In vitro modulation of multidrug resistance by pregnane steroids and in vivo inhibition of tumour development by 7α-OBz-11α(R)-OTHP-5β-pregnanedione in K562/R7 and H295R cell xenografts

Ghina Alameh,Agnès Emptoz-Bonneton,Marc Rolland De Ravel,Eva L Matera,Elisabeth Mappus,Patrick Balaguer,Luc Rocheblave,Thierry Lomberget,Charles Dumontet,Marc Le Borgne,Michel Pugeat,Catherine Grenot,Claude Y Cuilleron

doi:10.1080/14756366.2019.1575825

Abstract

Synthetic progesterone and 5α/β-pregnane-3,20-dione derivatives were evaluated as in vitro and in vivo modulators of multidrug-resistance (MDR) using two P-gp-expressing human cell lines, the non-steroidogenic K562/R7 erythroleukaemia cells and the steroidogenic NCI-H295R adrenocortical carcinoma cells, both resistant to doxorubicin. The maximal effect in both cell lines was observed for 7α-O-benzoyloxy,11α(R)-O-tetrahydropyranyloxy-5β-pregnane-3,20-dione 4. This modulator co-injected with doxorubicin significantly decreased the tumour size and increased the survival time of immunodeficient mice xenografted with NCI-H295R or K562/R7 cells.

Highlights

Reversion of multidrug resistance (MDR) remains an important goal to improve the efficiency of cancer chemotherapy
We report results of new biological investigations aimed at evaluating whether the nine progesterone and 5a/b-pregnane-3,20-dione MDR modulators 1–9 (Figure 1) previously selected using the K562/R7 cell line can maintain a high level of activity in vivo
This work reports in vitro and in vivo data on K562/R7 and NCIH295R cell lines that revealed the potency of the 7a-OBz,11a(R)OTHP-5b-pregnane-3,20-dione lead compound 415 to modulate Pgp-mediated MDR and to inhibit the development of tumour cell xenografts

Summary

Introduction

Reversion of multidrug resistance (MDR) remains an important goal to improve the efficiency of cancer chemotherapy. A major contributor to the MDR phenotype is P-glycoprotein (P-gp/ABCB1), a transmembrane protein belonging to the ABC (ATP-binding cassette) family of ATP-dependent transporters. This protein is often overexpressed in tumour cells after treatment by cytotoxic drugs and is present in normal tissues such as blood-brain barrier, adrenal glands, kidney or liver, for which it has a physiological role to eliminate xenobiotics, toxics or drugs[1]. P-gp transports a wide variety of structurally unrelated molecules including most of the anticancer drugs, which undergo a mechanism of inactivation by drug efflux, at the origin of chemoresistance. Comparative studies have revealed favourable structural features[5] and provided data on the localisation of interaction sites with substrates or modulators[6] including photoaffinity labelling[7] and mutagenesis experiments[8]

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Results

Conclusion