Pharmacogenomic and molecular docking studies on the cytotoxicity of the natural steroid wortmannin against multidrug-resistant tumor cells

Wortmannin is a cytotoxic compound derived from the endophytic fungi Fusarium oxysporum, Penicillium wortmannii and Penicillium funiculosum that occurs in many plants, including medicinal herbs. The rationale to develop novel anticancer drugs is the frequent development of tumor resistance to the existing antineoplasic agents. Therefore, it is mandatory to analyze resistance mechanisms of novel drug candidates such as wortmannin as well to bring effective drugs into the clinic that have the potential to bypass or overcome resistance to established drugs and to substantially increase life span of cancer patients. In the present project, we found that P-glycoprotein-overexpressing tumor cells displaying the classical multidrug resistance phenotype toward standard anticancer drugs were not cross-resistant to wortmannin. Furthermore, three point-mutated PIK3CA protein structures revealed similar binding energies to wortmannin than wild-type PIK3CA. This protein is the primary target of wortmannin and part of the PI3K/AKT/mTOR signaling pathway. PIK3CA mutations are known to be associated with worse response to therapy and shortened its activity toward wild-type and mutant PIK3CA with similar efficacy. [Display omitted]