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

J Enzyme Inhib Med Chem. 2019 Dec;34(1):684-691. 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.

Keywords: Multidrug resistance; P-glycoprotein; non-steroidogenic and steroidogenic cell lines; pregnane modulators; xenografts.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Drug Resistance, Multiple / drug effects*
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Screening Assays, Antitumor
  • Female
  • Humans
  • Mice
  • Mice, SCID
  • Molecular Conformation
  • Neoplasms, Experimental / drug therapy
  • Neoplasms, Experimental / pathology
  • Pregnanes / chemical synthesis
  • Pregnanes / chemistry
  • Pregnanes / pharmacology*
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Pregnanes

Grants and funding

This study was supported by funds from INSERM, “Université Claude Bernard Lyon 1” and “Hospices Civils de Lyon.”