Vitamin D for the prevention and treatment of pancreatic cancer

Abstract

Pancreatic cancer is ranked fifth among cancer-related deaths worldwide with a 5-year survival rate of less than 5%. Currently, surgery is the only effective therapy. However, most patients are diagnosed in the late stage and are not suitable for receiving curative surgery. Moreover, pancreatic cancer doesn't respond well to traditional chemotherapy and radiotherapy, leaving little effective treatment for advanced pancreatic cancer cases. 1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)], the biologically active form of vitamin D(3), was originally identified during studies of calcium and bone metabolism, though it is now recognized that it exerts biological effects in almost every tissue in the body. Abundant evidence has shown that 1alpha,25(OH)(2)D(3) has antiproliferative, apoptotic, pro-differentiation and antiangiogensis effects in many types of cancer cells in vivo and in vitro, including breast, prostate, and colon. Similarly, the antitumor growth effect of 1alpha,25(OH)(2)D(3) on pancreatic cells has been demonstrated. The clinical use of 1alpha,25(OH)(2)D(3) is impeded by the lethal side effects of hypercalcemia and hypercalciuria. Therefore, 1alpha,25(OH)(2)D(3) analogs, which are either equipotent or more potent than 1alpha,25(OH)(2)D(3) in inhibiting tumor cell growth but with fewer hypercalcemic and hypercalciuric side effects, have been developed for the treatment of different cancers. Recently, a pre-clinical study demonstrated that a less calcemic analog of 1alpha,25(OH)(2)D(3), 19-nor-1alpha,25(OH)(2)D(2) (Paricalcitol), is effective in inhibiting tumor growth in vitro and in vivo, via upregulation of p21 and p27 tumor suppressor genes. Studies on the anti-tumor effects of a more potent analog of Paricalcitol are underway. 1alpha,25(OH)(2)D(3) and its analogs are potentially attractive novel therapies for pancreatic cancer.

Figure 1

Mechanisms of Vitamin D₃ action on pancreas cells. Both 1,25(OH)₂D₃ and 25(OH)D₃ can enter pancreas cells, where 25(OH)D₃ can be converted to 1,25(OH)₂D₃ by 1α-OHase. 1,25(OH)₂D₃ can bind the VDR and further combine with the retinoid X receptor (RXR) to form a heterodimer, VDR-RXR. The VDR-RXR heterodimer binds to specific vitamin D response elements located in the promoter region of vitamin D-responsive genes, which in turn induces gene transcription. So far, in terms of pancreas cells, inhibition of CDK2, CDK4, Cyclin D1, Cyclin E, Cyclin A and upregulation of p21 and p27 have been demonstrated, leading to a block in the cell cycle at G0/G1. Regarding induction of differentiation, apoptosis and other anticancer mechanisms, further studies are required.