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
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Dose-Response Relationship, Drug
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Drug Resistance, Multiple / drug effects*
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Drug Resistance, Neoplasm / drug effects*
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Drug Screening Assays, Antitumor
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Female
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Humans
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Mice
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Mice, SCID
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Molecular Conformation
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Neoplasms, Experimental / drug therapy
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Neoplasms, Experimental / pathology
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Pregnanes / chemical synthesis
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Pregnanes / chemistry
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Pregnanes / pharmacology*
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Structure-Activity Relationship
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Tumor Cells, Cultured
Substances
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Antineoplastic Agents
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Pregnanes
Grants and funding
This study was supported by funds from INSERM, “Université Claude Bernard Lyon 1” and “Hospices Civils de Lyon.”