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RRR--Vitamin E Succinate Potentiates the Antitumor Effect of Calcitriol in Prostate Cancer without Overt Side Effects

Authors' Affiliations: ¹ Departments of Urology and Pathology, University of Rochester Medical Center, Rochester, New York; and ² Institute of Urology, Peking University, Beijing, PR China

Requests for reprints: Shuyuan Yeh, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642. Phone: 585-273-2750; Fax: 585-756-4133; E-mail: shuyuan_yeh{at}urmc.rochester.edu.

Purpose: To determine the antitumor efficacy of using calcitriol combined with RRR--vitamin E succinate (VES) on prostate cancer.

Experimental Design: The effects of VES or VES in combination with calcitriol on the calcitriol target genes were evaluated by Western blot and real-time PCR. The antiproliferation effect of the combination in prostate cancer cells was evaluated by the combination index method. The role of the vitamin D₃ receptor (VDR) in the enhanced antitumor effects of the combination was confirmed by small interfering RNA knockdown strategy. Xenograft-bearing mice were used to reaffirm the antitumor efficacy of this combination. Pathohistology analyses and expressions of VDR and its target genes were analyzed in untreated and treated tumors.

Results: VES selectively increased VDR protein in different prostate cancer cells. Low doses of calcitriol combined with VES were significantly superior to the additive effect of individual treatments against prostate cancer cell proliferation. The expression of VDR target genes involved in antiproliferation were further sensitized in the presence of VES. Knockdown of VDR expression abolished the combination benefits in LNCaP and PC3 cells. Consistently, in prostate cancer xenograft models, VES enhanced the therapeutic efficacy of a tolerated dose of calcitriol yet without overt evidence of systemic toxicity and hypercalcemia. This notable in vivo effect was also accompanied by up-regulation of VDR target genes.

Conclusions: Low-dose calcitriol combined with vitamin E analogue could be a solution to the calcemic side effect. The demonstration of superior antitumor activity of low-dose calcitriol plus VES provides the preclinical basis for developing a useful therapeutic strategy for prostate cancer.