卵巣癌の進展と抗がん剤耐性化に関与する分子の同定 : その分子標的治療の可能性(<特集>第56回日本産科婦人科学会シンポジウム3 : 卵巣癌の進展とその制御)

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Although ovarian cancer patients show high response rates to initial chemotherapy after cytoreductive surgery, most patients also develop resistance to chemotherapy during treatment. Because of the serious problem of clinical resistance to chemotherapy, we examined the mechanism of the resistance to cisplatin and paclitaxel in human ovarian cancer cells. The sensitivity and resistance of cells to chemotherapeutic drugs appear to depend on the balance between apoptotic and antiapoptotic signals. The extracellular signal regulated protein kinase(ERK; a member of the mitogen-activated protein kinase family) cascade and the phosphatidylinositol 3-kinase (PI-3K)-Akt survival cascade are known to be antiapoptotic signals. BAD, a pro-apoptotic member of the Bcl-2 family, was found to be a downstream target of both the PI3K-Akt and ERK cascades, and thus an intersection point of pro- and anti- apoptotic regulatory cascades. Recently, transcription factor NFicB, which is one of the substrates of Akt, has been implicated in angiogenesis and metastasis in addition to cell survival. Therefore, we focused on ERK, Akt, BAD, and NFxfi as molecules for molecular targeting therapy. Cisplatin but not the transplatin isomer induced the ERK activity in both the cisplatin resistant Caov-3 and sensitive A2780 human ovarian cancer cell lines. Taxol also induced the ERK activity in the paclitaxel-resistant SW626 human ovarian cancer cell line. Interference with the ERK cascade by treatment with an MEK inhibitor, PD98059, in Caov-3 and A2780 cells caused decreased cell viability following treatment with cisplatin. Interference with the ERK cascade by treatment with an MEK inhibitor, PD98059, in SW626 and Caov-3 cells also caused decreased cell viability following treatment with paclitaxel. Cisplatin induced the Akt activity in both Caov-3 and A2780 cells. Taxol also induced the Akt activity in SW626 cells. Interference with the Akt cascade by exogenous expression of a kinase-deficient Akt (AktK179M)in Caov-3 and A2780 cells caused decreased cell viability following treatment with cisplatin. Interference with the Akt cascade by treatment with PI-3K inhibitor (wortmannin or LY294002) in SW626 and Caov-3 cells also caused decreased cell viability following treatment with paclitaxel. BAD Ser-136 and Ser-112 were phosphorylated by Akt and ERK, respectively. Exogenous expression of each of the singly mutated BADS112A or BADS136A in both Caov-3 and A2780 cells decreased the viability following treatment with cisplatin to a degree intermediate between that caused by exogenous expression of empty vector and doubly mutated BAD2SA. Exogenous expression of doubly substituted BAD2SA in SW626 cells also caused decreased viability following treatment with paclitaxel. Inhibition of NFKB activity by treatment with iKBa phosphorylation inhibitor (BAY 11-7085) increased the efficacy of the cisplatin-induced attenuation of both the cell viability and the cell invasion through Matrigel. Moreover, treatment with BAY 11-7085 increased the efficacy of both the cisplatin- and the paclitaxel-induced inhibition of the intraabdominal dissemination and production of ascites using athymic nude mice inoculated i.p. with Caov-3 cells. We also identified that topotecan, which is the key drug for the 2nd line chemotherapy of ovarian cancer, inhibited both the basal and the cisplatin-induced phosphorylation of Akt in Caov-3 cells, suggesting that topotecan also has a role in molecular targeting therapy of Akt in addition to the topoisomerase I inhibitor. Thus, inactivation of ERK, Akt, BAD and NFKB by a small molecular inhibitor or a genetic approach sensitizes ovarian cancer cells to both cisplatin and paclitaxel in in vitro. Therefore, ERK, Akt, BAD, and NFKB are promising new targets for the development of molecular targeting therapy and we now await the results of currently ongoing clinical trials with some small molecular inhibitors of the ERK, Akt, and NFKB, such as ZD1839 and proteasome inhibitor (PS-341).
2004-11-01

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