Backstabbing P-gp: Side-Chain Cleaved Ecdysteroid 2,3-Dioxolanes Hyper-Sensitize MDR Cancer Cells to Doxorubicin without Efflux Inhibition

Abstract

P-glycoprotein (P-gp, ABCB1) over-expression, causing a multi-drug resistant (MDR) phenotype, is a major problem in cancer chemotherapy that urgently requires novel approaches. Our previous studies showed certain ecdysteroid derivatives as promising chemo-sensitizers against MDR and non-MDR cancer cell lines while also exerting mild to moderate inhibition of P-gp function. Here we report the preparation of a set of substituted 2,3-dioxolane derivatives of poststerone, a known in vivo metabolite of 20-hydroxyecdysone (20E). In contrast with previously studied ecdysteroid dioxolanes, the majority of the new compounds did not inhibit the efflux function of P-gp. Nevertheless, a strong, dose dependent sensitization to doxorubicin was observed on a P-gp transfected cancer cell line and on its susceptible counterpart. We also observed that the MDR cell line was more sensitive to the compounds’ effect than the non-MDR. Our results showed for the first time that the chemo-sensitizing activity of ecdysteroids can be fully independent of functional efflux pump inhibition, and suggest these compounds as favorable leads against MDR cancer.

Stereochemistry and complete 1H and 13C NMR signal assignment of C‐20‐oxime derivatives of posterone 2,3‐acetonide in solution state

“…Poststerone 2,3‐acetonide ( 1 ) was prepared according to previously published procedures . Oximation of derivative 1 was performed at RT, by dissolving 42.2 mg (0.104 mmol) of the substrate in a round‐bottom flask in freshly distilled pyridine.…”

“…Less polar derivatives of ecdysteroids, and particularly their acetonides and other dioxolane analogs, were previously shown by our group to exert a strong chemo‐sensitizing activity on cancer cells to common chemotherapeutics, including doxorubicin, vincristine, and paclitaxel . While this sensitizing activity could also be observed on drug‐susceptible cancer cells, a high selectivity was found towards multidrug resistant (MDR) cancer cell lines transfected to overexpress the ABCB1 multidrug transporter . Interestingly, the chemo‐sensitizing activity was independent of a functional efflux inhibition: even though some of the tested compounds showed a mild to moderate ABCB1 inhibitory activity; structure–activity relationships for efflux inhibition were significantly different to those describing chemo‐sensitizing activity .…”

“…Interestingly, the chemo‐sensitizing activity was independent of a functional efflux inhibition: even though some of the tested compounds showed a mild to moderate ABCB1 inhibitory activity; structure–activity relationships for efflux inhibition were significantly different to those describing chemo‐sensitizing activity . In particular, several poststerone derivatives, containing a substituted dioxolane (e.g., acetonide) moiety connected to their A‐ring, were found to be free from the efflux pump inhibitory activity, while acting as strong chemo‐sensitizers in combination with doxorubicin . In addition to this, ecdysteroid 6‐oximes and oxime ethers demonstrated markedly increased ABCB1 inhibitory activity, while acting as similarly potent chemo‐sensitizers as their corresponding 6‐oxo analogs …”

Effects of major parameters of nanoparticles on their physical and chemical properties and recent application of nanodrug delivery system in targeted chemotherapy

“…[15][16][17][18][19][20] There has been much research on the mechanism of MDR in the recent years, 21,22 and scientists are trying to explore the mechanisms to overcome MDR such that chemotherapy drugs could exhibit a higher efficacy.…”

Wnt/β‑catenin inhibition reverses multidrug resistance in pediatric acute lymphoblastic leukemia

“…The mechanisms of drug resistance are associated with the overexpression of drug-efflux pumps, including MDR1-encoded and membrane-located P-glycoprotein (P-gp) and MRP. The overexpression of drug-efflux pumps promotes the cellular escape of anticancer drugs, especially natural drugs and anthracyclines, including vinca alkaloids, vinblastine, vincristine (5) and doxorubicin. Therefore, it is urgent to develop novel therapeutic strategies to increase sensitivity of ALL to chemotherapeutic drugs.…”