Nutritional factors have been hypothesized to be critical in the development of numerous cancers, and this holds true for prostate cancer. On the basis of geographic patterns of ultraviolet radiation throughout the contiguous United States, and on epidemiological data on prostate cancer incidence, the hypothesis was raised by Schwartz and colleagues that vitamin D deficiency may be a prostate cancer risk factor, and that increased exposure to sunlight may protect against clinical prostate cancer. In vitro studies have shown that treatment with 1α, 25(OH)2D3 (1,25-VD), a active form of vitamin D, decreases proliferation and increases differentiation of prostate cancer cells. Prostate cancer cells contain a specific receptor for 1,25-VD (the vitamin D receptor, VDR) that is known to mediate inhibition of proliferation, tumor invasiveness, the induction of apoptosis, and differentiation of prostate cancer cells. In this chapter, we will summarize recent progress in the study of vitamin D in prostate cancer, including epidemiological analyses, the vitamin D anti-tumor mechanisms, and vitamin D-based treatment in clinical trials. Understanding how vitamin D acts in the prostate is of great importance for the continued advancement of prostate cancer therapy and prevention.
Development of New Vitamin D Analogs and Their Use in Combination Therapy for Prostate Cancer
The beneficial effects of 1,25-VD against cancer cell proliferation have been supported by many in vitro studies, yet the therapeutic window of 1,25-VD usefulness is extremely narrow and effective doses cannot be administered without inducing hypercalcemia. The increase in calcium is achieved both by enhanced intestinal absorption and by liberation of calcium from the bone, eventually leading to decreased bone mass at higher doses. Therefore, much effort has been directed toward the identification of new analogs, which retain the favorable activities of 1,25-VD while avoiding the side effects. Several synthetic vitamin D analogs have been reported to exert promising anti-cancer effects with reduced hypercalcemia. Skowronski et al. showed that selected vitamin D analogs displayed reduced calcemic effects and that potency was even greater than 1,25-VD. Among those vitamin D analogs, one of the most promising synthetic analogs is Seocalcitol (EB1089, Leo Pharmaceutical Products). A considerable number of in vitro studies have been carried out with EB1089 and show that the analog is more potent than 1,25-VD with respect to regulation of cancer cell growth and differentiation, and the effect of EB1089 on calcium metabolism in vivo is approximately 50% less than that of 1,25-VD. The anti-cancer effects of EB1089 without induction of hypercalcemia were also demonstrated in vivo in a rat model of mammary gland carcinoma. Similar effects were seen in an in vivo prostate cancer study where EB1089 inhibited prostate cancer cell proliferation and reduced tumorigenesis as well as tumor metastases. Several other vitamin D analogs or structural VDR activators, such as Maxacalcitol (OCT) (Chugai Pharmaceutical Co. Ltd.), 16-ene analogs (Hoffmann LaRoche, Inc.), 19-nor analogs (Hoffmann LaRoche, Inc.), 1α-hydroxyvitamin D5. LG190119 (Ligand Pharmaceuticals Inc.), and 1α-hydroxyvitamin D2 have been developed and tested in clinical trials in the advanced prostate cancer patients. These compounds may have promise as therapeutic agents for cancer and other diseases, with fewer side effects than 1,25-VD.
Another strategy to preserve vitamin D anti-tumor effects while avoiding the side effects is vitamin D-based combination therapy in which other agents that either promote vitamin D responsiveness or reduce the hypercalcemia are used. The regimens used for vitamin D combination therapy include the chemotherapy drug (Paclitaxel, Taxotere), anti-mitotic agents (Genistein), differentiation agents (retinoic acid), and the agents that modulate vitamin D/VDR action (Dexamethasone). All regimens were shown to potentiate the anti-tumor effects of vitamin D and reduce vitamin-D associated hypercalcemia in prostate cancer cells and animal models, yet detailed mechanisms are not yet known and more clinical trials need to be done.
Vitamin D-Based Clinical Trials
Evidence accumulated from both experimental and epidemiological studies supports the idea that vitamin D could be used as a therapeutic drug to control prostate cancer, and several vitamin D-based clinical trials have been conducted, mainly enlisting patients with advanced androgen-independent prostate cancer (AIPC). Pilot studies from small numbers of patients that took daily orally doses of calcitriol found that the PSA levels in those patients were significantly lower before calcitriol therapy. However, there is incidence of hypercalciuria or hypercalcemia, and the development of renal stones in some patients, which limits its clinical usefulness. One Phase I clinical trial was conducted by injection of calcitriol subcutaneously every other day in the advanced malignancy patients and tested the tolerable toxicity via this route. Then, different calcitriol-based clinical trials, with either modifications in the schedules and route of administration, or combinations with dexamethasone, paclitaxel have been developed. In addition to the calcitriol, its analogs such as 1α-hydroxyvitamin D2 have been tested in clinical trial Phase I and II in the AIPC patients. The results from all these clinical trials suggest further clinical investigation of this disease with vitamin D, its analogs, or in combination with other agents, such as chemotherapy, should be further pursued.
In the past, chemotherapy was considered ineffective, however, newer chemotherapeutic drugs and drug combinations are now demonstrating improved response rates. Among those chemotherapy drugs, taxotere, a semisynthetic taxane, is commonly used as a chemotherapeutic agent by itself and in combination regimens in the treatment of hormone refractory prostate cancer (HRPC). 1,25-VD has been shown to sensitize prostate cancer cells to cytotoxic drugs, such as paclitaxel, platinum compounds, and Taxotere. The Phase II clinical trial of Taxotere® plus calcitriol has shown approximately twice the PSA decline response rate compared with taxotere alone, which provide very promising strategies for treatment of AIPC. Quality of life (QOL) and pain relief were also checked during the calcitriol and taxotere combination therapy. Significant analgesic activity was demonstrated, yet worsening in several QOL parameters was also observed in patients experiencing relatively low pain intensity
Loss of Vitamin D Anti-proliferative Responsiveness in Prostate Cancer
While current efforts focus on developing strategies to use vitamin D analogs to control prostate cancer, it is possible that prostate cancer cells could become resistant to the tumor suppressive effects of vitamin D. Some prostate cancer cells are already known to be resistant to growth inhibition by vitamin D. Analyses of experimental model systems reveal that prostate cancer cells become less sensitive to vitamin D through loss of vitamin D receptors, loss of signaling molecules that modulate vitamin D action, or through changes in metabolic enzymes, such as la-hydroxylase and 24-hydroxylase, that sensitize or degrade vitamin D compounds. Such changes have been found in experimental models, yet whether these alterations occur in human prostate cancer tissues in vivo, and the associated frequencies of occurrences still need to be determined. One study suggested that VDR levels were decreased in the prostate after age 60, which might be linked with increased incidence of prostate cancer with age, and development of vitamin D resistance during the disease progression.
In one of our current studies, we identified a prostate cancer cell subline, CWR22R-2, which displays more aggressive behavior in the tumor invasiveness than its parental CWR22R cells. This aggressive CWR22R-2 line displays reduced vitamin D anti-proliferative effects compared to CWR22R cells, which provides evidence that prostate cancer cells might develop resistance to vitamin D during disease progression. Further characterization of these two cell lines found reduced vitamin D transcriptional activity in CWR22R-2 cells, which might correlate with higher expression of VDR co-repressors such as SMRT and NCoR, and eventually result in reduced vitamin D responsiveness. More evidence from other prostate cancer cell lines with different vitamin D responses and from prostate cancer patient samples is needed to confirm our findings.
Selections from the book: “Prostate Cancer: Basic Mechanisms and Therapeutic Approaches”. Edited by Chawnshang Chang. 2005.