Vitamin D₃ potentiates the growth inhibitory effects of metformin in DU145 human prostate cancer cells mediated by AMPK/mTOR signalling pathway

Abstract

SUMMARYMetformin and vitamin D 3 both exhibit a strong antiproliferative action in numerous cancer cell lines, including in human prostate cancer cells. Here we showed that the combination of the two drugs had a much stronger effect on DU145 human prostate cancer cell growth than either drug alone. In this research, cell proliferation was measured by methylthiazol tetrazolium (MTT) assay. Cell apoptosis was determined with Hoechst 33342 staining. Western blotting and cell cycle analyses were used to elucidate potential mechanisms of interaction between the drugs. It is shown that in cultured DU145 cells, vitamin D 3 combined with metformin exhibits synergistic effects on cell proliferation and apoptosis. The underlying antitumor mechanisms may involve altered cycle distribution with a G1/S cell cycle arrest, activation of phospho-AMPK with subsequent inhibition of downstream mTOR signalling pathway, down-regulate c-Myc expression, and reducing the level of anti-apoptotic protein p-Bcl-2. In conclusion, metformin and vitamin D 3 synergistically inhibit DU145 cell growth, indicating a promising clinical therapeutic strategy for the treatment of androgen-independent prostate cancer.

1,25-Dihydroxy vitamin D3 stimulates system A amino acid transport in primary human trophoblast cells

“…This finding could be explained by observations that the effect of 1,25-dihydroxy vitamin D 3 on mTOR signaling is cell-specific. For example, VDR-bound 1,25-dihydroxy vitamin D 3 activates the mTOR pathway in human dendritic cells (Ferreira et al, 2015) but suppresses mTOR signaling in osteoblast and cancer cells (Li et al, 2015; Lisse et al, 2011). …”

Role of 1α,25-Dihydroxyvitamin D3 in Adipogenesis of SGBS Cells: New Insights into Human Preadipocyte Proliferation

“…The ability of 1,25(OH) 2 D 3 to induce growth arrest has been widely studied in cancer cells, such as ovarian, prostate, breast, and gastric cancer cells [36][37][38][39], but this is the first report of this effect in human preadipocytes.…”

Novel strategies for molecular targeting to cancer

“…As a pro‐oxidant that induces oxidative stress by generating ROS or inhibiting antioxidant systems, vitamin D at low levels may favor cell proliferation rather than differentiation. Insufficient vitamin D intake has been suggested to be prevalent among men at risk of prostate cancer, and as an active form of vitamin D3, calcitriol may have anti‐proliferative and pro‐differentiating effects on cancer cells . Li et al .…”

“…Li et al . reported that vitamin D3 when combined with metformin that is a popular first line anti‐diabetic drug and recently anti‐aging candidate exhibits a synergistic effect on prostate cancer cell apoptosis . Vitamin D3 plus metformin together induce prostate cancer DU145 cell apoptosis to a level greater than the sum induced by vitamin D3 and metformin singly .…”