A synthetic Bcl-XL antagonist induces apoptosis and chemosensitization in malignant pleural mesothelioma

IntroductionMalignant pleural mesothelioma (MPM) is often amenable to local control via surgical resection and adjuvant radiation therapy. Treatment failure ultimately results from chemotherapy-resistant micrometastatic disease. MPM express the anti-apoptotic protein Bcl-XL, and heterodimerization between Bcl-XL and pro-apoptotic Bcl-2 family members results in resistance to apoptosis and chemotherapy. BH3I-1 is a synthetic Bcl-XL antagonist which inhibits Bcl-XL heterodimerization with pro-apoptotic proteins. We propose that BH3I-1 may initiate apoptosis and chemosensitization of MPM. MethodsHuman MPM cell lines I45 and REN were exposed to BH3I-1 alone and in combination with cisplatin. Cell viability was determined by XTT assay. Apoptosis was assessed by fluorescence-activated cell sorter (FACS) determination of subdiploid populations, and western blot determination of cleavage of caspases 3 and 9. Isobologram analysis was performed to determine if combination therapy was synergistic. ResultsBH3I-1 alone resulted in decreased viability in both cell lines by XTT, and an increase in the SubG0 population compared to controls as determined by FACS [I45: 14.5% vs. 5.2%, REN: 29.2% vs. 5.4%, p<0.05]. Western blot demonstrated cleavage of caspases 3 and 9. Moreover, a subtherapeutic concentration of BH3I-1 sensitized both cell lines to cisplatin-induced apoptosis. Isobologram analysis demonstrated a synergistic effect. ConclusionsExposure of MPM cells to a synthetic Bcl-XL antagonist leads to apoptotic cell death and sensitization to the chemotherapeutic agent cisplatin. Such agents may circumvent resistance to conventional chemotherapy currently experienced in the adjuvant treatment of mesothelioma.