Abstract
BCR/ABL fusion tyrosine kinase is responsible for the initiation and maintenance of the Philadelphia chromosome (Ph1)-positive chronic myelogenous leukemia (CML) and a cohort of acute lymphocytic leukemias (ALL). STI571 (Gleevec), a novel anti-leukemia drug targeting BCR/ABL kinase can induce remissions of the Ph1-positive leukemias. STI571 was recently combined with the standard cytostatic drugs to achieve better therapeutic results and to overcome emerging drug resistance mechanisms. We decided to search for a more specific partner compound for STI571. Our previous studies showed that a signaling protein phosphatidylinositol-3 kinase (PI-3k) is essential for the growth of CML cells, but not of normal hematopoietic cells (Blood, 86:726,1995). Therefore the anti- Ph1-leukemia effect of the combination of BCR/ABL kinase inhibitor STI571 and PI-3k inhibitor wortmannin (WT) or LY294002 (LY) was tested. We showed that STI571+WT exerted a synergistic effect against the Ph1-positive cell lines, but did not affect the growth of Ph1-negative cell line. Moreover, the combinations of STI571+WT or STI571+LY were effective in the inhibition of clonogenic growth of CML-chronic phase and CML-blast crisis patient cells, while sparing normal bone marrow cells. Single colony RT–PCR assay showed that colonies arising from the mixture of CML cells and normal bone marrow cells after treatment with STI571+WT were selectively depleted of BCR/ABL-positive cells. Biochemical analysis of the CML cells after the treatment revealed that combination of STI571+WT caused a more pronounced activation of caspase-3 and induced massive apoptosis, in comparison to STI571 and WT alone. In conclusion, combination of STI571+WT or STI571+LY may represent a novel approach against the Ph1-positive leukemias.
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References
Arico M, Valsecchi MG, Camitta B, Schrappe M, Chessells J, Baruchel A, Gaynon P, Silverman L, Janka-Schaub G, Kamps W, Pui CH, Masera G . 2000 N. Engl. J. Med. 342: 998–1006
Canitrot Y, Lautier D, Laurent G, Frechet M, Ahmed A, Turhan AG, Salles B, Cazaux C, Hoffmann JS . 1999 Oncogene 18: 2676–2680
Carlesso N, Frank DA, Griffin JD . 1996 J. Exp. Med. 183: 811–820
Carpenter CL, Cantley LC . 1996 Curr. Opin. Cell. Biol. 8: 153–158
Chai SK, Nichols GL, Rothman P . 1997 J. Immunol. 159: 4720–4728
Clift RA, Storb R . 1996 Bone Marrow Transplant 17: Suppl S1–S3
Copelan EA, McGuire EA . 1995 Blood 85: 1151–1168
de Groot RP, Raaijmakers JA, Lammers JW, Jove R, Koenderman L . 1999 Blood 94: 1108–1112
Dhut S, Chaplin T, Young BD . 1990 Leukemia 4: 745–750
Donato NJ, Wu JY, Zhang L, Kantarjian H, Talpaz M . 2001 Blood 97: 2846–2853
Druker BJ, Lydon NB . 2000 J. Clin. Invest. 105: 3–7
Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM, Capdeville R, Talpaz M . 2001a N. Engl. J. Med. 344: 1038–1042
Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S, Sawyers CL . 2001b N. Engl. J. Med. 344: 1031–1037
Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S, Zimmermann J, Lydon NB . 1996 Nat. Med. 2: 561–566
Faderl S, Talpaz M, Estrov Z, O'Brien S, Kurzrock R, Kantarjian HM . 1999 N. Engl. J. Med. 341: 164–172
Fang G, Kim CN, Perkins CL, Ramadevi N, Winton E, Wittmann S, Bhalla KN . 2000 Blood 96: 2246–2253
Fry MJ, Waterfield MD . 1993 Philos. Trans. R. Soc. Lond. B. Biol. Sci. 340: 337–344
Gaiger A, Henn T, Horth E, Geissler K, Mitterbauer G, Maier-Dobersberger T, Greinix H, Mannhalter C, Haas OA, Lechner, Lioh T . 1995 Blood 86: 2371–2378
Gambacorti-Passerini C, Barni R, le Coutre P, Zucchetti M, Cabrita G, Cleris L, Rossi F, Gianazza E, Brueggen J, Cozens R, Pioltelli P, Pogliani E, Corneo G, Formelli F, D'Incalci M . 2000 J. Natl. Cancer. Inst. 92: 1641–1650
Gesbert F, Sellers WR, Signoretti S, Loda M, Griffin JD . 2000 J. Biol. Chem. 275: 39223–39230
Goga A, McLaughlin J, Afar DE, Saffran DC, Witte ON . 1995 Cell 82: 981–988
Gordon MY, Dazzi F, Marley SB, Lewis JL, Nguyen D, Grand FH, Davidson RJ, Goldman JM . 1999 Leukemia 13: Suppl S65–S71
Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN, Sawyers CL . 2001 Science 293: 876–880
Gratwohl A, Hermans J . 1996 Bone Marrow Transplant 17: Suppl S7–S9
Haseyama Y, Sawada K, Oda A, Koizumi K, Takano H, Tarumi T, Nishio M, Handa M, Ikeda Y, Koike T . 1999 Blood 94: 1568–1577
Hawkins PT, Welch H, McGregor A, Eguinoa A, Gobert S, Krugmann S, Anderson K, Stokoe D, Stephens L . 1997 Biochem. Soc. Trans. 25: 1147–1151
Hofmann WK, Jones LC, Lemp NA, de Vos S, Gschaidmeier H, Hoelzer D, Ottmann OG, Koeffler HP . 2002 Blood 99: 1860–1862
Horita M, Andreu EJ, Benito A, Arbona C, Sanz C, Benet I, Prosper F, Fernandez-Luna JL . 2000 J. Exp. Med. 191: 977–984
Ilaria Jr RL, Hawley RG, Van Etten RA . 1999 Blood 93: 4154–4166
Ilaria Jr RL, Van Etten RA . 1996 J. Biol. Chem. 271: 31704–31710
Kang CD, Do IR, Kim KW, Ahn BK, Kim SH, Chung BS, Jhun BH, Yoo MA . 1999 Exp. Mol. Med. 31: 76–82
Kang CD, Yoo SD, Hwang BW, Kim KW, Kim DW, Kim CM, Kim SH, Chung BS . 2000 Leuk. Res. 24: 527–534
Kano Y, Akutsu M, Tsunoda S, Mano H, Sato Y, Honma Y, Furukawa Y . 2001 Blood 97: 1999–2007
Kardinal C, Konkol B, Lin H, Eulitz M, Schmidt EK, Estrov Z, Talpaz M, Arlinghaus RB, Feller SM . 2001 Blood 98: 1773–1781
Katso R, Okkenhaug K, Ahmadi K, White S, Timms J, Waterfield MD . 2001 Annu. Rev. Cell. Dev. Biol. 17: 615–675
Klucher KM, Lopez DV, Daley GQ . 1998 Blood 91: 3927–3934
Kolonics A, Apati A, Janossy J, Brozik A, Gati R, Schaefer A, Magocsi M . 2001 Cell Signal 13: 743–754
Kulik G, Weber MJ . 1998 Mol. Cell. Biol. 18: 6711–6718
le Coutre P, Tassi E, Varella-Garcia M, Barni R, Mologni L, Cabrita G, Marchesi E, Supino R, Gambacorti-Passerini C . 2000 Blood 95: 1758–1766
Lugo TG, Pendergast AM, Muller AJ, Witte ON . 1990 Science 247: 1079–1082
Mahon FX, Deininger MW, Schultheis B, Chabrol J, Reiffers J, Goldman JM, Melo JV . 2000 Blood 96: 1070–1079
Marley SB, Deininger MW, Davidson RJ, Goldman JM, Gordon MY . 2000 Exp. Hematol. 28: 551–557
Neshat MS, Raitano AB, Wang HG, Reed JC, Sawyers CL . 2000 Mol. Cell. Biol. 20: 1179–1186
Nguyen MH, Ho JM, Beattie BK, Barber DL . 2001 J. Biol. Chem. 276: 32704–32713
Nieborowska-Skorska M, Wasik MA, Slupianek A, Salomoni P, Kitamura T, Calabretta B, Skorski T . 1999 J. Exp. Med. 189: 1229–1242
Nielsen M, Svejgaard A, Skov S, Dobson P, Bendtzen K, Geisler C, Odum N . 1996 J. Immunol. 157: 5350–5358
Pendergast AM, Quilliam LA, Cripe LD, Bassing CH, Dai Z, Li N, Batzer A, Rabun KM, Der CJ, Schlessinger J, Gishizky ML . 1993 Cell 75: 175–185
Peruzzi F, Prisco M, Dews M, Salomoni P, Grassilli E, Romano G, Calabretta B, Baserga R . 1999 Mol. Cell. Biol. 19: 7203–7215
Puil L, Liu J, Gish G, Mbamalu G, Bowtell D, Pelicci PG, Arlinghaus R, Pawson T . 1994 EMBO J. 13: 764–773
Raitano AB, Whang YE, Sawyers CL . 1997 Biochim. Biophys. Acta 1333: F201–F216
Sacchi S, Kantarjian HM, O'Brien S, Cortes J, Rios MB, Giles FJ, Beran M, Koller CA, Keating MJ, Talpaz M . 1999 Cancer 86: 2632–2641
Salloukh HF, Laneuville P . 2000 Leukemia 14: 1401–1404
Sattler M, Salgia R . 1997 Cytokine Growth Factor Rev. 8: 63–79
Sawyers CL . 1999 N. Engl. J. Med. 340: 1330–1340
Sawyers CL, McLaughlin J, Witte ON . 1995 J. Exp. Med. 181: 307–313
Schindler T, Bornmann W, Pellicena P, Miller WT, Clarkson B, Kuriyan J . 2000 Science 289: 1938–1942
Segouffin-Cariou C, Billaud M . 2000 J. Biol. Chem. 275: 3568–3576
Sillaber C, Gesbert F, Frank DA, Sattler M, Griffin JD . 2000 Blood 95: 2118–2125
Silver RT, Woolf SH, Hehlmann R, Appelbaum FR, Anderson J, Bennett C, Goldman JM, Guilhot F, Kantarjian HM, Lichtin AE, Talpaz M, Tura S . 1999 Blood 94: 1517–1536
Skorski T, Bellacosa A, Nieborowska-Skorska M, Majewski M, Martinez R, Choi JK, Trotta R, Wlodarski P, Perrotti D, Chan TO, Wasik MA, Tsichlis PN, Calabretta B . 1997a EMBO J. 16: 6151–6161
Skorski T, Kanakaraj P, Ku DH, Nieborowska-Skorska M, Canaani E, Zon G, Perussia B, Calabretta B . 1994 J. Exp. Med. 179: 1855–1865
Skorski T, Kanakaraj P, Nieborowska-Skorska M, Ratajczak MZ, Wen SC, Zon G, Gewirtz AM, Perussia B, Calabretta B . 1995a Blood 86: 726–736
Skorski T, Nieborowska-Skorska M, Barletta C, Malaguarnera L, Szcyzlik C, Chen ST, Lange B, Calabretta B . 1993 J. Clin. Invest. 92: 194–202
Skorski T, Nieborowska-Skorska M, Campbell K, Iozzo RV, Zon G, Darzynkiewicz Z, Calabretta B . 1995b J. Exp. Med. 182: 1645–1653
Skorski T, Nieborowska-Skorska M, Wlodarski P, Perrotti D, Hoser G, Kawiak J, Majewski M, Christensen L, Iozzo RV, Calabretta B . 1997b J. Natl. Cancer Inst. 89: 124–133
Skorski T, Nieborowska-Skorska M, Wlodarski P, Zon G, Iozzo RV, Calabretta B . 1996 Blood 88: 1005–1012
Skorski T, Szczylik C, Ratajczak MZ, Malaguarnera L, Gewirtz AM, Calabretta B . 1992 J. Exp. Med. 175: 743–750
Slupianek A, Nieborowska-Skorska M, Hoser G, Morrione A, Majewski M, Xue L, Morris SW, Wasik MA, Skorski T . 2001 Cancer Res. 61: 2194–2199
Somwar R, Niu W, Kim DY, Sweeney G, Randhawa VK, Huang C, Ramlal T, Klip A . 2001 J. Biol. Chem. 276: 46079–46087
Stephens LR, Jackson TR, Hawkins PT . 1993 Biochim. Biophys. Acta 1179: 27–75
Sun X, Layton JE, Elefanty A, Lieschke GJ . 2001 Blood 97: 2008–2015
Talpaz M, Kantarjian H, McCredie K, Trujillo J, Keating M, Gutterman JU . 1987 Cancer 59: 664–667
Teglund S, McKay C, Schuetz E, van Deursen JM, Stravopodis D, Wang D, Brown M, Bodner S, Grosveld G, Ihle JN . 1998 Cell 93: 841–850
Thiesing JT, Ohno-Jones S, Kolibaba KS, Druker BJ . 2000 Blood 96: 3195–3199
Timokhina I, Kissel H, Stella G, Besmer P . 1998 EMBO J. 17: 6250–6262
Toker A, Cantley LC . 1997 Nature 387: 673–676
Topaly J, Zeller WJ, Fruehauf S . 2001 Leukemia 15: 342–347
Van Etten RA . 2001 Blood Cells Mol. Dis. 27: 201–205
Varticovski L, Daley GQ, Jackson P, Baltimore D, Cantley LC . 1991 Mol. Cell. Biol. 11: 1107–1113
von Bubnoff N, Schneller F, Peschel C, Duyster J . 2002 Lancet 359: 487–491
Weisberg E, Griffin JD . 2000 Blood 95: 3498–3505
Welham MJ, Duronio V, Sanghera JS, Pelech SL, Schrader JW . 1992 J. Immunol. 149: 1683–1693
Wetzler M, Talpaz M, Van Etten RA, Hirsh-Ginsberg C, Beran M, Kurzrock R . 1993 J. Clin. Invest. 92: 1925–1939
Xie S, Wang Y, Liu J, Sun T, Wilson MB, Smithgall TE, Arlinghaus RB . 2001 Oncogene 20: 6188–6195
Yu C, Krystal G, Varticovski L, McKinstry R, Rahmani M, Dent P, Grant S . 2002 Cancer Res. 62: 188–199
Acknowledgements
This work was supported in part by NIH CA87300. T Skorski is a Scholar of the Leukemia and Lymphoma Society. A Slupianek is a recipient of the fellowship from Leukemia Research Foundation and was also supported by Elsa U Pardee grant. A Morrione was supported by the KO1 DK02896.
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Klejman, A., Rushen, L., Morrione, A. et al. Phosphatidylinositol-3 kinase inhibitors enhance the anti-leukemia effect of STI571. Oncogene 21, 5868–5876 (2002). https://doi.org/10.1038/sj.onc.1205724
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DOI: https://doi.org/10.1038/sj.onc.1205724
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