Cryotherapy has emerged as a primary treatment option for prostate cancer (CaP); however, incomplete ablation in the periphery of the cryogenic lesion can lead to recurrence. Accordingly, we investigated the use of a non-toxic adjunctive agent, vitamin D3 (VD3), with cryotherapy to sensitize CaP to low temperature-induced, non-ice rupture-related cell death. VD3 (calcitriol) has been identified as a possible adjunct in the treatment of cancer because of its antiproliferative and antitumorigenic properties. This study aimed to identify the cellular responses and molecular pathways activated when VD3 (calcitriol) is combined with cryotherapy in a murine CaP model. Single freeze–thaw events above −15 °C had little effect on cancer cell viability; however, pretreatment with calcitriol in conjunction with cryo significantly increased cell death. The −15 °C calcitriol combination increased cell death to 55% following a single freeze compared with negligible cell loss by freezing or calcitriol alone. Repeated cryo combination yielded 90% cell death compared with 65% in dual freeze-only cycles. Western blot analysis following calcitriol cryosensitization regimes confirmed the activation of apoptosis. Specifically, proapoptotic Bid and procaspase-3 were found to decrease at 1 h following combination treatment, indicating cleavage to the active forms. A parallel in vivo study confirmed the increased cell death when combining cryotherapy with calcitriol pretreatment. The development of an adjunctive therapy combining calcitriol and cryotherapy represents a potentially highly effective, less toxic, minimally invasive treatment option. These results suggest a role for calcitriol and cryo as a combinatorial treatment for CaP, with the potential for clinical translation.
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The authors would like to acknowledge that this work has been partially funded by the CPSI Biotech and the National Institutes of Health, grant numbers R43CA1123993-01A1 and R43CA118537-01A1.
In the spirit of full disclosure, the authors declare that Dr KL Santucci receives compensation as a consultant for CPSI Biotech; Dr KK Snyder, Dr JM Baust and Dr RG Van Buskirk are employed by CPSI Biotech; Dr JG Baust, Dr V Mouraviev, Dr TJ Polascik and Dr AA Gage declare no conflict of interest.
This work is an original research article and has not been previously published or submitted for publication elsewhere.
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Santucci, K., Snyder, K., Baust, J. et al. Use of 1,25α dihydroxyvitamin D3 as a cryosensitizing agent in a murine prostate cancer model. Prostate Cancer Prostatic Dis 14, 97–104 (2011). https://doi.org/10.1038/pcan.2010.52
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