Fall 9-24-2013 Prostate Cancer Stem Cell-Targeted Efficacy of a New-Generation Taxoid , SBT-1214 and Novel Polyenolic Zinc-Binding Curcuminoid , CMC 2 . 24

Background: Prostate cancer is the second leading cause of cancer death among men. Multiple evidence suggests that a population of tumor-initiating, or cancer stem cells (CSCs) is responsible for cancer development and exceptional drug resistance, representing a highly important therapeutic target. The present study evaluated CSCspecific alterations induced by new-generation taxoid SBT-1214 and a novel polyenolic zinc-binding curcuminoid, CMC2.24, in prostate CSCs. Principal Findings: The CD133high/CD44high phenotype was isolated from spontaneously immortalized patientderived PPT2 cells and highly metastatic PC3MM2 cells. Weekly treatment of the NOD/SCID mice bearing PPT2and PC3MM3-induced tumors with the SBT-1214 led to dramatic suppression of tumor growth. Four of six PPT2 and 3 of 6 PC3MM2 tumors have shown the absence of viable cells in residual tumors. In vitro, SBT-1214 (100nM-1μM; for 72 hr) induced about 60% cell death in CD133high/CD44+/high cells cultured on collagen I in stem cell medium (in contrast, the same doses of paclitaxel increased proliferation of these cells). The cytotoxic effects were increased when SBT-1214 was combined with the CMC2.24. A stem cell-specific PCR array assay revealed that this drug combination mediated massive inhibition of multiple constitutively up-regulated stem cell-related genes, including key pluripotency transcription factors. Importantly, this drug combination induced expression of p21 and p53, which were absent in CD133high/CD44high cells. Viable cells that survived this treatment regimen were no longer able to induce secondary spheroids, exhibited significant morphological abnormalities and died in 2-5 days. Conclusions: We report here that the SBT-1214 alone, or in combination with CMC2.24, possesses significant activity against prostate CD133high/CD44+/high tumor-initiating cells. This drug combination efficiently inhibits expression of the majority of stem cell-related genes and pluripotency transcription factors. In addition, it induces a previously absent expression of p21 and p53 (“gene wake-up”), which can potentially reverse drug resistance by increasing sensitivity to anti-cancer drugs. Citation: Botchkina GI, Zuniga ES, Rowehl RH, Park R, Bhalla R, et al. (2013) Prostate Cancer Stem Cell-Targeted Efficacy of a New-Generation Taxoid, SBT-1214 and Novel Polyenolic Zinc-Binding Curcuminoid, CMC2.24. PLoS ONE 8(9): e69884. doi:10.1371/journal.pone.0069884 Editor: Dean G. Tang, The University of Texas M.D Anderson Cancer Center, United States of America Received May 1, 2013; Accepted June 13, 2013; Published September 24, 2013 Copyright: © 2013 Zuniga et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by NIH R21 CA150085, NYSTAR grant 1072170, and in part, by the Stony Brook University Institute of Chemical Biology & Drug Discovery (ICB&DD); Stony Brook University Cancer Center, NY; ChemMaster International, NY and SBU VP for Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: The role of ChemMaster International, Inc., as the inventor of CMC2.24 was to synthesize and provide, in kind, the material for the current study. This company is a semi-academic entity (President, Francis Johnson, PhD, is Professor of the Department of Chemistry and Department of Pharmacological Sciences at SBU) that specializes in multistep syntheses for academic and industrial groups. This company didn’t provide any support relating to employment, consultancy, patents, or products in development or marketed ones. The authors confirm that providing current research with CMC2.24 does not alter their adherence to all the PLOS ONE policies on sharing data and materials. The authors do not have any potential financial or non-financial, professional, or personal competing interests. * E-mail: gbotchkina@stonybrookmedicine.edu PLOS ONE | www.plosone.org 1 September 2013 | Volume 8 | Issue 9 | e69884