PMID: Biochim Biophys Acta Mol Basis Dis. 2021 03 1 ;1867(3):166040. Epub 2020 Dec 16. PMID: 33338596 Abstract Title: Chemopreventive effects of vitamin Dand its analogue, paricalcitol, in combination with 5-fluorouracil against colorectal cancer: The role of calcium signalling molecules. Abstract: BACKGROUND: Although vitamin D (VD) is chemoprotective and enhances 5-fluorouracil (5-FU) cytotoxicity against colorectal cancer (CRC), little is known about its potential calcium (Ca)-mediated anti-tumorigenic actions. Therefore, this study compared between VD and its non-calcaemic analogue, Paricalcitol (Pcal),± 5-FU in relation to chemoprevention and Ca-mediated apoptosis in vivo and in vitro.METHODS: Seventy male mice were distributed to: negative controls, positive controls (PC), VD, Pcal, 5-FU, VD + 5-FU and Pcal+5-FU groups. All groups, except negative, received two consecutive azoxymethane (AOM)-injections (10 mg/Kg/week) for CRC induction. VD(1000 IU/kg; three times/week) and Pcal (1.25 μg/kg; three times/week) injections started week-16 post-AOM and for 10 weeks. Three successive 5-FU cycles began at week-21 (50 mg/Kg/week). Similar protocols with VD, Pcal and/or 5-FU were applied in the HT29 colon cancer cells.RESULTS: The PC group had abundant malignant tumours, markedly elevated proliferation markers (survivin/CCND1) and declines in cyclin-dependent kinase-inhibitor-1A, pro-apoptotic molecules (p53/BAX/cytochrome_C/caspase-3), tissue Caconcentrations and Ca-dependent proteins (CaSR/CAM/CAMKIIA). All monotherapies equally reduced tumour numbers and proliferation markers whilst promoting the anti-tumorigenic molecules. VD and/or 5-FU, but not Pcal monotherapy, enhanced Calevels and Ca-related molecules (CaSR/CAM/CAMKIIA/BAX/cytochrome_C) in vivo and in vitro. However, VD + 5-FU co-therapy showed the lowest tumour numbers, the highest cell numbers in sub-G1 phase of cell cycle, alongside the most effective modulations of oncogenes, tumour suppressors and Ca-related molecules at the gene and protein levels in vivo and in vitro.CONCLUSIONS: VDwas superior than Paricalcitol in potentiating 5-FU cytotoxicity, possibly by upregulating several Ca-related molecules involved in tumour suppression.
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