Effect of a Vitamin D3 derivative (B3CD) with postulated anti-cancer activity in an ovarian cancer animal model

Abstract

Summary The objective of the present study was to test the hypothesis that Calcidiol derivative B3CD qualifies as a potential anti-cancer drug in vivo employing an ovarian cancer xenograft model in mice. In addition, the selectivity of B3CD on viability and proliferation of platinum-resistant human ovarian cancer cell lines in comparison to control cell lines was analyzed in vitro. B3CD displayed cell line-specific cytotoxicity screened against a panel of ovarian and other carcinoma cell lines, endothelial and control cells. B3CD, at sub-cytotoxic concentrations, revealed stronger effects on the proliferation of SKOV-3 ovarian cancer cells vs. primary fibroblasts as determined by BrdU incorporation analysis. Treatment with B3CD at 0.5 μM resulted in highly condensed chromatin and fragmented nuclei in SKOV-3 cells but not in primary fibroblasts. B3CD induced cell death at low drug concentrations (≤0.5 μM) in SKOV-3 ovarian cancer cells is mediated by the p38 MAPK signaling pathway: B3CD induced p38 MAPK expression and activation in SKOV-3 cells and inhibition of p38 signaling counteracted B3CD induced cell death in vitro. An ovarian cancer cell animal model (human SKOV-3 cell derived xenografts in nude mice) revealed that tumor growth in few B3CD treated mice accelerated while the majority of B3CD treated mice displayed delayed tumor growth or full tumor regression. B3CD possesses anti-ovarian cancer properties in vitro and in vivo. We propose the further development of non-calcemic bromoacetoxy derivatives of vitamin D3 as potential anti-cancer therapeutics.

A coumarin derivative (RKS262) inhibits cell-cycle progression, causes pro-apoptotic signaling and cytotoxicity in ovarian cancer cells

“…Recent approaches to understand the mechanism of anticancer drugs in general, and in ovarian cancer cells in particular, have focused regularly on the involvement of MAP-Kinases [27, 28]. Based on immunoblot experiments, we assessed that contrary to many cytotoxic agents, RKS262-induced cytotoxicity is not significantly correlated with the activation of key pro-apoptotic MAPK P38 and SAP/JNK.…”

Vitamin D receptor polymorphisms and prognosis of patients with epithelial ovarian cancer

“…In turn, if a cell becomes malignant, 1,25-dihydroxyvitamin D can induce apoptosis and prevent angiogenesis, thereby reducing the potential for the malignant cell to survive. Vitamin D3 derivative was shown to induce apoptosis of ovarian cells but not of primary fibroblasts and to suppress ovarian tumour growth in a mice model (Zhang et al, 2005;Lange et al, 2009).…”

Vitamin D in Oncology

“…Analyzing data from 2 large observational studies, Skinner et al [43] (table 2). This includes cancer cell lines of the prostate [66], lung [66], pancreas [67][68][69], liver [70], kidney [71], bladder [72], ovaries [73], as well as melanoma [74,75], myeloma [66] and tumor-derived murine endothelial [76] cells. In addition, calcitriol has been shown to enhance the anti-tumor activity of several chemotherapeutic agents, including cisplatin and gemcitabine [67,72] as well as the cytotoxic effects of gamma irradiation [65,77].…”

“…Interestingly, glucocorticoids enhance the anti-tumor effects of calcitriol [66]. The effects induced in malignant cells differ from those in non-malignant cells [72][73][74]76]. The observed mechanisms of anti-tumor activity include anti-proliferative and apoptotic effects [71], inhibition of cell cycle progression [66,71,76], induction of p27 [66,76], p73 [72] and p38 MAPK expression [73], and cleavage of caspases [66].…”