Effects of 1,25(OH)2D3 on Cancer Cells and Potential Applications in Combination with Established and Putative Anti-Cancer Agents

Abstract

The diverse effects of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), the bio-active form of vitamin D, on cancer cell metabolism and proliferation has made it an interesting candidate as a supporting therapeutic option in cancer treatment. An important strategy in cancer therapy is the use of combination chemotherapy to overcome drug resistance associated with numerous anti-cancer agents and to provide better means of avoiding undesirable side effects. This complex strategy is widely adopted by oncologists and several established “cocktails” of chemotherapeutics are routinely administered to cancer patients. Among the principles followed in designing such treatment regimens is the use of drugs with different mechanisms of action to overcome the issue of tumor heterogeneity and to evade resistance. In light of the profound and diverse effects of 1,25(OH)2D3 reported by in vitro and in vivo studies, we discuss how these effects could support the use of this molecule in combination with “classical” cytotoxic drugs, such as platins and anti-metabolites, for the treatment of solid and hematological tumors. We also examine recent evidence supporting synergistic activities with other promising anti-cancer drug candidates, and postulate mechanisms through which 1,25(OH)2D3 may help evade chemoresistance.

Vitamin D Analogues Tacalcitol and Calcipotriol Inhibit Proliferation and Migration of T98G Human Glioblastoma Cells

“…Previous studies have shown that active vitamin D metabolites can inhibit cell proliferation and/or cell survival in various tumour types from different tissues [29]. Studies on the effects of active vitamin D in different cancer cell lines indicate effects on proliferation in some cell types but not in others [30].…”

Differences in p53 status significantly influence the cellular response and cell survival to 1,25‐dihydroxyvitamin D3‐metformin cotreatment in colorectal cancer cells

“…On the other hand, 1,25D3 has been shown to induce genomic as well as rapid, non‐genomic effects that lead to regulation of cancer cell proliferation and survival . Furthermore, several studies have shown enhanced anti‐tumor effects upon combining 1,25D3 with established chemotherapeutics, such as anti‐metabolites, namely gemcitabine and 5‐fluorouracil, as well as platinum‐based drugs, for example, cisplatin and oxaliplatin . Another promising combination is the 1,25D3‐metformin combination, which has shown advantageous effects in different tumor models compared to either molecule alone …”

“…10 Furthermore, several studies have shown enhanced antitumor effects upon combining 1,25D3 with established chemotherapeutics, such as anti-metabolites, namely gemcitabine and 5fluorouracil, as well as platinum-based drugs, for example, cisplatin and oxaliplatin. 34 Another promising combination is the 1,25D3-metformin combination, which has shown advantageous effects in different tumor models compared to either molecule alone. 34 The impact of p53 on the chemo-and radio-sensitivity of cancer cells has been previously shown, with different reports showing a context-dependent impact of p53 status on cellular outcome.…”

“…34 Another promising combination is the 1,25D3-metformin combination, which has shown advantageous effects in different tumor models compared to either molecule alone. 34 The impact of p53 on the chemo-and radio-sensitivity of cancer cells has been previously shown, with different reports showing a context-dependent impact of p53 status on cellular outcome. For example, loss of wt p53 function has been shown to reduce as well as enhance anti-cancer drug efficacy in different tumor models.…”

Vitamin D as a Novel Regulator of Tumor Metabolism: Insights on Potential Mechanisms and Implications for Anti-Cancer Therapy

“…With regards to cancer, large clinical trials are underway to assess the molecule’s therapeutic utility, whereas in vitro and in vivo studies have largely demonstrated profound anti-tumor potential associated with the active form [ 19 , 20 ]. Additionally, 1,25(OH) 2 D 3 and its analogues have been shown to be promising candidates for combination chemotherapy [ 21 ], due to their ability to augment the effects of conventional anti-cancer drugs including various anti-metabolites and platinum-based drugs.…”