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Vitamin D signalling pathways in cancer: potential for anticancer therapeutics

Key Points

  • Epidemiological studies point to a relationship between vitamin D deficiency and cancer risk.

  • Alterations in vitamin D receptor expression, and in the synthesis (25-hydroxylase and 1α-hydroxylase) and catabolism (24-hydroxylase) of vitamin D metabolites are involved in the growth regulation of tumours; thus, compromising 1α,25(OH)2D3 (also known as calcitriol; the active metabolite of vitamin D signalling) sensitivity and 1α,25(OH)2D3 signalling.

  • The antiproliferative effects of 1α,25(OH)2D3 have been demonstrated in various tumour types, as determined by preclinical trials.

  • The anti-tumour effects of 1α,25(OH)2D3 involve mechanisms that are associated with G0/G1 arrest, differentiation, induction of apoptosis and modulating different signalling pathways in tumour cells, as well as inhibiting tumour angiogenesis.

  • Glucocorticoids potentiate the anti-tumour effects of 1α,25(OH)2D3 and decrease 1α,25(OH)2D3-induced hypercalcemia. 1α,25(OH)2D3 also potentiates the anti-tumour effects of many chemotherapeutic agents such as platinum analogues, taxanes and DNA-intercalating agents.

  • Given that the major vitamin D catabolizing enzyme, CYP24A1 (24-hydroxylase), is often amplified and overexpressed in tumour cells, agents that inhibit this enzyme can potentiate 1α,25(OH)2D3 anti-tumour effects.

  • Preclinical data indicate that maximal anti-tumour effects are seen with pharmacological doses of 1α,25(OH)2D3, and can be safely achieved in animals using a high-dose, intermittent schedule of administration. Some clinical trial data indicates that 1α,25(OH)2D3 is well-tolerated in cancer patients within a proper dosing schedule.

  • Data support the hypothesis that vitamin D compounds may have an important role in cancer therapy and prevention, and merit further investigation.

Abstract

Epidemiological studies indicate that vitamin D insufficiency could have an aetiological role in various human cancers. Preclinical research indicates that the active metabolite of vitamin D, 1α,25(OH)2D3, also known as calcitriol, or vitamin D analogues might have potential as anticancer agents because their administration has antiproliferative effects, can activate apoptotic pathways and inhibit angiogenesis. In addition, 1α,25(OH)2D3 potentiates the anticancer effects of many cytotoxic and antiproliferative anticancer agents. Here, we outline the epidemiological, preclinical and clinical studies that support the development of 1α,25(OH)2D3 and vitamin D analogues as preventative and therapeutic anticancer agents.

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Figure 1: Vitamin D metabolism.
Figure 2: 1α,25(OH)2D3-mediated transcriptional regulation.
Figure 3: Key cancer-related signalling pathways targeted by 1α,25(OH)2D3.
Figure 4: Development of 1α,25(OH)2D3 and vitamin D analogues as anticancer drugs.

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Acknowledgements

D.L.T. and C.S.J. are supported by grants from the US National Cancer Institute, Department of Defense, American Cancer Society and The Roswell Park Alliance Foundation. C.S.J. is also supported by the Robert, Lew and Ann Wallace Endowment Fund.

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Correspondence to Candace S. Johnson.

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C.S. Johnson and D.L. Trump receive research support from Novacea, Inc. and are co-inventors of a patent related to vitamin D-based cancer therapy held by the University of Pittsburgh and licensed to Novacea, Inc. D. L. Trump receives research support from AstraZeneca, Sanofi-Aventis and Amgen, Inc.

Authors' homepage: http://www.roswellpark.org

Supplementary information

Supplementary information S1 (table)

Preclinical Anti–tumour Activity of 1α,25(OH)2D3 and Vitamin D Analogues (PDF 566 kb)

Supplementary information S2 (table)

Clinical Trials of Vitamin D3, 1α,25(OH)2D3 and its Analogues. (PDF 218 kb)

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Glossary

Secosteroid hormones

Molecules that are very similar in structure to steroids but with a broken ring; two of the Bring carbon atoms (C-9 and 10) of the four steroid rings are not joined.

Autocrine

A substance secreted by a cell that acts on the surface receptors of the same cell.

Paracrine

A substance secreted by a cell that acts on adjacent cells.

Platinum analogues

Platinum-based chemotherapeutics that crosslink DNA and therefore impair the progression of DNA replication machinery.

Taxanes

Drugs that inhibit microtubule dynamics by stabilizing GDP-bound tubulin. Microtubules form the mitotic spindle and so taxanes prevent the completional of mitosis.

Myelodysplasia

Any of a group of bone marrow disorders that have markedly abnormal reduction in one or more types of circulating blood cells owing to defective growth and maturation of blood-forming cells in the bone marrow.

Hypercalcemia

Excess of Ca2+ in the blood. Chronic elevated serum levels of Ca2+ (12.0 mg dL) can result in urinary calculi (renal or bladder stones) and abnormal heart rhythms. Severe hypercalcemia (above 15–16 mg dL) can result in coma and cardiac arrest.

Osteodystrophy

Defective bone ossification that occurs when the kidney fails to maintain proper levels of Pi and Ca2+. This results in slowed bone growth and causes bone deformities in children. In adults, renal osteodystrophy results in thin and weak bones, bone and joint pain and vulnerability to osteoporosis.

Osteoporosis

A condition that is characterized by a decrease in bone mass with decreased density and enlargement of bone spaces producing porosity and brittleness of the bone.

Pharmacokinetics

The characteristic interactions of a drug and the body in terms of its absorption, distribution, metabolism and excretion.

Area under the curve

(AUC). In pharmacokinetics, the area under the curve is a plot of concentration of drug in serum over time that represents the measure of an individuals exposure to the drug.

Bioavailability

Measurement of an administered dose of a therapeutically active drug that reaches the systemic circulation and depends on the mode of administration.

Cmax

Maximum or 'peak' concentration of a drug observed after its administration.

Glucocorticoids

Corticosteroids are involved in carbohydrate, protein and fat metabolism to regulate liver glycogen and blood sugar by increasing gluconeogenesis; clinically used for anti-inflammatory and immunosuppressive effects.

1α,25(OH)2D3 intoxication

The symptoms of hypervitaminosis D (excessive doses of vitamin D) are a result of hypercalcemia caused by increased intestinal Ca2+ absorption. Gastrointestinal symptoms include anorexia, nausea and vomiting.

Hypercalciuria

Excessive urinary Ca2+ excretion. The morbidity associated with hypercalciuria is related to kidney stone disease and bone demineralization leading to osteopaenia (decrease in bone density) and osteoporosis.

Thromboembolic complications

Associated with blockage of a blood vessel by a particle that has dislodged from a blood clot at its primary formation site.

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Deeb, K., Trump, D. & Johnson, C. Vitamin D signalling pathways in cancer: potential for anticancer therapeutics. Nat Rev Cancer 7, 684–700 (2007). https://doi.org/10.1038/nrc2196

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