title: Use of 1,25α dihydroxyvitamin D3 as a cryosensitizing agent in a murine prostate cancer model.
abstract: 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.
authors.affiliation: Department of Biological Sciences, Institute of Biomedical Technology, State University of New York, Binghamton, NY 13902, USA.
authors.forename: K L
authors.initials: KL
authors.lastname: Santucci
authors.forename: K K
authors.initials: KK
authors.lastname: Snyder
authors.forename: J M
authors.initials: JM
authors.lastname: Baust
authors.forename: R G
authors.initials: RG
authors.lastname: Van Buskirk
authors.forename: V
authors.initials: V
authors.lastname: Mouraviev
authors.forename: T J
authors.initials: TJ
authors.lastname: Polascik
authors.forename: A A
authors.initials: AA
authors.lastname: Gage
authors.forename: J G
authors.initials: JG
authors.lastname: Baust
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002117:Calcitriol / Q000627:therapeutic use*; D016923:Cell Death / Q000187:drug effects; D017024:Chemotherapy, Adjuvant / Q000379:methods; D003131:Combined Modality Therapy / Q000379:methods; D017679:Cryotherapy / Q000379:methods*; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D051379:Mice; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D002117:Calcitriol