Synthesis and Comparison of the Antitumor Activities of Steroids on ABCB1-transfected Mouse Lymphoma and Human Ovary Carcinoma

Background: Multidrug resistance modifiers were indentified against ABC transporters such as ABCB1, but there are other resistance mechanisms based upon such transporters as CTR1 or ATP7A/B membrane proteins. Cisplatin resistance due to the lower expression of CTR1 or to the over-expression of ATP7A/B is also responsible for therapeutic failures in many cancer types. Materials and Methods: 35 modified steroid derivatives were tested for their multidrug reversal and proliferation inhibitory activity comparing their effects in human ABCB1-transfected mouse T-cell lymphoma and cisplatin resistant human ovary carcinoma cell lines. The selected potent resistance reversal agents were tested in a checkerboard assay in the presence of the anticancer drug doxorubicin on mouse lymphoma or cisplatin on human ovary cancer cell lines. Results: Correlations between chemical structure of different steroidal compounds on their effects on drug resistance were investigated. A common characteristic feature of D-ring substituents with N or O atom in the position of 1,3 was found within the effective inhibitors of proliferation when comparing the effective compounds on the two cancer cell lines. Conclusion: We assume that the polar substituents forming a bidentate part may serve as a binding moiety on the polar protein-glycan surface of the cells and can result in an effect independent of the structure of the A ring.