Molecular mechanisms of apoptosis and chemosensitivity to platinum and paclitaxel in ovarian cancer: biological data and clinical implications

Apoptosis is a genetically regulated biological process that plays a major role in chemotherapy-induced tumor cell killing. It may be triggered by two major intracellular signaling cascades, the mitochondrial pathway and the death receptor pathway, both leading to caspase activation and cleavage of specific cellular substrates. The p53 gene is involved in the regulation of apoptosis. Caspase activation following wild-type p53 induction is associated with the release of the apoptogenic factors cytochrome c and Smac/DIABLO from the mitochondria, that is in turn controlled by the pro-apoptotic and anti-apoptotic Bcl-2 family proteins. In ovarian cancer p53 status is a strong predictor of response to platinum-based chemotherapy. Patients whose tumors have p53 mutations experience a lower chance of achieving a complete response following platinum-based regimens when compared to patients without p53 mutations. Conversely, experimental and clinical data seem to show that paclitaxel enhances apoptosis through a p53-independent pathway, that probably involves the Bax gene. Whereas patients with wild-type p53 tumors have a good chance to respond to platinum, patients with mutant p53 tumors may have a clinical benefit from the addition of paclitaxel to platinum-based chemotherapy. Therefore determining p53 status can be useful in predicting therapeutic response to specific drugs. Moreover the understanding of cellular mechanisms regulating apoptosis might offer a strong rationale for the combination of chemotherapy with other biological treatments.

Apoptosis; Ovarian Cancer; p53; bcl-2; Chemotherapy

[1] Hickman J. A.: "Apoptosis induced by anticancer drugs". Cancer Metastasis Rev., 1992, 11, 121.

[2] Inoue S., Salah-Eldin A. E., Omoteyama K.: "Apoptosis and anticancer drug resistance". Hum. Cell., 2001, 14, 211.

[3] Wyllie A.H.: "Apoptosis (the 1992 Frank Rose Memorial Lecture)". Br. J. Cancer, 1993, 67, 205.

[4] Zimmermann K. C., Bonzon C., Green D. R.: "The machinery of programmed cell death". Pharmacol. Ther., 2001, 92, 57.

[5] Lotan R.: "New strategies and agents for targeting apoptotic pathways for cancer prevention and therapy". In: " Twelfth International Congress on Anti-Cancer Treatment", Paris February 4th-7th, 2002, Proceeding Book, EL-32, 45.

[6] Antonsson B.: "Bax and other pro-apoptotic Bcl-2 family'killerproteins' and their victim in the mitochondrion". Cell Tissue Res. 2001, 306, 347.

[7] Bacso Z., Eliason J. F.: "Measurement of DNA damage associated with apoptosis by laser scanning cytometry". Cytometry 2001, 45, 180.

[8] Span L. F., Pennings A.H., Vierwinden G., Boezeman J. B., Raymakers R. A., de Witte T.: "The dynamic process of apoptosis analyzed by flow cytometry using Annexin-V /propidium iodide and a modified in situ end labeling technique". Cytometry, 2002, 47, 24.

[9] Lane D. P.. "p53, guardian of the genome". Nature, 1992, 538, 15.

[10] Kastan M. B., Onyekwere 0., Sidransky D., Vogelstein B., Craig R. W.: "Participation of p53 protein in the cellular response to DNA damage". Cancer Res., 1991, 5I, 6304.

[11] el-Deiry W. S., Tokino T., Velculescu V. E., Levy D. B., Parson R., Trent J. M. et al.: "WAFI, a potential mediator of p53 tumor suppression". Cell., 1993, 75, 817.

[12] Miyashita T.,K rajewski S.,K rajewska M.,W ang H. G.,L inH . K., Liebermann D. A. et al.: "Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo". Oncogene, 1994, 9, 1799.

[13] Mitsuuchi Y., Johnson S. W., Selvakumaran M., Williams S. J., Hamilton T. C., Testa J. R.: "The phosphatidylinositol 3-kinase/AKT signal transduction pathway plays a critical role in the expression of p21 WAFI/CIPI/SDII induced by cisplatin and paclitaxel". Cancer Res., 2000, 60, 5390.

[14] Schmitz I., Kirchhoff S., Krammer P. H.: "Regulation of death receptor-mediated apoptosis pathways". Int. J. Biochem. Cell. Biol., 2000, 32, 1123.

[15] Schuler M., Green D. R.: "Mechanisms of p53-dependent apoptosis". Biochem. Soc. Trans., 2001, 29, 684.

[16] Reed J. C.: "Bcl-2 family proteins". Oncogene, 1998, 17, 3225.

[17] Gao C. F., Ren S., Zhang L., Nakajima T., Ichinose S., Hara T. et al.: "Caspase-dependent cytosolic release of cytochrome c and membrane translocation of Bax in p53-induced apoptosis". Exp. Cell Res., 2001, 265, 145.

[18] Lacasse E. C., Baird S., Korneluk R. G., MacKenzie A. E.: "The inhibitors of apoptosis (IAPs) and their emerging role in cancer". Oncogene, 1998, 17, 3247.

[19] Adrain C., Creagh E. M., Martin S. J.: "Apoptosis-associated release of Smac/DIABLO from mitochondria require active caspases and is blocked by Bcl-2". EMBO J., 2001, 20, 6627.

[20] Verhagen A. M., Coulson E. J., Vaux D. L.: "Inhibitor of apoptosis proteins and their relatives: TAPs and other BIRPs". Genome Biol., 2001, 2, Reviews 3009.

[21] Riedl S. J., Renatus M., Schwarzenbacher R., Zhou Q., Sun C., Fesik S. W. et al.: Structural basis for the inhibition of caspase-3 by XIAP. Cell 2001; 104: 791-800.

[22] Suzuki Y., Nakabayashi Y., Nakata K., Reed J. C., Takahashi R.: "X-linked inhibitor of apoptosis protein (XIAP) inhibits caspase- 3 and -7 in distinct modes". J. Biol. Chem., 2001, 276, 27058.

[23] Boldin M. P., Goncharov T. M., Goltsev Y. V., Wallach D.: "Involvement of MACH, a novel MRTI/FJ\DD-interacting protease, in Fas/AP0-1-and TNF receptor-induced cell death". Cell., 1996, 85, 803.

[24] Ashkenazi A., Dixit V. M.: "Death receptors: signaling and modulation". Science, 1998, 281, 1305.

[25] Seo! D. W., Li J., Seo! M. H., Park S. Y., Talanian R. V., Billiar T. R.: "Signaling events triggered by tumor necrosis factor- related apoptosis-inducing ligand (TRAIL): caspase-8 is required for TRAIL-induced apoptosis". Cancer Res., 2001, 61, 1138.

[26] Sun X. M., Bratton S. B., Butterworth M., Macfarlane M., Cohen G. M.: "Bcl-2 and Bcl-xL inhibit CD95-mediated apoptosis by preventing mithocondrial release of Smac/DTABLO and subsequent inactivation of XIAP". J. Biol. Chem. (in press).

[27] Sun S. Y., Yue P., Zhou J. Y., Wang Y., Choi Kim H. R., Lotan R., Wu G. S.: "Overexpression of BCL2 blocks TNF-related apoptosis- inducing ligand (TRAIL)-induced apoptosis in human lung cancer cells". Biochem. Biophys. Res. Commun., 2001, 280, 788.

[28] Deng Y., Lin Y., Wu X.: "TRAIL-induced apoptosis requires Baxdependent mitochondrial release of Smac/DIABLO". Genes Dev., 2002, 16, 33.

[29] Zhang X. D., Zhang X. Y., Gray C. P., Nguyen T., Hersey P.: "Tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis of human melanoma is regulated by smac/DIABLO release from mitochondria". Cancer Res., 2001, 61, 7339.

[30] Suda T.,T akahashi T.,G oldstein P.,N egata S.: "Molecular clomng and expression of the fas ligand, a novel member of the tumor necrosis factor family". Cell., 1993, 75, 1169.

[31] Itoh N, Yonehara S, Ishii A, Yonehara M, Mizushima S, Samesin M. et al.: "The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis". Cell., 1991, 66, 233.

[32] Boldrini L., Faviana P., Gisfredi S., Di Quirico D., Lucchi M., Mussi A. et al.: "Identification of Fas (AP0-1/CD95) and p53 gene mutations in non-small cell lung cancer". Int. J. Oncol., 2002, 20, 155.

[33] Mitsiades N., Poulaki V., Kotoula V., Leone A., Tsokos M.: "Fas ligand is present in tumors of the Ewing's sarcoma family and is cleaved into a soluble form by a metalloproteinase". Am. J. Pathol., 1998, 153, 1947.

[34] Mitsiades N., Poulaki V., Leone A., Tsokos M.: "Fas-mediated apoptosis in Ewing's sarcoma cell lines by metalloproteinase inhibitors". J. Natl. Cancer Inst.: 1999, 91, 1678.

[35] Mitsiades N., Yu W. H., Poulaki V., Tsokos M., Stamenkovic I.: "Matrix metalloproteinase-7-mediated cleavage of Fas ligand protects tumor cells from chemotherapeutic drug cytotoxicity". Cancer Res., 2001, 61,577.

[36] Anderson K. C., Poulaki V., Mitsiades C. S., Mitsiades N.: "Induction of tumour cell apoptosis by matrix metalloproteinase inhibitors: new tricks from a (not so) old drug". Expert. Opin. Investig. Drugs, 2001, 10, 1075.

[37] Cheng J., Zhou T., Liu C., Shapiro J. P., Brauer M. J., Kiefer M. C., et al.: "Protection from Fas-mediated apoptosis by a soluble form of the Fas molecule". Science, 1994, 263, 1759.

[38] Pervan M., Panjonk F., Sun J. R., Withers H. R., McBride W. H.: "Molecular pathways that modify tumor radiation response". Am J. Clin. Oncol., 2001, 24, 481.

[39] Murray R. Z., Norbury C.: "Proteasome inhibitors as anti-cancer agents". Anticancer Drugs, 2000, 11, 407.

[40] Cusack J. C. Jr., Liu R., Houston M., Abendroth K., Elliott P. J., Adams J., Baldwin A. S. Jr.: "Enhanced chemosensitivity to CPTI I with proteasome inhibitors PS-341: implications for systemic nuclear factor-kappaB inhibition". Cancer Res., 2001, 61, 3535.

[41] Rivett A. J.,G ardner R. C.: "Proteasome inhibitors: from in vitro uses to clinical trials". J. Pept. Sci., 2000, 6, 478.

[42] Wolf J. S., Chen Z., Dong G., Sunwoo J.B., Bancroft C. C., Capo D. E. et al.: "IL (interleukin)-! alpha promotes nuclear factorkappaB and AP-I-induced IL-8 expression, cell survival, and proliferation in head and neck squamous cell carcinoma". Clin. Cancer Res., 2001, 7, 1812.

[43] Shah S. A., Potter M. W., Callery M. P.: "Ubiquitin proteasome pathway: implications and advances in cancer therapy". Surg. Oncol., 2001, 10, 43.

[44] Elliot P. J., Ross J. S.: "The proteasome: a new target for novel drug therapies". Am. J. Clin. Pathol., 2001, 116, 637.

[45] Adams J.: "Proteasome inhibition in cancer: development of PS- 341". Semin. Oncol., 2001, 28, 613.

[46] Russo S. M., Tepper J. E., Baldwin A. S. Jr., Liu R., Adams J., Elliott P., Cusack J. C. Jr.: "Enhancement of radiosensitivity by proteasome inhibition: implications for a role of NF-kappaB". Int. J. Radiat. Oncol. Biol. Phys., 2001, 50, 183.

[47] Havrilevsky L. J., Elbendary A, Hurteau JA, Whitaker RS, Rodriguez GC, Berchuck A. Chemotherapy-induced apoptosis in epithelial ovarian cancers. Obstet. Gynecol., 1995, 85: 1007.

[48] Marks J. R., Davidoff A. M., Kerns B. J., Humphrey P. A., Pence J. C., Doge R. K. et al.: "Overexpression and mutation of p53 in epithelial ovarian cancer". Cancer Res., 1991, 51, 2979.

[49] Kupryjanczyk J., Thor A. D., Beauchamp R., Merritt V., Edgerton S. M., Bell D. A., Yandell D. W.: "p53 gene mutations and protein accumulation in human ovarian cancer". Proc. Natl. Acad. Sci. USA, 1993, 90, 4961.

[50] Kohler M. F., Kerns B. J.,H umphrey P. A., Marks J. R.,B ast R. C. Jr, Berchuck A.: "Mutation and overexpression of p53 in early stage epithelial ovarian cancer". Obstet. Gynecol., 1993, 81, 643.

[51] Herod J. J. 0., Eliopoulos A.G., WarwickJ., Niedobitek G., Young L. S., Kerr D. J.: "The prognostic significance of Bcl-2 and p53 expression in ovarian carcinoma". Cancer Res., 1996, 56, 2178.

[52] Casey G., Lopez M. E., Ramos J. C., Plummer S. J., Arboleda M. J., Shaughnessy M. et al.: "DNA sequence analysis of exons 2 through 11 and immunohistochemical staining are required to detect all known p53 alterations in human malignancies". Oncogene, 1996, 13, 1971.

[53] Sakamoto T., Nomura N., Mori H., Wake N.: "Poor correlation with loss of heterozygosity on chromosome I 7p and p53 mutations in ovarian cancers". Gynecol. Oneal., 1996, 63, 173.

[54] Righetti S. C.,D ella TorreG .,P ilotti S.,M enard S.,O ttone F.,C olnaghi M. I. et al.: "A comparative study of p53 gene mutations, protein accumulation, and response to cisplatin-based chemotherapy in advanced ovarian carcinoma". Cancer Res., 1996, 56, 689.

[55] Buttitta F.,M archetti A.,G adducci A.,P ellegrini S.,M organti M., Carnicelli V. et al.: "p53 alterations are predictive of chemoresis stance and aggressiveness in ovarian carcinomas: a molecular and immunohistochemical study". Br. J. Cancer, 1997, 75, 230.

[56] Smith-Sorensen B., Kaern J., Holm R., Dorum A., Trope C., Borresen-Dale A. L.: "T herapy effect of either paclitaxel or cyclophosphamide combination treatment in patients with epithelial ovarian cancer and relation to T P53 gene status". Br. J. Cancer, 1998, 78, 375.

[57] Mano Y., Kikuchi Y., Yamamoto K., Kita T., Hirata J., Tode T. et al.: "Bcl-2 as a predictor of chemosensitivity and prognosis in primary epithelial ovarian cancer". Eur. J. Cancer, 1999, 35, 1214.

[58] Gadducci A., Cianci C., Cosio S., Camino F., Fanucchi A., Buttitta F. et al.: "p53 status is neither a predictive nor a prognostic variable in patients with advanced ovarian cancer treated with a paclitaxel-based regimen". Anticancer Res., 2000, 20, 4793.

[59] Laframboise S.,C hapmam W.,M cLaughlinJ .,A ndrulis I. L.: "p53 mutations in epithelial ovarian cancers: possible role in predicting chemoresistance". Cancer J., 2000, 6, 302.

[60] Lavarino C.,P ilotti S.,O ggionni M.,G atti L.,P erego P., Bresciani G. et al.: "p53 gene status and response to platinum/paclitaxelbased chemotherapy in advanced ovarian carcinoma". J. Clin. Oneal., 2000, 18, 3936.

[61] Reles A., Wen W. H., Schmider A.,G ee C., Runnebaum I. B., Kilian U. et al.: "Correlation of p53 mutations with resistance to platinum-based chemotherapy and shortened survival in ovarian cancer". Clin. Cancer Res., 2001, 7, 2984.

[62] Perego P.,G iarola M.,R ighetti S. C.,S upino R.,C aserini C., Delia D. et al.: "Association between cisplatin resistance and mutation of p53 gene and reduced bax expression in ovarian carcinoma cell systems". Cancer Res., 1996, 56, 556.

[63] Fajac A., Da Silva J., Ahomadegbe J. C., Rateau J. G., Bernaudin JF, Riou G,B enard J.: "Cisplatin-induced apoptosis and p53 gene status in a cisplatin-resistant human ovarian carcinoma cell line". Int. J. Cancer, 1996, 68, 67.

[64] Vaisman A., Varchenko M., Said I., Chaney S. G.: "Cell cycle changes associated with formation of Pt-DNA adducts in human ovarian carcinoma cells with different cisplatin sensitivity". Cytometry, 1997, 27, 54.

[65] Song K., Li Z., Seth P., Cowan K. H., Sinha B. K.: "Sensitization of cis-platinum by a recombinant adenovirus vector expressing wild-type p53 gene in human ovarian carcinomas". Oneal. Res., 1997, 9,603.

[66] Kigawa J., Sato S., Shimada M., Takahashi M., Itamochi H., Kanamori Y.,T erakawa N.: "p53 gene status and chemosensitivity in ovarian cancer". Hum. Cell., 2001, 14, 165.

[67] Calvert A. H.,G hokul S.,A l-Azraqi A.,W rightJ .,L ind M., Bailey N. et al.: "Carboplatin and paclitaxel, alone and in combination : dose escalation,m easurement of renal function,a nd role of the p53 tumor suppressor gene". Semin. Oneal., 1999, 26 (Suppl. 2), 90.

[68] Asselin E.,M illsG . B.,T sang B. K.: "XIAP regulates Akt activity and caspase-3-dependent cleavage during cisplatin-induced apoptosis in human ovarian epithelial cancer cells". Cancer Res., 2001, 61, 1862.

[69] Li J., Feng Q., Kim J. M., Schneiderman D., Liston P., Li M. et al.: "Human ovarian cancer and cisplatin resistance: possible role of inhibitor of apoptosis proteins". Endocrinol., 2001, 142, 370.

[70] Li J., Sasaki H., Sheng Y. L., Schneiderman D., Xiao C. W., Kotsuji F.,T sang B. K.: "Apoptosis and chemoresistance in human ovarian cancer: is Xiap a determinant?". Biol. Signals Recept., 2000, 9, 122.

[71] Munakata S., Enomoto T., Tsujimoto M., Otsuki Y., Miwa H., Kanno H.,A ozasa K.: "Expressions of F as ligand and other apoptosis-related genes and their prognostic significance in epithelial ovarian neoplasms". Br. J. Cancer, 2000, 82, 1446.

[72] Baekelandt M., Holm R., Nesland J. M., Trope C. G., Kristensen G. B.: "Expression of apoptosis-related proteins is an independent determinant of patient prognosis in advanced ovarian cancer". J. Clin. Oneal., 2000, 18, 3775.

[73] Tai Y T, Lee S, Niloff E, Weisman C, Strobel T, Cannistra SA. Bax protein expression and clinical outcome in epithelial ovarian cancer. J. Clin. Oncol. 1998; 16: 2583-2590.

[74] Weherli B. M., Krajewski S.,G ascoyne R. D., Reed J. C., Gilks C. B.: "Immunostochemical analysis of bcl-2, bax, mcl-1, and bclx expression in ovarian surface epithelial tumors". Int. J. Gynecol. Pathol., 1998, 17, 255.

[75] Henriksen R.. Wilander E., Oberg K.: "Expression and prognostic significance of BCL-2 in ovarian tumours". Br. J. Cancer, 1995, 72, 1324.

[76] Schuyer M., van der Burg M. E., Henzen-Logmans S. C., Fieret J. H., Klijn J. G., Look M. P. et al.: "Reduced expression of BAX is associated with poor prognosis in patients with epithelial ovarian cancer: a multifactorial analysis of TP53,p 21,B AX and BCL-2". Br. J. Cancer, 2001, 85, 1359.

[77] Liu J. R., Fletcher B., Page C., Hu C., Nunez G., Baker V.: "BelxL is expressed in ovarian carcinoma and modulates chemotherapy-induced apoptosis". Gyneco/. Oneal., 1998, 70, 398.

[78] Xiang J.,G omez-Navarro J., Arafat W., Liu B., Barker S. D., Alvarez R. D. et al.: "Pro-apoptotic treatment with an adenovirus encoding BAX enhances the effect of chemotherapy in ovarian cancer". J. Gene Med., 2000, 2, 97.

[79] Strobel T., Swanson L., Korsmeyer S., Cannistra S. A.: "BAX enhances paclitaxel-induced apoptosis through a p53-independent pathway". Proc. Natl. Acad. Sci., 1996, 93, 14094.

[80] Vasey P. A., Jones N. A., Jenkins S., Dive C., Brown R.: "Cisplatin, camptothecin and taxol sensitivities of cells with p53 associated multiagent resistance". Mo/. Pharmacol., 1996, 50, 1536.

[81] Debernardis D., Sire E.G., De Feudis P., Vikhanskaya F., Valenti M., Russo P. et al.: "p53 status does not affect sensitivity of human ovarian cancer cell lines to paclitaxel''. Cancer Res., 1997, 57, 870.

[82] Takahashi M., Kigawa J., Minagawa Y., ltamochi H., Shimada M., Kamazawa S. et al.: "Sato S, Akeshima R, Terakawa N. Sensitivity to paclitaxel is not related to p53-dependent apoptosis in ovarian cancer cells". Eur. J. Cancer, 2000, 36, 1863.

[83] McDonald A. C., Brown R.: "Induction of p53-dependent and p53-independent cellular responses by topoisomerase I inhibitors". Br. J. Cancer, 1998, 78, 745.

[84] Chadebech P., Truchet I., Brichese L., Valette A.: "Up-regulation of cdc2 protein during paclitaxel-induced apoptosis". Int. J. Cancer, 2000, 87, 779.

[85] Yu D.: "Mechanisms of the ErbB2-mediated paclitaxel resistance and trastuzumab-mediated paclitaxel sensitization in ErbB2-overexpressing breast cancers". Semin. Oncol., 2001, 28 (Suppl 5), 12.

[86] Cassinelli G., Supino R., Perego P., Polizzi D., Lanzi C., Pratesi G., Zunino F.: "A role for loss of p53 function in sensitivity of ovarian carcinoma cells to taxanes". Int. J. Cancer, 2001, 92, 738.

[87] Lavarino C., Delia D., Di Palma S., Zunino F., Pilotti S.: "p53 in drug resistance in ovarian cancer". Lancet, 1997, 349, 1556.

[88] Page C., Lin H. J., Jin Y., Castle V. P., Nunez G., Huang M., Lin J.: "Overexpression of Akt/AKT can modulate chemotherapyinduced apoptosis". Anticancer Res., 2000, 20, 407.

[89] Blajeski A. L., Kottke T. J., Kaufmann S. H.: "A multistep model for paclitaxel-induced apoptosis in human breast cancer cell lines". Exp. Cell Res., 2001, 270, 277.

[90] Motwani M., Delohery T. M., Schwartz G. K.: "Sequential dependent enhancement of caspase activation and apoptosis by flavopiridolon paclitaxel-treated human gastric and breast cancer cells. Clin". Cancer Res., 1999, 5, 1876.

[91] Cuello M., Ettenberg S. A., Nau M. M., Lipkowitz S.: "Synergistic induction of apoptosis by the combination of trail and chemotherapy in resistant ovarian cancer cells". Gynecol. Oncol., 2001, 81, 380.

[92] Vignati S., Codegoni A., Polato F., Broggini M.: "Trail activity in human ovarian cancer cells. Potentiation of the action of cytotoxic drugs". Eur. J. Cancer, 2002, 38, 177.

[93] Ghahremani M., Foghi A., Dorrington J. H.: "Activation of Fas ligand/receptor system kills ovarian cancer cell lines by an apoptotic mechanism". Gynecol. Oneal., 1998, 70, 275.

[94] Das H., Koizumi T., Sugimoto T., Chakraborty S., Ichimura T, Hasegawa K., Nishimura R.: "Quantitation of Fas and Fas ligand gene expression in human ovarian, cervical and endometrial carcinomas using real-time quantitative RT-PCR". Br. J. Cancer, 2000, 82, 1682.

[95] Konno R., Takano T., Sato S., Yajima A.: "Serum soluble fas level as a prognostic factor in patients with gynecologic malignancies". Clin. Cancer Res., 2000, 6, 3576.

[96] Hefler L., Mayerhofer K., Nardi A., Reinthaller A., Kainz C., Tempfer C.: "Serum soluble Fas levels in ovarian cancer". Obstet. Gynecol., 2000, 96, 65.

[97] Meinhold-Heerlein I., Stenner-Liewen F., Liewen H., Kitada S., Krajewska M., Krajewski S. et al.: "Expression and potential role of Fas-associated phosphatase- I in ovarian cancer". Am. J. Pathol., 2001, 158, 1335