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 (1, 2) , Agnès Emptoz-Bonneton (1, 3) , Marc Rolland de Ravel (1, 4) , Eva Matera (4) , Elisabeth Mappus (1) , Patrick Balaguer (5) , Luc Rocheblave (6) , Thierry Lomberget (6) , Charles Dumontet (4) , Marc Le Borgne (6) , Michel Pugeat (7) , Catherine Grenot (8, 1) , Claude Yves Cuilleron (8, 1)

1 UCBL ISPB - Université Claude Bernard Lyon 1 - Institut des Sciences Pharmaceutiques et Biologiques
2 Hormones steroïdes et protéines de liaison
3 HCL - Hospices Civils de Lyon
4 UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon
5 IRCM - U1194 Inserm - UM - Institut de Recherche en Cancérologie de Montpellier
6 B2MC - Molécules bioactives et chimie médicinale
7 CarMeN - Cardiovasculaire, métabolisme, diabétologie et nutrition
8 Interactions stéroïdes-protéines et applications immunodiagnostiques et biocliniques

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.

Mots clés: Multidrug resistance; P-glycoprotein; xenografts; pregnane modulators; non-steroidogenic and steroidogenic cell lines

Domaines: Pharmacologie; Médicaments; Chimie thérapeutique

Ghina Alameh, Agnès Emptoz-Bonneton, Marc Rolland de Ravel, Eva Matera, Elisabeth Mappus, et al.. 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. Journal of Enzyme Inhibition and Medicinal Chemistry, 2019, 34 (1), pp.684-691. ⟨10.1080/14756366.2019.1575825⟩. ⟨hal-02077612⟩