Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Prospects of RNA interference therapy for cancer

Gene Therapy volume 13, pages 464–477 (2006)Cite this article

Abstract

RNA interference (RNAi) is a powerful gene-silencing process that holds great promise in the field of cancer therapy. The discovery of RNAi has generated enthusiasm within the scientific community, not only because it has been used to rapidly identify key molecules involved in many disease processes including cancer, but also because RNAi has the potential to be translated into a technology with major therapeutic applications. Our evolving understanding of the molecular pathways important for carcinogenesis has created opportunities for cancer therapy employing RNAi technology to target the key molecules within these pathways. Many gene products involved in carcinogenesis have already been explored as targets for RNAi intervention, and RNAi targeting of molecules crucial for tumor–host interactions and tumor resistance to chemo- or radiotherapy has also been investigated. In most of these studies, the silencing of critical gene products by RNAi technology has generated significant antiproliferative and/or proapoptotic effects in cell-culture systems or in preclinical animal models. Nevertheless, significant obstacles, such as in vivo delivery, incomplete suppression of target genes, nonspecific immune responses and the so-called off-target effects, need to be overcome before this technology can be successfully translated into the clinical arena. Significant progress has already been made in addressing some of these issues, and it is foreseen that early phase clinical trials will be initiated in the very near future.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Caplen NJ . Gene therapy progress and prospects. Downregulating gene expression: the impact of RNA interference. Gene Therapy 2004; 11: 1241–1248.

    CAS  PubMed  Google Scholar 

  2. Dorsett Y, Tuschl T . siRNAs: applications in functional genomics and potential as therapeutics. Nat Rev Drug Discov 2004; 3: 318–329.

    CAS  PubMed  Google Scholar 

  3. Shankar P, Manjunath N, Lieberman J . The prospect of silencing disease using RNA interference. Jama 2005; 293: 1367–1373.

    CAS  PubMed  Google Scholar 

  4. Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC . Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 1998; 391: 806–811.

    Article  CAS  PubMed  Google Scholar 

  5. Tuschl T, Zamore PD, Lehmann R, Bartel DP, Sharp PA . Targeted mRNA degradation by double-stranded RNA in vitro. Genes Dev 1999; 13: 3191–3197.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Hamilton AJ, Baulcombe DC . A species of small antisense RNA in posttranscriptional gene silencing in plants. Science 1999; 286: 950–952.

    CAS  PubMed  Google Scholar 

  7. Jackson AL, Linsley PS . Noise amidst the silence: off-target effects of siRNAs? Trends Genet 2004; 20: 521–524.

    CAS  PubMed  Google Scholar 

  8. Ameyar-Zazoua M, Guasconi V, Ait-Si-Ali S . siRNA as a route to new cancer therapies. Expert Opin Biol Ther 2005; 5: 221–224.

    CAS  PubMed  Google Scholar 

  9. Leung RK, Whittaker PA . RNA interference: from gene silencing to gene-specific therapeutics. Pharmacol Ther 2005; 107: 222–239.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Vogelstein B, Kinzler KW . Cancer genes and the pathways they control. Nat Med 2004; 10: 789–799.

    CAS  PubMed  Google Scholar 

  11. Sordella R, Bell DW, Haber DA, Settleman J . Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science 2004; 305: 1163–1167.

    CAS  PubMed  Google Scholar 

  12. Yang G, Cai KQ, Thompson-Lanza JA, Bast Jr RC, Liu J . Inhibition of breast and ovarian tumor growth through multiple signaling pathways by using retrovirus-mediated small interfering RNA against Her-2/neu gene expression. J Biol Chem 2004; 279: 4339–4345.

    CAS  PubMed  Google Scholar 

  13. Sithanandam G, Fornwald LW, Fields J, Anderson LM . Inactivation of ErbB3 by siRNA promotes apoptosis and attenuates growth and invasiveness of human lung adenocarcinoma cell line A549. Oncogene 2005; 24: 1847–1859.

    CAS  PubMed  Google Scholar 

  14. Surmacz E . Growth factor receptors as therapeutic targets: strategies to inhibit the insulin-like growth factor I receptor. Oncogene 2003; 22: 6589–6597.

    CAS  PubMed  Google Scholar 

  15. Macaulay VM . The IGF receptor as anticancer treatment target. Novartis Found Symp 2004; 262: 235–243.

    CAS  PubMed  Google Scholar 

  16. Panta GR, Nwariaku F, Kim LT . RET signals through focal adhesion kinase in medullary thyroid cancer cells. Surgery 2004; 136: 1212–1217.

    PubMed  Google Scholar 

  17. Chen LM, Le HY, Qin RY, Kumar M, Du ZY, Xia RJ et al. Reversal of the phenotype by K-rasval12 silencing mediated by adenovirus-delivered siRNA in human pancreatic cancer cell line Panc-1. World J Gastroenterol 2005; 11: 831–838.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Brummelkamp TR, Bernards R, Agami R . Stable suppression of tumorigenicity by virus-mediated RNA interference. Cancer Cell 2002; 2: 243–247.

    Article  CAS  PubMed  Google Scholar 

  19. Aharinejad S, Paulus P, Sioud M, Hofmann M, Zins K, Schafer R et al. Colony-stimulating factor-1 blockade by antisense oligonucleotides and small interfering RNAs suppresses growth of human mammary tumor xenografts in mice. Cancer Res 2004; 64: 5378–5384.

    CAS  PubMed  Google Scholar 

  20. Chen J, Wall NR, Kocher K, Duclos N, Fabbro D, Neuberg D et al. Stable expression of small interfering RNA sensitizes TEL-PDGFbetaR to inhibition with imatinib or rapamycin. J Clin Invest 2004; 113: 1784–1791.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Walters DK, Stoffregen EP, Heinrich MC, Deininger MW, Druker BJ . RNAi-induced down-regulation of FLT3 expression in AML cell lines increases sensitivity to MLN518. Blood 2005; 105: 2952–2954.

    CAS  PubMed  Google Scholar 

  22. Ma PC, Jagadeeswaran R, Jagadeesh S, Tretiakova MS, Nallasura V, Fox EA et al. Functional expression and mutations of c-Met and its therapeutic inhibition with SU11274 and small interfering RNA in non-small cell lung cancer. Cancer Res 2005; 65: 1479–1488.

    CAS  PubMed  Google Scholar 

  23. Duxbury MS, Ito H, Zinner MJ, Ashley SW, Whang EE . EphA2: a determinant of malignant cellular behavior and a potential therapeutic target in pancreatic adenocarcinoma. Oncogene 2004; 23: 1448–1456.

    CAS  PubMed  Google Scholar 

  24. Sumimoto H, Miyagishi M, Miyoshi H, Yamagata S, Shimizu A, Taira K et al. Inhibition of growth and invasive ability of melanoma by inactivation of mutated BRAF with lentivirus-mediated RNA interference. Oncogene 2004; 23: 6031–6039.

    CAS  PubMed  Google Scholar 

  25. Karasarides M, Chiloeches A, Hayward R, Niculescu-Duvaz D, Scanlon I, Friedlos F et al. B-RAF is a therapeutic target in melanoma. Oncogene 2004; 23: 6292–6298.

    CAS  PubMed  Google Scholar 

  26. Pal A, Ahmad A, Khan S, Sakabe I, Zhang C, Kasid UN et al. Systemic delivery of RafsiRNA using cationic cardiolipin liposomes silences Raf-1 expression and inhibits tumor growth in xenograft model of human prostate cancer. Int J Oncol 2005; 26: 1087–1091.

    CAS  PubMed  Google Scholar 

  27. Zhang SQ, Du QY, Ying Y, Ji ZZ, Wang SQ . Polymerase synthesis and potential interference of a small-interfering RNA targeting hPim-2. World J Gastroenterol 2004; 10: 2657–2660.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Wohlbold L, van der Kuip H, Miething C, Vornlocher HP, Knabbe C, Duyster J et al. Inhibition of bcr-abl gene expression by small interfering RNA sensitizes for imatinib mesylate (STI571). Blood 2003; 102: 2236–2239.

    CAS  PubMed  Google Scholar 

  29. Lefevre G, Glotin AL, Calipel A, Mouriaux F, Tran T, Kherrouche Z et al. Roles of stem cell factor/c-Kit and effects of Glivec/STI571 in human uveal melanoma cell tumorigenesis. J Biol Chem 2004; 279: 31769–31779.

    CAS  PubMed  Google Scholar 

  30. Duxbury MS, Ito H, Zinner MJ, Ashley SW, Whang EE . siRNA directed against c-Src enhances pancreatic adenocarcinoma cell gemcitabine chemosensitivity. J Am Coll Surg 2004; 198: 953–959.

    PubMed  Google Scholar 

  31. Verma UN, Surabhi RM, Schmaltieg A, Becerra C, Gaynor RB . Small interfering RNAs directed against beta-catenin inhibit the in vitro and in vivo growth of colon cancer cells. Clin Cancer Res 2003; 9: 1291–1300.

    CAS  PubMed  Google Scholar 

  32. van de Wetering M, Oving I, Muncan V, Pon Fong MT, Brantjes H, van Leenen D et al. Specific inhibition of gene expression using a stably integrated, inducible small-interfering-RNA vector. EMBO Rep 2003; 4: 609–615.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Wang YH, Liu S, Zhang G, Zhou CQ, Zhu HX, Zhou XB et al. Knockdown of c-Myc expression by RNAi inhibits MCF-7 breast tumor cells growth in vitro and in vivo. Breast Cancer Res 2005; 7: R220–R228.

    CAS  PubMed  Google Scholar 

  34. Valsesia-Wittmann S, Magdeleine M, Dupasquier S, Garin E, Jallas AC, Combaret V et al. Oncogenic cooperation between H-Twist and N-Myc overrides failsafe programs in cancer cells. Cancer Cell 2004; 6: 625–630.

    CAS  PubMed  Google Scholar 

  35. Bienvenu F, Barre B, Giraud S, Avril S, Coqueret O . Transcriptional regulation by a DNA-associated form of cyclin D1. Mol Biol Cell 2005; 16: 1850–1858.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Zhang L, Yang N, Liang S, Barchetti A, Vezzani C, Huang J et al. RNA interference: a potential strategy for isoform-specific phosphatidylinositol 3-kinase targeted therapy in ovarian cancer. Cancer Biol Ther 2004; 3: 1283–1289.

    CAS  PubMed  Google Scholar 

  37. Gagnon V, Mathieu I, Sexton E, Leblanc K, Asselin E . AKT involvement in cisplatin chemoresistance of human uterine cancer cells. Gynecol Oncol 2004; 94: 785–795.

    CAS  PubMed  Google Scholar 

  38. Vandermoere F, El Yazidi-Belkoura I, Adriaenssens E, Lemoine J, Hondermarck H . The antiapoptotic effect of fibroblast growth factor-2 is mediated through nuclear factor-kappaB activation induced via interaction between Akt and IkappaB kinase-beta in breast cancer cells. Oncogene 2005; 24: 5482–5491.

    CAS  PubMed  Google Scholar 

  39. Guo J, Verma UN, Gaynor RB, Frenkel EP, Becerra CR . Enhanced chemosensitivity to irinotecan by RNA interference-mediated down-regulation of the nuclear factor-kappaB p65 subunit. Clin Cancer Res 2004; 10: 3333–3341.

    CAS  PubMed  Google Scholar 

  40. Zheng L, Liu J, Batalov S, Zhou D, Orth A, Ding S et al. An approach to genomewide screens of expressed small interfering RNAs in mammalian cells. Proc Natl Acad Sci USA 2004; 101: 135–140.

    CAS  PubMed  Google Scholar 

  41. Dohjima T, Lee NS, Li H, Ohno T, Rossi JJ . Small interfering RNAs expressed from a Pol III promoter suppress the EWS/Fli-1 transcript in an Ewing sarcoma cell line. Mol Ther 2003; 7: 811–816.

    CAS  PubMed  Google Scholar 

  42. Chansky HA, Barahmand-Pour F, Mei Q, Kahn-Farooqi W, Zielinska-Kwiatkowska A, Blackburn M et al. Targeting of EWS/FLI-1 by RNA interference attenuates the tumor phenotype of Ewing's sarcoma cells in vitro. J Orthop Res 2004; 22: 910–917.

    CAS  PubMed  Google Scholar 

  43. Sowter HM, Raval RR, Moore JW, Ratcliffe PJ, Harris AL . Predominant role of hypoxia-inducible transcription factor (Hif)-1alpha versus Hif-2alpha in regulation of the transcriptional response to hypoxia. Cancer Res 2003; 63: 6130–6134.

    CAS  PubMed  Google Scholar 

  44. Zhang X, Kon T, Wang H, Li F, Huang Q, Rabbani ZN et al. Enhancement of hypoxia-induced tumor cell death in vitro and radiation therapy in vivo by use of small interfering RNA targeted to hypoxia-inducible factor-1alpha. Cancer Res 2004; 64: 8139–8142.

    CAS  PubMed  Google Scholar 

  45. Romero-Ramirez L, Cao H, Nelson D, Hammond E, Lee AH, Yoshida H et al. XBP1 is essential for survival under hypoxic conditions and is required for tumor growth. Cancer Res 2004; 64: 5943–5947.

    CAS  PubMed  Google Scholar 

  46. Jiang M, Milner J . Selective silencing of viral gene expression in HPV-positive human cervical carcinoma cells treated with siRNA, a primer of RNA interference. Oncogene 2002; 21: 6041–6048.

    CAS  PubMed  Google Scholar 

  47. DuPree EL, Mazumder S, Almasan A . Genotoxic stress induces expression of E2F4, leading to its association with p130 in prostate carcinoma cells. Cancer Res 2004; 64: 4390–4393.

    CAS  PubMed  Google Scholar 

  48. Butz K, Ristriani T, Hengstermann A, Denk C, Scheffner M, Hoppe-Seyler F . siRNA targeting of the viral E6 oncogene efficiently kills human papillomavirus-positive cancer cells. Oncogene 2003; 22: 5938–5945.

    CAS  PubMed  Google Scholar 

  49. Yoshinouchi M, Yamada T, Kizaki M, Fen J, Koseki T, Ikeda Y et al. In vitro and in vivo growth suppression of human papillomavirus 16-positive cervical cancer cells by E6 siRNA. Mol Ther 2003; 8: 762–768.

    CAS  PubMed  Google Scholar 

  50. Danovi D, Meulmeester E, Pasini D, Migliorini D, Capra M, Frenk R et al. Amplification of Mdmx (or Mdm4) directly contributes to tumor formation by inhibiting p53 tumor suppressor activity. Mol Cell Biol 2004; 24: 5835–5843.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Purow BW, Haque RM, Noel MW, Su Q, Burdick MJ, Lee J et al. Expression of Notch-1 and its ligands, Delta-like-1 and Jagged-1, is critical for glioma cell survival and proliferation. Cancer Res 2005; 65: 2353–2363.

    CAS  PubMed  Google Scholar 

  52. Yuan J, Yan R, Kramer A, Eckerdt F, Roller M, Kaufmann M et al. Cyclin B1 depletion inhibits proliferation and induces apoptosis in human tumor cells. Oncogene 2004; 23: 5843–5852.

    CAS  PubMed  Google Scholar 

  53. Roberson RS, Kussick SJ, Vallieres E, Chen SY, Wu DY . Escape from therapy-induced accelerated cellular senescence in p53-null lung cancer cells and in human lung cancers. Cancer Res 2005; 65: 2795–2803.

    CAS  PubMed  Google Scholar 

  54. Zen Y, Harada K, Sasaki M, Chen TC, Chen MF, Yeh TS et al. Intrahepatic cholangiocarcinoma escapes from growth inhibitory effect of transforming growth factor-beta1 by overexpression of cyclin D1. Lab Invest 2005; 85: 572–581.

    CAS  PubMed  Google Scholar 

  55. Xiao Z, Xue J, Sowin TJ, Rosenberg SH, Zhang H . A novel mechanism of checkpoint abrogation conferred by Chk1 downregulation. Oncogene 2005; 24: 1403–1411.

    CAS  PubMed  Google Scholar 

  56. Abedini MR, Qiu Q, Yan X, Tsang BK . Possible role of FLICE-like inhibitory protein (FLIP) in chemoresistant ovarian cancer cells in vitro. Oncogene 2004; 23: 6997–7004.

    CAS  PubMed  Google Scholar 

  57. Zangemeister-Wittke U . Antisense to apoptosis inhibitors facilitates chemotherapy and TRAIL-induced death signaling. Ann NY Acad Sci 2003; 1002: 90–94.

    CAS  PubMed  Google Scholar 

  58. Yano J, Hirabayashi K, Nakagawa S, Yamaguchi T, Nogawa M, Kashimori I et al. Antitumor activity of small interfering RNA/cationic liposome complex in mouse models of cancer. Clin Cancer Res 2004; 10: 7721–7726.

    CAS  PubMed  Google Scholar 

  59. Holle L, Hicks L, Song W, Holle E, Wagner T, Yu X . Bcl-2 targeting siRNA expressed by a T7 vector system inhibits human tumor cell growth in vitro. Int J Oncol 2004; 24: 615–621.

    CAS  PubMed  Google Scholar 

  60. Lima RT, Martins LM, Guimaraes JE, Sambade C, Vasconcelos MH . Specific downregulation of bcl-2 and xIAP by RNAi enhances the effects of chemotherapeutic agents in MCF-7 human breast cancer cells. Cancer Gene Ther 2004; 11: 309–316.

    CAS  PubMed  Google Scholar 

  61. Tran NL, McDonough WS, Savitch BA, Sawyer TF, Winkles JA, Berens ME . The tumor necrosis factor-like weak inducer of apoptosis (TWEAK)-fibroblast growth factor-inducible 14 (Fn14) signaling system regulates glioma cell survival via NFkappaB pathway activation and BCL-XL/BCL-W expression. J Biol Chem 2005; 280: 3483–3492.

    CAS  PubMed  Google Scholar 

  62. Zhu H, Guo W, Zhang L, Davis JJ, Teraishi F, Wu S et al. Bcl-XL small interfering RNA suppresses the proliferation of 5-fluorouracil-resistant human colon cancer cells. Mol Cancer Ther 2005; 4: 451–456.

    CAS  PubMed  Google Scholar 

  63. Ning S, Fuessel S, Kotzsch M, Kraemer K, Kappler M, Schmidt U et al. siRNA-mediated down-regulation of survivin inhibits bladder cancer cell growth. Int J Oncol 2004; 25: 1065–1071.

    CAS  PubMed  Google Scholar 

  64. Kappler M, Bache M, Bartel F, Kotzsch M, Panian M, Wurl P et al. Knockdown of survivin expression by small interfering RNA reduces the clonogenic survival of human sarcoma cell lines independently of p53. Cancer Gene Ther 2004; 11: 186–193.

    CAS  PubMed  Google Scholar 

  65. Uchida H, Tanaka T, Sasaki K, Kato K, Dehari H, Ito Y et al. Adenovirus-mediated transfer of siRNA against survivin induced apoptosis and attenuated tumor cell growth in vitro and in vivo. Mol Ther 2004; 10: 162–171.

    CAS  PubMed  Google Scholar 

  66. Caldas H, Jiang Y, Holloway MP, Fangusaro J, Mahotka C, Conway EM et al. Survivin splice variants regulate the balance between proliferation and cell death. Oncogene 2005; 24: 1994–2007.

    CAS  PubMed  Google Scholar 

  67. Cheng SQ, Wang WL, Yan W, Li QL, Wang L, Wang WY . Knockdown of survivin gene expression by RNAi induces apoptosis in human hepatocellular carcinoma cell line SMMC-7721. World J Gastroenterol 2005; 11: 756–759.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Kappler M, Taubert H, Bartel F, Blumke K, Panian M, Schmidt H et al. Radiosensitization, after a combined treatment of survivin siRNA and irradiation, is correlated with the activation of caspases 3 and 7 in a wt-p53 sarcoma cell line, but not in a mt-p53 sarcoma cell line. Oncol Rep 2005; 13: 167–172.

    CAS  PubMed  Google Scholar 

  69. Hatano M, Mizuno M, Yoshida J . Enhancement of C2-ceramide antitumor activity by small interfering RNA on X chromosome-linked inhibitor of apoptosis protein in resistant human glioma cells. J Neurosurg 2004; 101: 119–127.

    CAS  PubMed  Google Scholar 

  70. Li S, Rosenberg JE, Donjacour AA, Botchkina IL, Hom YK, Cunha GR et al. Rapid inhibition of cancer cell growth induced by lentiviral delivery and expression of mutant-template telomerase RNA and anti-telomerase short-interfering RNA. Cancer Res 2004; 64: 4833–4840.

    CAS  PubMed  Google Scholar 

  71. Patry C, Bouchard L, Labrecque P, Gendron D, Lemieux B, Toutant J et al. Small interfering RNA-mediated reduction in heterogeneous nuclear ribonucleoparticule A1/A2 proteins induces apoptosis in human cancer cells but not in normal mortal cell lines. Cancer Res 2003; 63: 7679–7688.

    CAS  PubMed  Google Scholar 

  72. Zheng W, Wang H, Xue L, Zhang Z, Tong T . Regulation of cellular senescence and p16(INK4a) expression by Id1 and E47 proteins in human diploid fibroblast. J Biol Chem 2004; 279: 31524–31532.

    CAS  PubMed  Google Scholar 

  73. Kitajima S, Kudo Y, Ogawa I, Bashir T, Kitagawa M, Miyauchi M et al. Role of Cks1 overexpression in oral squamous cell carcinomas: cooperation with Skp2 in promoting p27 degradation. Am J Pathol 2004; 165: 2147–2155.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Sumimoto H, Yamagata S, Shimizu A, Miyoshi H, Mizuguchi H, Hayakawa T et al. Gene therapy for human small-cell lung carcinoma by inactivation of Skp-2 with virally mediated RNA interference. Gene Therapy 2005; 12: 95–100.

    CAS  PubMed  Google Scholar 

  75. Kudo Y, Kitajima S, Ogawa I, Kitagawa M, Miyauchi M, Takata T . Small interfering RNA targeting of S phase kinase-interacting protein 2 inhibits cell growth of oral cancer cells by inhibiting p27 degradation. Mol Cancer Ther 2005; 4: 471–476.

    CAS  PubMed  Google Scholar 

  76. Muerkoster S, Arlt A, Sipos B, Witt M, Grossmann M, Kloppel G et al. Increased expression of the E3-ubiquitin ligase receptor subunit betaTRCP1 relates to constitutive nuclear factor-kappaB activation and chemoresistance in pancreatic carcinoma cells. Cancer Res 2005; 65: 1316–1324.

    PubMed  Google Scholar 

  77. Zheng X, Chou PM, Mirkin BL, Rebbaa A . Senescence-initiated reversal of drug resistance: specific role of cathepsin L. Cancer Res 2004; 64: 1773–1780.

    CAS  PubMed  Google Scholar 

  78. Futreal PA, Coin L, Marshall M, Down T, Hubbard T, Wooster R et al. A census of human cancer genes. Nat Rev Cancer 2004; 4: 177–183.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Blume-Jensen P, Hunter T . Oncogenic kinase signalling. Nature 2001; 411: 355–365.

    CAS  PubMed  Google Scholar 

  80. Wilda M, Fuchs U, Wossmann W, Borkhardt A . Killing of leukemic cells with a BCR/ABL fusion gene by RNA interference (RNAi). Oncogene 2002; 21: 5716–5724.

    CAS  PubMed  Google Scholar 

  81. Zhang M, Zhang X, Bai CX, Chen J, Wei MQ . Inhibition of epidermal growth factor receptor expression by RNA interference in A549 cells. Acta Pharmacol Sin 2004; 25: 61–67.

    PubMed  Google Scholar 

  82. Choudhury A, Charo J, Parapuram SK, Hunt RC, Hunt DM, Seliger B et al. Small interfering RNA (siRNA) inhibits the expression of the Her2/neu gene, upregulates HLA class I and induces apoptosis of Her2/neu positive tumor cell lines. Int J Cancer 2004; 108: 71–77.

    CAS  PubMed  Google Scholar 

  83. Kaelin Jr WG . Functions of the retinoblastoma protein. Bioessays 1999; 21: 950–958.

    PubMed  Google Scholar 

  84. zur Hausen H . Papillomaviruses and cancer: from basic studies to clinical application. Nat Rev Cancer 2002; 2: 342–350.

    CAS  PubMed  Google Scholar 

  85. Harris SL, Levine AJ . The p53 pathway: positive and negative feedback loops. Oncogene 2005; 24: 2899–2908.

    CAS  PubMed  Google Scholar 

  86. Taniai M, Grambihler A, Higuchi H, Werneburg N, Bronk SF, Farrugia DJ et al. Mcl-1 mediates tumor necrosis factor-related apoptosis-inducing ligand resistance in human cholangiocarcinoma cells. Cancer Res 2004; 64: 3517–3524.

    CAS  PubMed  Google Scholar 

  87. July LV, Beraldi E, So A, Fazli L, Evans K, English JC et al. Nucleotide-based therapies targeting clusterin chemosensitize human lung adenocarcinoma cells both in vitro and in vivo. Mol Cancer Ther 2004; 3: 223–232.

    CAS  PubMed  Google Scholar 

  88. He J, Chang LJ . Functional characterization of hepatoma-specific stem cell antigen-2. Mol Carcinog 2004; 40: 90–103.

    CAS  PubMed  Google Scholar 

  89. Liao X, Zhang L, Thrasher JB, Du J, Li B . Glycogen synthase kinase-3beta suppression eliminates tumor necrosis factor-related apoptosis-inducing ligand resistance in prostate cancer. Mol Cancer Ther 2003; 2: 1215–1222.

    CAS  PubMed  Google Scholar 

  90. Izeradjene K, Douglas L, Delaney A, Houghton JA . Influence of casein kinase II in tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in human rhabdomyosarcoma cells. Clin Cancer Res 2004; 10: 6650–6660.

    CAS  PubMed  Google Scholar 

  91. Liekens S, De Clercq E, Neyts J . Angiogenesis: regulators and clinical applications. Biochem Pharmacol 2001; 61: 253–270.

    CAS  PubMed  Google Scholar 

  92. Takei Y, Kadomatsu K, Yuzawa Y, Matsuo S, Muramatsu T . A small interfering RNA targeting vascular endothelial growth factor as cancer therapeutics. Cancer Res 2004; 64: 3365–3370.

    CAS  PubMed  Google Scholar 

  93. Filleur S, Courtin A, Ait-Si-Ali S, Guglielmi J, Merle C, Harel-Bellan A et al. SiRNA-mediated inhibition of vascular endothelial growth factor severely limits tumor resistance to antiangiogenic thrombospondin-1 and slows tumor vascularization and growth. Cancer Res 2003; 63: 3919–3922.

    CAS  PubMed  Google Scholar 

  94. Schiffelers RM, Ansari A, Xu J, Zhou Q, Tang Q, Storm G et al. Cancer siRNA therapy by tumor selective delivery with ligand-targeted sterically stabilized nanoparticle. Nucleic Acids Res 2004; 32: e149.

    PubMed  PubMed Central  Google Scholar 

  95. Kilic N, Oliveira-Ferrer L, Wurmbach JH, Loges S, Chalajour F, Neshat-Vahid S et al. Pro-angiogenic signaling by the endothelial presence of CEACAM1. J Biol Chem 2005; 280: 2361–2369.

    CAS  PubMed  Google Scholar 

  96. Salvi A, Arici B, De Petro G, Barlati S . Small interfering RNA urokinase silencing inhibits invasion and migration of human hepatocellular carcinoma cells. Mol Cancer Ther 2004; 3: 671–678.

    CAS  PubMed  Google Scholar 

  97. Gondi CS, Lakka SS, Dinh DH, Olivero WC, Gujrati M, Rao JS . RNAi-mediated inhibition of cathepsin B and uPAR leads to decreased cell invasion, angiogenesis and tumor growth in gliomas. Oncogene 2004; 23: 8486–8496.

    CAS  PubMed  Google Scholar 

  98. Lakka SS, Gondi CS, Dinh DH, Olivero WC, Gujrati M, Rao VH et al. Specific interference of uPAR and MMP-9 gene expression induced by double-stranded RNA results in decreased invasion, tumor growth and angiogenesis in gliomas. J Biol Chem 2005; 280: 21882–21892.

    CAS  PubMed  Google Scholar 

  99. Edovitsky E, Elkin M, Zcharia E, Peretz T, Vlodavsky I . Heparanase gene silencing, tumor invasiveness, angiogenesis, and metastasis. J Natl Cancer Inst 2004; 96: 1219–1230.

    CAS  PubMed  Google Scholar 

  100. Liu N, Bi F, Pan Y, Sun L, Xue Y, Shi Y et al. Reversal of the malignant phenotype of gastric cancer cells by inhibition of RhoA expression and activity. Clin Cancer Res 2004; 10: 6239–6247.

    CAS  PubMed  Google Scholar 

  101. Lipscomb EA, Dugan AS, Rabinovitz I, Mercurio AM . Use of RNA interference to inhibit integrin (alpha6beta4)-mediated invasion and migration of breast carcinoma cells. Clin Exp Metastasis 2003; 20: 569–576.

    CAS  PubMed  Google Scholar 

  102. Chen Y, Stamatoyannopoulos G, Song CZ . Down-regulation of CXCR4 by inducible small interfering RNA inhibits breast cancer cell invasion in vitro. Cancer Res 2003; 63: 4801–4804.

    CAS  PubMed  Google Scholar 

  103. Liang Z, Yoon Y, Votaw J, Goodman MM, Williams L, Shim H . Silencing of CXCR4 blocks breast cancer metastasis. Cancer Res 2005; 65: 967–971.

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Lee EJ, Mircean C, Shmulevich I, Wang H, Liu J, Niemisto A et al. Insulin-like growth factor binding protein 2 promotes ovarian cancer cell invasion. Mol Cancer 2005; 4: 7.

    PubMed  PubMed Central  Google Scholar 

  105. Osta WA, Chen Y, Mikhitarian K, Mitas M, Salem M, Hannun YA et al. EpCAM is overexpressed in breast cancer and is a potential target for breast cancer gene therapy. Cancer Res 2004; 64: 5818–5824.

    CAS  PubMed  Google Scholar 

  106. Dunn GP, Old LJ, Schreiber RD . The three Es of cancer immunoediting. Annu Rev Immunol 2004; 22: 329–360.

    CAS  PubMed  Google Scholar 

  107. Khong HT, Restifo NP . Natural selection of tumor variants in the generation of ‘tumor escape’ phenotypes. Nat Immunol 2002; 3: 999–1005.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Gorelik L, Flavell RA . Immune-mediated eradication of tumors through the blockade of transforming growth factor-beta signaling in T cells. Nat Med 2001; 7: 1118–1122.

    CAS  PubMed  Google Scholar 

  109. Yin JQ, Gao J, Shao R, Tian WN, Wang J, Wan Y . siRNA agents inhibit oncogene expression and attenuate human tumor cell growth. J Exp Ther Oncol 2003; 3: 194–204.

    CAS  PubMed  Google Scholar 

  110. Yue FY, Dummer R, Geertsen R, Hofbauer G, Laine E, Manolio S et al. Interleukin-10 is a growth factor for human melanoma cells and down-regulates HLA class-I, HLA class-II and ICAM-1 molecules. Int J Cancer 1997; 71: 630–637.

    CAS  PubMed  Google Scholar 

  111. McCarthy BA, Mansour A, Lin YC, Kotenko S, Raveche E . RNA interference of IL-10 in leukemic B-1 cells. Cancer Immun 2004; 4: 6.

    PubMed  Google Scholar 

  112. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 2002; 8: 793–800.

    CAS  PubMed  Google Scholar 

  113. Munn DH, Mellor AL . IDO and tolerance to tumors. Trends Mol Med 2004; 10: 15–18.

    CAS  PubMed  Google Scholar 

  114. Rubinstein N, Alvarez M, Zwirner NW, Toscano MA, Ilarregui JM, Bravo A et al. Targeted inhibition of galectin-1 gene expression in tumor cells results in heightened T cell-mediated rejection: a potential mechanism of tumor-immune privilege. Cancer Cell 2004; 5: 241–251.

    CAS  PubMed  Google Scholar 

  115. Groh V, Wu J, Yee C, Spies T . Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation. Nature 2002; 419: 734–738.

    CAS  PubMed  Google Scholar 

  116. Wu H, Hait WN, Yang JM . Small interfering RNA-induced suppression of MDR1 (P-glycoprotein) restores sensitivity to multidrug-resistant cancer cells. Cancer Res 2003; 63: 1515–1519.

    CAS  PubMed  Google Scholar 

  117. Nieth C, Priebsch A, Stege A, Lage H . Modulation of the classical multidrug resistance (MDR) phenotype by RNA interference (RNAi). FEBS Lett 2003; 545: 144–150.

    CAS  PubMed  Google Scholar 

  118. Yague E, Higgins CF, Raguz S . Complete reversal of multidrug resistance by stable expression of small interfering RNAs targeting MDR1. Gene Therapy 2004; 11: 1170–1174.

    CAS  PubMed  Google Scholar 

  119. Duan Z, Brakora KA, Seiden MV . Inhibition of ABCB1 (MDR1) and ABCB4 (MDR3) expression by small interfering RNA and reversal of paclitaxel resistance in human ovarian cancer cells. Mol Cancer Ther 2004; 3: 833–838.

    CAS  PubMed  Google Scholar 

  120. Peng Z, Xiao Z, Wang Y, Liu P, Cai Y, Lu S et al. Reversal of P-glycoprotein-mediated multidrug resistance with small interference RNA (siRNA) in leukemia cells. Cancer Gene Ther 2004; 11: 707–712.

    CAS  PubMed  Google Scholar 

  121. Huang Y, Anderle P, Bussey KJ, Barbacioru C, Shankavaram U, Dai Z et al. Membrane transporters and channels: role of the transportome in cancer chemosensitivity and chemoresistance. Cancer Res 2004; 64: 4294–4301.

    CAS  PubMed  Google Scholar 

  122. Chang IY, Kim MH, Kim HB, Lee do Y, Kim SH, Kim HY et al. Small interfering RNA-induced suppression of ERCC1 enhances sensitivity of human cancer cells to cisplatin. Biochem Biophys Res Commun 2005; 327: 225–233.

    CAS  PubMed  Google Scholar 

  123. Youn CK, Kim MH, Cho HJ, Kim HB, Chang IY, Chung MH et al. Oncogenic H-Ras up-regulates expression of ERCC1 to protect cells from platinum-based anticancer agents. Cancer Res 2004; 64: 4849–4857.

    CAS  PubMed  Google Scholar 

  124. Chow TY, Alaoui-Jamali MA, Yeh C, Yuen L, Griller D . The DNA double-stranded break repair protein endo-exonuclease as a therapeutic target for cancer. Mol Cancer Ther 2004; 3: 911–919.

    CAS  PubMed  Google Scholar 

  125. Lin ZP, Belcourt MF, Cory JG, Sartorelli AC . Stable suppression of the R2 subunit of ribonucleotide reductase by R2-targeted short interference RNA sensitizes p53(−/−) HCT-116 colon cancer cells to DNA-damaging agents and ribonucleotide reductase inhibitors. J Biol Chem 2004; 279: 27030–27038.

    CAS  PubMed  Google Scholar 

  126. Collis SJ, Swartz MJ, Nelson WG, DeWeese TL . Enhanced radiation and chemotherapy-mediated cell killing of human cancer cells by small inhibitory RNA silencing of DNA repair factors. Cancer Res 2003; 63: 1550–1554.

    CAS  PubMed  Google Scholar 

  127. Ryther RC, Flynt AS, Phillips III JA, Patton JG . siRNA therapeutics: big potential from small RNAs. Gene Therapy 2005; 12: 5–11.

    CAS  PubMed  Google Scholar 

  128. Carette JE, Overmeer RM, Schagen FH, Alemany R, Barski OA, Gerritsen WR et al. Conditionally replicating adenoviruses expressing short hairpin RNAs silence the expression of a target gene in cancer cells. Cancer Res 2004; 64: 2663–2667.

    CAS  PubMed  Google Scholar 

  129. Song J, Pang S, Lu Y, Yokoyama KK, Zheng JY, Chiu R . Gene silencing in androgen-responsive prostate cancer cells from the tissue-specific prostate-specific antigen promoter. Cancer Res 2004; 64: 7661–7663.

    CAS  PubMed  Google Scholar 

  130. Duxbury MS, Ito H, Benoit E, Zinner MJ, Ashley SW, Whang EE . Retrovirally mediated RNA interference targeting the M2 subunit of ribonucleotide reductase: a novel therapeutic strategy in pancreatic cancer. Surgery 2004; 136: 261–269.

    PubMed  Google Scholar 

  131. Razorenova OV, Ivanov AV, Budanov AV, Chumakov PM . Virus-based reporter systems for monitoring transcriptional activity of hypoxia-inducible factor 1. Gene 2005; 350: 89–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Xu D, McCarty D, Fernandes A, Fisher M, Samulski RJ, Juliano RL . Delivery of MDR1 small interfering RNA by self-complementary recombinant adeno-associated virus vector. Mol Ther 2005; 11: 523–530.

    PubMed  Google Scholar 

  133. Ito M, Yamamoto S, Nimura K, Hiraoka K, Tamai K, Kaneda Y . Rad51 siRNA delivered by HVJ envelope vector enhances the anti-cancer effect of cisplatin. J Gene Med 2005; 7: 1044–1052.

    CAS  PubMed  Google Scholar 

  134. Sui G, Shi Y . Gene silencing by a DNA vector-based RNAi technology. Methods Mol Biol 2005; 309: 205–218.

    CAS  PubMed  Google Scholar 

  135. Brummelkamp TR, Bernards R, Agami R . A system for stable expression of short interfering RNAs in mammalian cells. Science 2002; 296: 550–553.

    CAS  PubMed  Google Scholar 

  136. Kawasaki H, Taira K . Short hairpin type of dsRNAs that are controlled by tRNA(Val) promoter significantly induce RNAi-mediated gene silencing in the cytoplasm of human cells. Nucl Acids Res 2003; 31: 700–707.

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Sledz CA, Holko M, de Veer MJ, Silverman RH, Williams BR . Activation of the interferon system by short-interfering RNAs. Nat Cell Biol 2003; 5: 834–839.

    CAS  PubMed  Google Scholar 

  138. Bridge AJ, Pebernard S, Ducraux A, Nicoulaz AL, Iggo R . Induction of an interferon response by RNAi vectors in mammalian cells. Nat Genet 2003; 34: 263–264.

    CAS  PubMed  Google Scholar 

  139. Stark GR, Kerr IM, Williams BR, Silverman RH, Schreiber RD . How cells respond to interferons. Annu Rev Biochem 1998; 67: 227–264.

    CAS  PubMed  Google Scholar 

  140. Kariko K, Bhuyan P, Capodici J, Weissman D . Small interfering RNAs mediate sequence-independent gene suppression and induce immune activation by signaling through toll-like receptor 3. J Immunol 2004; 172: 6545–6549.

    CAS  PubMed  Google Scholar 

  141. Scherr M, Eder M . RNAi in functional genomics. Curr Opin Mol Ther 2004; 6: 129–135.

    CAS  PubMed  Google Scholar 

  142. Saxena S, Jonsson ZO, Dutta A . Small RNAs with imperfect match to endogenous mRNA repress translation. Implications for off-target activity of small inhibitory RNA in mammalian cells. J Biol Chem 2003; 278: 44312–44319.

    CAS  PubMed  Google Scholar 

  143. Boese Q, Leake D, Reynolds A, Read S, Scaringe SA, Marshall WS et al. Mechanistic insights aid computational short interfering RNA design. Methods Enzymol 2005; 392: 73–96.

    CAS  PubMed  Google Scholar 

  144. Wu HL, Huang LR, Huang CC, Lai HL, Liu CJ, Huang YT et al. RNA interference-mediated control of hepatitis B virus and emergence of resistant mutant. Gastroenterology 2005; 128: 708–716.

    CAS  PubMed  Google Scholar 

  145. Westerhout EM, Ooms M, Vink M, Das AT, Berkhout B . HIV-1 can escape from RNA interference by evolving an alternative structure in its RNA genome. Nucl Acids Res 2005; 33: 796–804.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This review is not intended to be an encyclopedic one, and we apologize to any authors not cited. We thank Drs Richard Roden and Ralph Hruban for their critical review of the manuscript.

Author information

Authors and Affiliations

  1. Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Medical Institutions, Baltimore, MD, USA

    S I Pai

  2. Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA

    Y-Y Lin, B Macaes, C-F Hung & T-C Wu

  3. Department of Surgery, Johns Hopkins Medical Institutions, Baltimore, MD, USA

    A Meneshian

  4. Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD, USA

    C-F Hung & T-C Wu

  5. Department of Obstetrics and Gynecology, Johns Hopkins Medical Institutions, Baltimore, MD, USA

    T-C Wu

  6. Department of Molecular Microbiology and Immunology, Johns Hopkins Medical Institutions, Baltimore, MD, USA

    T-C Wu

Authors
  1. S I Pai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Y-Y Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. B Macaes
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Meneshian
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C-F Hung
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. T-C Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to T-C Wu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pai, S., Lin, YY., Macaes, B. et al. Prospects of RNA interference therapy for cancer. Gene Ther 13, 464–477 (2006). https://doi.org/10.1038/sj.gt.3302694

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3302694

Keywords

This article is cited by

Search

Advanced search

Quick links