Calcitriol (1,25-dihydroxycholecalciferol) enhances paclitaxel antitumor activity in vitro and in vivo and accelerates paclitaxel-induced apoptosis

We demonstrated that calcitriol has antiproliferative activity in squamous cell carcinoma and prostatic adenocarcinoma and enhances the antitumor acti vity of platinum-based agents, In this study, we examined whether calcitrio l also increases paclitaxel cytotoxicity, The effect of treatment on growth of the murine squamous cell carcinoma (SCCVII/SF) and human prostatic aden ocarcinoma (PC-3) was determined by clonogenic assay, 3-(4,5-dimethylthiazo l-2-yl)-2,5-diphenyltetrazolium bromide assay, and monitoring tumor growth. Treatment of SCC or PC-3 cells in vitro with calcitriol prior to paclitaxe l significantly reduced clonogenic survival compared with either agent alon e. Median-dose effect analysis revealed that calcitriol and paclitaxel inte ract synergistically, Treatment of SCC or PC-3 tumor-bearing mice with calc itriol prior to paclitaxel resulted in substantially greater growth inhibit ion than was achieved with either agent alone, supporting the combined use of calcitriol and paclitaxel in the treatment of solid tumors. To explore t he molecular basis for the enhanced antitumor activity of this combination, the effect of treatment on p21(Waf-1) (p21), Bcl-2, and poly(ADP-ribose) p olymerase expression was evaluated in PC-3, A 72-h pretreatment with calcit riol reduced p21 expression and increased paclitaxel cytotoxicity (measured after 24 h) without evidence of apoptosis [poly(ADP-ribose) polymerase cle avage]. After 48 h, paclitaxel induced apoptosis, the extent of which was i ncreased similarly by pretreatment or concurrent treatment with calcitriol, We therefore propose a model for carcitriol enhancement of paclitaxel cyto toxicity in which the "early" (24 h) effects are schedule dependent and not attributed to enhancement of paclitaxel-induced apoptosis, In contrast, th e "delayed" (48-h) enhancement of paclitaxel activity by carcitriol is sche dule independent and associated with acceleration of apoptosis.