posted on 2020-08-13, 22:03authored byRoberta Bortolozzi, Andrea Luraghi, Elena Mattiuzzo, Alessandro Sacchetti, Alessandra Silvani, Giampietro Viola
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.