. (2002). J. Immunol., 168, 5024–5031. | PubMed | ISI | ChemPort |
167. Strasser A, O'Connor L and Dixit V. (2000). Annu. Rev. Biochem., 69, 217–247. | Article | PubMed | ISI | ChemPort |
168. Strobel T, Swanson L, Korsmeyer S and Cannistra SA. (1996). Proc. Natl. Acad. Sci. USA, 93, 14094–14099. | Article | PubMed | ChemPort |
169. Strobel T, Tai YT, Korsmeyer S and Cannistra SA. (1998). Oncogene, 17, 2419–2427. | Article | PubMed | ISI | ChemPort |
170. Tai YT, Storbel T, Kufe D and Cannistra SA. (1999). Cancer Res., 59, 2121–2126. | PubMed | ISI | ChemPort |
171. Tan M, Jing T, Lan KH, Neal CL, Li P, Lee S, Fang D, Nagata Y, Liu J, Arlinghaus R, Hung MC and Yu D. (2002). Mol. Cell, 9, 993–1104. | Article | PubMed | ChemPort |
172. Tang C, Willingham MC, Reed JC, Miyashita T, Tourkina E, Ponnathpur V, Huang Y, Ray S, Mahoney ME, Bullock G and Bhalla K. (1994). Leukemia, 8, 1960–1969. | PubMed |
173. Tassin A and Bornens M. (1999). Biol. Cell, 91, 343–354. | Article | PubMed | ISI | ChemPort |
174. Tassone P, Tagliaferri P, Perricelli A, Blotta S, Quaresima B, Martelli ML, Goel A, Barbieri V, Costa F, Boland CR and Venuta S. (2003). Br. J. Cancer, 88, 1285–1291. | Article | PubMed | ISI | ChemPort |
175. Thangaraju M, Kaufmann SH and Couch FJ. (2000). J. Biol. Chem., 275, 33487–33496. | Article | PubMed | ChemPort |
176. Vander Heiden M and Thompson C. (1999). Nat. Cell Biol., 1, E209–E216. | Article | PubMed | ISI | ChemPort |
177. Vasey PA, Jones NA, Jenkins S, Dive C and Brown R. (1996). Mol. Pharmacol., 50, 1536–1540. | PubMed | ChemPort |
178. Vilenchik M, Raffo AJ, Benimetskaya L, Shames D and Stein CA. (2002). Cancer Res., 62, 2175–2183. | PubMed |
179. Vivanco I and Sawyers CL. (2002). Nat. Rev. Cancer, 2, 489–501. | Article | PubMed | ISI | ChemPort |
180. Wahl AF, Donaldson KL, Fairchild C, Lee FY, Foster SA, Demers GW and Galloway DA. (1996). Nat. Med., 2, 72–79. | Article | PubMed | ISI | ChemPort |
181. Wall NR, O'Connor DS, Plescia J, Pommier Y and Altieri DC. (2003). Cancer Res., 63, 230–235. | PubMed | ISI | ChemPort |
182. Walter AO, Seghezzi W, Korver W, Sheung J and Lees E. (2000). Oncogene, 19, 4906–4916. | Article | PubMed | ISI | ChemPort |
183. Wang CY, Mayo MW, Korneluk RG, Goeddel DV and Baldwin Jr AS. (1998a). Science, 281, 1680–1683. | Article | PubMed | ISI | ChemPort |
184. Wang H-G and Bhalla K. (2003). Personal communication.
185. Wang J, Zhang ZJ, Choksi S, Shan S, Lu Z, Croce C, Alnemri E, Korngold R and Huang Z. (2000a). Cancer Res., 60, 1498–1502. | PubMed | ISI | ChemPort |
186. Wang JL, Liu D, Zhang ZJ, Shan S, Han X, Srinivasula S, Croce C, Alnemri E and Huang Z. (2000b). Proc. Natl. Acad. Sci. USA, 97, 7124–7129. | Article | PubMed | ChemPort |
187. Wang S, Wang Z, Boise L, Dent P and Grant S. (1999a). Biochem. Biophys. Res. Commun., 259, 67–72. | Article | PubMed | ISI | ChemPort |
188. Wang TH, Popp DM, Wang HS, Saitoh M, Mural JG, Henley DC, Ichijo H and Wimalasena J. (1999b). J. Biol. Chem., 274, 8208–8216. | Article | PubMed | ISI | ChemPort |
189. Wang TH, Wang HS, Ichijo H, Giannakakou P, Foster JS, Fojo T and Wimalasena J. (1998b). J. Biol. Chem., 273, 4928–4939. | Article | PubMed | ISI | ChemPort |
190. Wang TH, Wang HS and Soong YK. (2000c). Cancer, 88, 2619–2628. | Article | PubMed | ISI | ChemPort |
191. Wang X. (2001). Genes Dev., 15, 2922–2933. | PubMed | ISI | ChemPort |
192. Wei M, Lindsten T, Mootha VK, Weiler S, Gross A, Ashiya M, Thompson CB and Korsmeyer SJ. (2000). Genes Dev., 14, 2060–2071. | PubMed | ISI | ChemPort |
193. Wei MC, Zong WX, Cheng EH, Lindsten T, Panoutsakopoulou V, Ross AJ, Roth KA, MacGregor GR, Thompson CB and Korsmeyer SJ. (2001). Science, 292, 727–730. | Article | PubMed | ISI | ChemPort |
194. Widmann C, Gibson S, Jarpe MB and Johnson GL. (1999). Physiol. Rev., 79, 143–180. | PubMed | ISI | ChemPort |
195. Wittmann S, Bali P, Donapaty S, Nimmanapalli R, Guo F, Huang M, Jove R, Wang HG and Bhalla K. (2003). Cancer Res., 63, 93–99. | PubMed | ChemPort |
196. Wittmann S and Bhalla K. (2003). Personal conversation.
197. Woods CM, Zhu J, McQueney PA, Bollag D and Lazsarides E. (1995). Mol. Med., 1, 506–526. | PubMed | ISI | ChemPort |
198. Yamaguchi H, Paranawithana S, Lee M, Huang Z, Bhalla K and Wang HG. (2002). Cancer Res., 62, 466–471. | PubMed | ISI | ChemPort |
199. Yamaguchi H and Wang H-G. (2002). J. Biol. Chem., 277, 41604–41612. | Article | PubMed | ChemPort |
200. Yamamoto K, Ichijo H and Korsmeyer SJ. (1999). Mol. Cell. Biol., 19, 8469–8478. | PubMed | ISI | ChemPort |
201. Yang J, Liu X, Bhalla K, Kim CN, Ibrado AM, Cai J, Peng TI, Jones DP and Wang X. (1997). Science, 275, 1129–1132. | Article | PubMed | ISI | ChemPort |
202. Yang Q-H, Church-Hajduk R, Ren J, Newton ML and Du C. (2003). Genes Dev., 17, 1487–1496. | Article | PubMed | ISI | ChemPort |
203. Yang Y, Fang S, Jensen J, Weissman A and Ashwell J. (2000). Science, 288, 874–877. | Article | PubMed | ISI | ChemPort |
204. Yu C, Wang S, Dent P and Grant S. (2001). Mol. Pharmacol., 60, 143–154. | PubMed | ChemPort |
205. Yu D, Jing T, Liu B, Yao J, Tan M, McDonnell TJ and Hung MC. (1998). Mol. Cell, 2, 581–591. | Article | PubMed | ISI | ChemPort |
206. Yu D, Liu B, Tan M, Li J, Wang S-S and Hung M-C. (1996). Oncogene, 13, 1359–1365. | PubMed | ISI | ChemPort |
207. Zangemeister-Wittke U, Leech S, Olie R, Simoes-Wust AP, Gautschi O, Luedke G, Natt F, Haner R, Martin P, Hall J, Nalin C and Stahel R. (2000). Clin. Cancer Res., 6, 2547–2555. | PubMed | ISI | ChemPort |
208. Zha J, Harada H, Yang E, Jockel J and Korsmeyer SJ. (1996). Cell, 87, 619–628. | Article | PubMed | ISI | ChemPort |
209. Zhang CC, Yang JM, White E, Murphy M, Levine A and Hait WN. (1998). Oncogene, 16, 1617–1624. | Article | PubMed | ISI | ChemPort |
210. Zhou C, Smith JL and Liu J. (2003). Oncogene, 22, 2396–2404. | Article | PubMed |
211. Zhou H, Kuang J, Zhong L, Kuo WL, Gray J, Sahin A, Brinkley BR and Sen S. (1998). Nat. Genet., 20, 189–193. | Article | PubMed | ISI | ChemPort |
212. Zong WX, Lindsten T, Ross A, MacGregor G and Thompson C. (2001). Genes Dev., 15, 1481–1486. | Article | PubMed | ISI | ChemPort |
213. Zou H, Li Y, Liu X and Wang X. (1998). J. Biol. Chem., 274, 11549–11556.