Drug resistance is a crucial factor in the failure of
cancer chemotherapy. In this study, we explored the effect of combining
alkylating agents and
arsenic trioxide (ATO) on the suppression of
tumor cells with inherited or acquired resistance to therapeutic agents. Our results showed that combining ATO and a synthetic derivative of 3a-aza-cyclopenta[a]
indenes (BO-1012), a bifunctional
alkylating agent causing
DNA interstrand cross-links, was more effective in killing human
cancer cell lines (H460, H1299, and PC3) than combining ATO and
melphalan or
thiotepa. We further demonstrated that the combination treatment of H460 cells with
BO-1012 and ATO resulted in severe G(2)/M arrest and apoptosis. In a xenograft mouse model, the combination treatment with
BO-1012 and ATO synergistically reduced
tumor volumes in nude mice inoculated with H460 cells. Similarly, the combination of
BO-1012 and ATO effectively reduced the growth of
cisplatin-resistant NTUB1/P human bladder
carcinoma cells. Furthermore, the repair of BO-1012-induced
DNA interstrand cross-links was significantly inhibited by ATO, and consequently, gammaH2AX was remarkably increased and formed nuclear foci in H460 cells treated with this
drug combination. In addition, Rad51 was activated by translocating and forming foci in nuclei on treatment with
BO-1012, whereas its activation was significantly suppressed by ATO. We further revealed that ATO might mediate through the suppression of AKT activity to inactivate Rad51. Taken together, the present study reveals that a combination of bifunctional
alkylating agents and ATO may be a rational strategy for treating
cancers with inherited or acquired drug resistance.