Disulfiram’s Antineoplastic Effects on Ovarian CancerReport as inadecuate




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Objective: Aldehyde dehydrogenase ALDH enzymatic activity identifiesovarian cancer stem-like cells. We investigated the antineoplastic activity ofthe ALDH inhibitor Disulfiram on bulk ovarian cancer cells and CD133+-ALDH+ cancer stem-like cells. Study Design: Ovarian cancer cell lines, human ovariansurface epithelial cells, and mesenchymal stem cells were treated withincreasing concentrations of Disulfiram and-or Cisplatin in vitro. Treated cells were assessed for viability or FACS-analyzedfor either percentage of ovarian cancer stem-like cells or induction ofapoptosis. Disulfiram’s impact on cancer stem-like cells was tested in vitro using tumor sphere formation assaysand in vivo using tumor initiationassays with in vitro-treated A2780cells in NSG mice. Finally, Disulfiram’s invivo activity was assessed versus CD133+-ALDH+ cell-initiated tumor xenografts. Results: Disulfiram demonstratedantineoplastic activity against multiple ovarian cancer cell lines. WhileDisulfiram had limited in vitro toxicity against human ovarian surface epithelial cells or mesenchymal stemcells IC50 of ~15 μM and >30 μM, respectively, its antineoplastic activityagainst cell lines was comparable to Cisplatin IC50 ~1.5 μM.Disulfiram-mediated cell death was due, at least in part, to induction ofapoptosis. Disulfiram activity was additive with chemotherapy. Disulfiramdemonstrated selective depletion of CD44+ cells but not the CD133+ cancer stem-like cells. Disulfiram had no therapeutic impact on tumorinitiation studies or in vivo therapyof whole cell line or stem cell-initiated tumor xenografts. Conclusions: Inbiologically relevant concentrations, Disulfiram has clear antineoplasticactivity against ovarian cancer cells invitro. Disulfiram selectively depleted CD44+ but not CD133+ ovarian cancer stem-like cells in vitro.However, Disulfiram had no significant activity in vivo. Thus, improved and more selective ALDH inhibitors may berequired to target ovarian cancer stem cells.

KEYWORDS

Antineoplastic, ALDH, Disulfiram, NSG Mice, Ovarian Cancer Stem Cells

Cite this paper

Rezk, Y. , Yang, K. , Bai, S. , Mclean, K. , Johnston, C. , Reynolds, R. and Buckanovich, R. 2015 Disulfiram’s Antineoplastic Effects on Ovarian Cancer. Journal of Cancer Therapy, 6, 1196-1205. doi: 10.4236-jct.2015.614130.





Author: Youssef A. Rezk1, Kun Yang2, Shoumei Bai2, Karen Mclean1, Carolyn Johnston1, R. Kevin Reynolds1, Ronald J. Buckanovich1,2*

Source: http://www.scirp.org/



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