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Review
. 2017 Jan 23;9(1):87.
doi: 10.3390/nu9010087.

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

Mohamed A Abu El Maaty  1 , Stefan Wölfl  2
Affiliations
Review

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

Mohamed A Abu El Maaty et al. Nutrients. .

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.

Keywords: 1,25-dihydroxyvitamin D3; anti-cancer effects; combination chemotherapy.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Dual targeting of AMPK signaling by 1,25(OH)2D3 and metformin. Hypothesized mechanisms through which 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) influences the activity of AMP-activated protein kinase (AMPK) and hence cell survival are depicted by dashed lines and include: (1) Modulation of mitochondrial biogenesis/activity with the subsequent deregulation of energy status; (2) Induction of LKB1 expression/activity; (3) Disruption of non-mitochondrial energy-producing processes (e.g., cellular glucose uptake and glycolysis); (4) Direct AMPK activation via induction of AMPK expression or inhibition of inactivating phosphatase expression.
Figure 2
Figure 2
Potential cooperative targeting of the thioredoxin system by 1,25(OH)2D3 and auranofin. Induction of thioredoxin-interacting protein (TXNIP)/ vitamin D3-upregulated protein 1 (VDUP1) expression with 1,25(OH)2D3 and inhibition of thioredoxin reductase (TrxR) by auranofin and other gold complexes could synergistically inhibit the reductive capacity of the thioredoxin (Trx) system, subsequently increasing intracellular reactive oxygen species (ROS) levels, which activate apoptotic signaling. Besides influencing redox balance, 1,25(OH)2D3-mediated TXNIP induction may alter glucose homeostasis given the latter’s role in regulating intracellular glucose levels. Although this effect is independent of other players of the Trx system (hence not presented in figure), it could define novel anti-tumor roles of 1,25(OH)2D3.
Figure 3
Figure 3
Overcoming chemoresistance with 1,25(OH)2D3. Through genomic or non-genomic mechanisms, 1,25(OH)2D3 may affect the various players involved in mediating resistance to chemotherapeutics, such as modulating tumor microenvironment, cancer stem cell signaling, as well as drug influx, efflux, and metabolism.
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