Calcitriol and cancer therapy: A missed opportunity

Abstract

The vitamin D receptor is expressed in most tissues of the body – and the cancers that arise from those tissues. The vitamin D signaling pathway is active in those tissues and cancers. This is at least consistent with the hypothesis that perturbing this signaling may have a favorable effect on the genesis and growth of cancers. Epidemiologic data indicate that vitamin D signaling may be important in the initiation and outcome of a number of types of cancer. Many studies have shown that calcitriol (1,25 dihydroxycholecalciferol) and other vitamin D compounds have antiproliferative, pro-apoptotic, anti-cell migration and antiangiogenic activity in a number of preclinical studies in many different cancer types. Unfortunately, the assessment of the activity of calcitriol or other vitamin D analogues in the treatment of cancer, as single agents or in combination with other anticancer agents has been stymied by the failure to adhere to commonly accepted principles of drug development and clinical trials conduct.

Calcitriol Inhibits Viability and Proliferation in Human Malignant Pleural Mesothelioma Cells

“…Herein, we show that, in addition to the effect per se , calcitriol also acted in a synergistic manner with the antifolate compound PEM, which, in association with cisplatin, is currently the standard first-line treatment for patients with advanced MPM ( 4 ). To the best of our knowledge, this is the first evidence on the effective combination of calcitriol and PEM in cancer cells, despite vitamin D derivatives previously showed the ability to potentiate in vitro and in vivo the antitumor effects of platinum analogs like carboplatin and cisplatin ( 5 , 9 , 45 ). Therefore, although not suitable as a single use against cancer, vitamin D derivatives might be considered as adjuvants in combination therapy with cytotoxic compounds, as already described for other types of cancers ( 9 , 11 ).…”

“…The biological activity of calcitriol is mainly regulated by VDR, which modulates the expression of many target genes ( 5 , 28 ). Importantly, it has been shown that tumor progression may be correlated with lower VDR levels in different types of cancer ( 5 – 9 ), and a positive association between expression of VDR/calcitriol with improved prognosis was found in patients with lung adenocarcinoma ( 29 , 30 ). Furthermore, it has been recently demonstrated that vitamin D deficiency exacerbates pulmonary fibrosis in mice ( 31 ), whereas lung cancer cells expressing VDR are more responsive to the antiproliferative effect of calcitriol; in addition, high nuclear VDR expression has been associated with increased survival in lung cancer patients ( 29 , 30 , 32 ).…”

“…The antitumor role of calcitriol and vitamin D derivatives in different types of cancer was demonstrated in several in vitro and in vivo studies, including lung cancer, suggesting that vitamin D may be a promising agent, in combination with anticancer therapies ( 5 , 7 – 9 , 38 ). Importantly, inflammation is one of the main hallmarks of cancer ( 39 ) and different studies have demonstrated the ability of vitamin D to modulate the innate and adaptive immune responses and to exert antinflammatory effects in tumorigenesis, by interfering with the tumor microenvironment through the regulation of key inflammatory pathways ( 5 , 40 , 41 ).…”

“…Although the antitumor effects of calcitriol in preclinical models has been largely demonstrated, the single vitamin D analogs have limited efficacy in cancer therapy; thus, combination therapies with calcitriol and compounds such as glucocorticoids, cytotoxic drugs, inhibitors or retinoids have been widely investigated ( 9 ). Herein, we show that, in addition to the effect per se , calcitriol also acted in a synergistic manner with the antifolate compound PEM, which, in association with cisplatin, is currently the standard first-line treatment for patients with advanced MPM ( 4 ).…”

“…Moreover, calcitriol and its analogs, alone or in combination with anticancer drugs, showed the ability to delay initiation and inhibit tumor progression in vivo , in animal models of cancer ( 5 – 7 ). Clinical trials have been also undertaken in different cancers; however, the responses were modest, likely because the doses of the compounds were too conservative, the studies inappropriately designed and conducted in patients with far-advanced disease ( 5 , 7 – 9 ).…”