S179D Prolactin Sensitizes Human PC3 Prostate Cancer Xenografts to Anti-tumor Effects of Well-Tolerated Doses of Calcitriol

Calcitriol has been shown to have multiple anti-prostate cancer effects both in vitro and in xenograft models, and associations between low levels of calcitriol and more aggressive forms of prostate cancer have been observed clinically. However, the concentrations of calcitriol required to have a substantive anti-cancer effect in vivo are toxic. In previous work, we had observed that the selective prolactin receptor modulator, S179D PRL, sensitized prostate cancer cells in vitro to physiological concentrations of calcitriol through an ability to increase expression of the vitamin D receptor. Here, we have investigated whether administration of S179D PRL would likewise sensitize androgen-insensitive human PC3 xenografts in vivo and do so without inducing tissue damage akin to hypervitaminosis D. Using low concentrations of both S179D PRL (250 ng/h) and calcitriol (up to 220 pg/h), we found no effect of each alone or in combination on the growth rate of tumors. However, there was increased central tumor death with their combination that was more than additive at 250 ng S179D PRL and 220 pg calcitriol per hour. Both S179D PRL and calcitriol alone were antiangiogenic, but their antiangiogenic effects were not additive. Also, both S179D PRL and calcitriol alone increased the number of apoptotic cells in tumor sections, but their combination reduced the number, suggesting more effective clearance of apoptotic cells. Histopathology of the livers and kidneys showed no changes consistent with hypervitaminosis D. We conclude that dual therapy holds promise as a means to harness the anti-tumor effects of well-tolerated doses of calcitriol.