The expression of multidrug resistance
P-glycoprotein (P-gp) by
cancer cells represents one of the major drawbacks to successful
cancer therapy. Accordingly, the development of drugs that inhibit the activity of this transporter remains a major challenge in
cancer drug discovery. In this context, several new
ecdysteroid derivatives have been synthesized and evaluated as P-gp inhibitors. Two of them (compounds 9 and 14) were able to resensitize CEMVbl100 and LoVoDoxo resistant cell lines to
vinblastine and
doxorubicin, respectively. Indeed, both compounds 9 and 14 increased the cellular accumulation of
rhodamine 123 in cells expressing P-gp and stimulated basal
P-glycoprotein-
ATPase activity at a 1 μM concentration, demonstrating their interference with the transport of other substrates in a competitive mode. Moreover, in a
medulloblastoma cell line (DAOY), compounds 9 and 14 reduced the side population representing cancer stem cells, which are characterized by a high expression of ABC drug transporters. Further, in DAOY cells, the same two compounds synergized with
cisplatin and
vincristine, two drugs used commonly in the
therapy of
medulloblastoma. Molecular docking studies on the homology-modeled structure of the human
P-glycoprotein provided a rationale for the biological results, validating the binding mode within the receptor site, in accordance with lipophilicity data and observed structure-activity relationship information. Altogether, the present results endorse these derivatives as promising P-gp inhibitors, and they may serve as candidates to reverse drug resistance in
cancer cells.