DNA Repair in Despair—Vitamin D Is Not Fair

Abstract

The role of vitamin D as a treatment option for neoplastic diseases, once considered to have a bright future, remains controversial. The preclinical studies discussed herein show compelling evidence that Vitamin D Derivatives (VDDs) can convert some cancer and leukemia cells to a benign phenotype, by differentiation/maturation, cell cycle arrest, or induction of apoptosis. Furthermore, there is considerable, though still evolving, knowledge of the molecular mechanisms underlying these changes. However, the attempts to clearly document that the treatment outcomes of human neoplastic diseases can be positively influenced by VDDs have been, so far, disappointing. The clinical trials to date of VDDs, alone or combined with other agents, have not shown consistent results. It is our contention, shared by others, that there were limitations in the design or execution of these trials which have not yet been fully addressed. Based on the connection between upregulation of JNK by VDDs and DNA repair, we propose a new avenue of attack on cancer cells by increasing the toxicity of the current, only partially effective, cancer chemotherapeutic drugs by combining them with VDDs. This can impair DNA repair and thus kill the malignant cells, warranting a comprehensive study of this novel concept. J. Cell. Biochem. 117: 1733-1744, 2016. © 2016 Wiley Periodicals, Inc.

Vitamin D status in children with leukemia, its predictors, and association with outcome

“…However, it was soon recognized that vitamin D concentrations required to induce cell differentiation would cause severe hypercalcemia and cannot be used in clinical practice. Many synthetic derivatives of vitamin D with less calcemic properties have since been synthesized, but their clinical efficacy has been inconsistent . Although it is unclear whether vitamin D or its synthetic derivatives have clinical effects in the treatment of malignancies, there is emerging evidence that low circulating 25(OH)D levels are associated with adverse outcome in adult patients with different hematological malignancies and solid tumors such as myelodysplastic syndrome, AML, chronic lymphocytic leukemia, colorectal and breast cancer, and non‐Hodgkin lymphoma …”

Prodifferentiation Activity of Novel Vitamin D2 Analogs PRI-1916 and PRI-1917 and Their Combinations with a Plant Polyphenol in Acute Myeloid Leukemia Cells

“…Therefore, a great number of synthetic 1,25D3 analogs (>3000) have been synthesized to date aiming to obtain a potent drug with reduced calcemic toxicity. However, apart from some encouraging results, the currently existent compounds that have reached clinical trials have not yet shown consistent clinical responses, and hypercalcemia still remains a major limiting factor [ 10 , 11 , 12 ]. One solution to this challenge is the use of compounds that can potentiate the anticancer effects, and not the toxicity, of low concentrations of vitamin D derivatives (VDDs) [ 13 , 14 , 15 , 16 , 17 ].…”