Defective Apoptosis Underlies Chemoresistance in Ovarian Cancer

Ovarian cancer is the second most common and the most lethal of malignancies arising in the female reproductive system. In 2006, over 20,000 new cases of ovarian cancer will be diagnosed, with the majority of these being advanced disease (stage III or stage IV). Survival varies by age, with overall 1-year and 5-year survival rates for new ovarian cancer patients of 76% and 45%, respectively (1). Survival rates drop dramatically with increasing stage at the time of diagnosis. The overall poor prognosis of ovarian cancer is largely attributable to both the late stage of diagnosis and the development of chemoresistance that limits treatment for recurrent disease. Although initial responses to chemotherapy are quite good, the majority of patients develop recurrent disease, and over time their tumors become resistant to current treatment modalities (23). Thus, identification and modulation of the mechanisms that underlie chemoresistance is central to improving patient outcomes for ovarian cancer.

The standard adjuvant therapy for ovarian cancer at this time is combination chemotherapy with a platinum-based drug and paclitaxel. The underlying principle of cancer therapy is the selective killing of malignant cells while limiting toxicity to normal cells. Multiple studies have demonstrated that platinum-containing agents, such as cisplatin and carboplatin, kill cancer cells by triggering a pathway of programmed cell death known as the intrinsic pathway of apoptosis (17, 28). Research has identified alterations in the molecules that carry out this cell death cascade in cells that are chemoresistant (17, 28). The specific cellular defects identified in ovarian cancer cells and potential therapeutic approaches to overcome these defects and restore chemosensitivity will be discussed, with specific emphasis on apoptosome defects in ovarian cancers.