Prostate cancer stem cell-targeted efficacy of a new-generation taxoid, SBT-1214 and novel polyenolic zinc-binding curcuminoid, CMC2.24

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...

Full description

Saved in:

Bibliographic Details
Published in:	PloS one Vol. 8; no. 9; p. e69884
Main Authors:	Botchkina, Galina I, Zuniga, Edison S, Rowehl, Rebecca H, Park, Rosa, Bhalla, Rahuldev, Bialkowska, Agnieszka B, Johnson, Francis, Golub, Lorne M, Zhang, Yu, Ojima, Iwao, Shroyer, Kenneth R
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 24-09-2013 Public Library of Science (PLoS)
Subjects:	Abnormalities Androgens Animals Antineoplastic Agents - pharmacology Apoptosis Binding Biology Cancer Cancer metastasis Cancer therapies CD44 antigen Cell cycle Cell death Cell Line, Tumor Cell proliferation Chemistry Chromosomes Collagen Collagen (type I) Combination drug therapy Curcumin - analogs & derivatives Curcumin - pharmacology Cyclin-dependent kinase inhibitor p21 Cytotoxicity Development and progression Drug development Drug resistance Drugs Gene amplification Gene expression Gene Expression Profiling Genes Health aspects Humans Male Metastases Mice Mice, Inbred NOD Mice, SCID Neoplastic Stem Cells - drug effects Neoplastic Stem Cells - metabolism p53 Protein Paclitaxel Pathology Phytochemicals Pluripotency Prostate cancer Prostatic Neoplasms - genetics Prostatic Neoplasms - pathology Spheroids Stem cell transplantation Stem cells Taxoids - pharmacology Transcription factors Tumor proteins Tumors Urology Xenograft Model Antitumor Assays Zinc New York United States > US
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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 CSC-specific alterations induced by new-generation taxoid SBT-1214 and a novel polyenolic zinc-binding curcuminoid, CMC2.24, in prostate CSCs. The CD133(high)/CD44(high) phenotype was isolated from spontaneously immortalized patient-derived PPT2 cells and highly metastatic PC3MM2 cells. Weekly treatment of the NOD/SCID mice bearing PPT2- and 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 (100 nM-1 µM; for 72 hr) induced about 60% cell death in CD133(high)/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 CD133(high)/CD44(high) 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. We report here that the SBT-1214 alone, or in combination with CMC2.24, possesses significant activity against prostate CD133(high)/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.
Bibliography:	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. Conceived and designed the experiments: ESZ RP RHR RB ABB FJ LMG YZ KRS IO GIB. Performed the experiments: ESZ RHR ABB YZ KRS GIB. Analyzed the data: ESZ RP RHR RB ABB FJ LMG YZ KRS IO GIB. Contributed reagents/materials/analysis tools: RP RP RB ABB FJ LMG YZ KRS IO GIB. Wrote the manuscript: GIB.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0069884