| Co-Investigator(Kenkyū-buntansha) |
KONISHI Ikuo Shinshu University, Graduate School of Medicine, Professor, 医学部, 教授 (90192062)
FUJII Shingo Kyoto University, Graduates School of Medicine, Professor, 医学研究科, 教授 (30135579)
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| Research Abstract |
The objective of this study is to clarify the association between the intracellular apoptotic signaling and the cytotoxic/therapeutic effect of cisplatin in ovarian cancer. Then, according to the findings obtained, we tried to develop a new strategy to manage cisplatin-resistant ovarian cancer.
Firstly, the influence of apoptosis on the effect of cisplatin is examined. Treatment with cisplatin in cisplatin-sensitive ovarian cancer cell line A2780 markedly induced apoptosis, which was detected both by morphological examination as well as quantification of apoptosis using cell death ELISA method or measurement of caspase 3 activity. In contrast, cisplatin in the same dose did not induce significant apoptosis in cisplatin-resistant SK-OV-3 cell line. In addition, an inhibitor of caspase 3, Ac-DEVD-CHO, reduced the cytotoxity of cisplatin, suggesting that the effect of cisplatin is closely linked to the induction of apoptosis in ovarian cancer cells.
Secondly, the role of pro-apoptotic Bax p
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rotein in the development of cisplatin-resistance of ovarian cancer was investigated. Immunohistochemical analysis revealed that decreased expression of Bax protein correlated with poor prognosis of patient with ovarian cancer. In vitro, Bax expression was attenuated in cisplatin-resistant ovarian cancers, A2780/cDDP and SK-OV-3, compared with cisplatin sensitive A2780. These findings suggest that the disturbance in pro-apoptotic signaling through Bax play an inportant role in the development of cisplatin-resistance. Accordingly, we tried to induce Bax protein in ovarian cancer cells using recombinant adenovirus which highly express the Bax protein. The pro-apoptotic effect of Bax induction was similarly intensive either in A2780 or A2780/cDDP, while it was minimum in SK-OV-3. Preliminarily, adenovirus-mediated transfer of the Bax gene into human ovarian xenografts showed suppressive effect on tumor growth. Therefore, adenovirus-mediated introduction of Bax may be a useful tool to manage a part of cisplatin-resistant ovarian cancer.
Thirdly, the influence of gonadotropins, luteinizing hormone (LH) and human chorionic gonadotropin (hCG), on the apoptosis of ovarian cancer was examined. More than a half of ovarian cancer specimens expressed LH/hCG receptor. hCG treatment markedly reduced cisplatin-induced apoptosis in LH/hCG receptor-positive ovarian cancer cell line, OVCAR-3, and induced insulin-like growth factor 1 (IGF-1 ) expression. IGF-1 also inhibited cisplatin-induced apoptosis and a neutralizing antibody to IGF-1 receptor restored apoptosis in OVCAR-3, suggesting that IGF-1 mediates anti-apoptotic signaling from hCG.Wortmannin, an inhibitor of phosphatidyl inositol 3 kinase (PI3K), blocked the anti-apoptotic effect of IGF-1 to restore the cisplatin-induced apoptosis. This indicates that specific phosphorylation signal is related to cisplatin-sensitivity/resistance of ovarian cancer.
In conclusion, both the intrinsic disturbance of intracellular apoptosis signal including Bax and the presence of anti-apoptotic extrinsic factors such as IGF-1 may cause the resistance to chemotherapy in ovarian cancer. Consequently, to regulate apoptosis-related gene and to facilitate apoptosis by the methods including adenovirus-mediated gene therapy may be a hopeful strategy to overcome drug-resistance. Less
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