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.

• Authors: Attila Hunyadi, József Csábi, Ana Martins, Joseph Molnár, Attila Balázs, Gábor Tóth
• Journal: Molecules (Basel, Switzerland) (Molecules) Vol. 22 Issue 2 (Jan 25 2017) ISSN: 1420-3049 [Electronic] Switzerland
• PMID: 28125071 (Publication Type: Journal Article)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents
• Dioxolanes
• Ecdysteroids
• Doxorubicin

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (antagonists & inhibitors, genetics, metabolism)
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Dioxolanes (chemistry, pharmacology)
• Doxorubicin (pharmacology)
• Drug Resistance, Multiple (drug effects, genetics)
• Drug Resistance, Neoplasm (drug effects, genetics)
• Drug Synergism
• Ecdysteroids (chemistry)
• Humans
• Inhibitory Concentration 50
• Magnetic Resonance Spectroscopy
• Molecular Structure