P-glycoprotein increases the efflux of the androgen dihydrotestosterone and reduces androgen responsive gene activity in prostate tumor cells.

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Fedoruk MN, Gimenez-Bonafe P, Guns ES, Mayer LD, Nelson CC

P-glycoprotein increases the efflux of the androgen dihydrotestosterone and reduces androgen responsive gene activity in prostate tumor cells.

Prostate. 2004 Apr 1;59(1):77-90.

PubMed ID

14991868 [ View in PubMed

]

Abstract

BACKGROUND: P-glycoprotein (P-gp) is commonly associated with multi-drug resistance (MDR) in cancer cells and the efflux of a broad spectrum of chemicals from the cell, including many chemotherapeutics and certain steroid hormones. The impact of P-gp and mechanisms involved in androgen transport and cellular accumulation within normal and malignant prostate cells remains unclear. METHODS: Following incubation of LNCaP, PC-3, HeLa, and HeLa FLAG-androgen receptor (AR) cells with (3)H-dihydrotestosterone (DHT) alone and in combination with P-gp inhibitors, PSC-833 and verapamil, we examined the cellular accumulation and efflux of androgens, as well as gene transcriptional response. RESULTS: Our data reveal that the cellular transport and accumulation of DHT is dependent on the expression of functional AR and modulated by P-gp. P-gp over-expression by both transient transfection and aspirin treatment in LNCaP cells showed decreased intracellular DHT accumulation, further suggesting DHT efflux is P-gp regulated. CONCLUSIONS: Androgen responsiveness may be modulated by P-gp in prostate cancer cells. The biological consequences of increased P-gp expression are decreased androgen accumulation and a corresponding decrease in androgen-regulated transcriptional activity and PSA gene expression.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Stanolone	P-glycoprotein 1	Protein	Humans	Unknown	Substrate	Details
Stanolone acetate	P-glycoprotein 1	Protein	Humans	Unknown	Substrate	Details
Vinblastine	P-glycoprotein 1	Protein	Humans	Unknown	Substrate Inhibitor Inducer	Details