Abstract 3331: New-generation taxoid SB-T-1214 inhibits stem cell-related gene expression in colon and prostate CSCs
Authors: Botchkina Galina I. , Ju Jingfang , Savitt Anne G. , Rowehl Rebecca A. , Zuniga Edison , Das Manisha , Wang Haichao , Zhu Shu , Ojima Iwao 
Published: February 2011

In vast majority of human cancers, malignant stem cells (CSCs) are responsible for tumor development, maintenance and resistance to drugs. Previously we have shown that colon and prostate CSCs are not only functionally and morphologically different from their bulk counterparts, but themselves may represent heterogeneous phenotypic populations. In contrast to the major (bulk) colon and prostate cancer cells expressing low levels of CD133 and CD44, cells with a high combined expression of these markers, as well as colon cancer cells lacking CD133, possessed several characteristic stem cell features, including high tumor initiating potential, profound self-renewal capacity, and an ability to give rise to different cell phenotypes. The present study was undertaken for two aims: a) to determine stem cell-related genomic characteristics of floating multicellular spheroids induced by candidate phenotypic cell populations; and b) to evaluate CSC-specific alterations induced by new-generation taxoid SB-T-1214 in 3D culture.

Experimental: Selected CSC phenotypes were isolated from highly invasive colon cancer HCT116 cells and prostate cancer PC3MM2 cells. A stem cell-specific PCR array (SABiosciences) revealed that 3D spheroids induced by either colon CD133high/CD44high or CD133neg cells, as well as by CD133high/CD44high prostate cancer cells expressed profound up-regulation of stem cell-related genes compared to their differentiated counterparts (68%, 56% and 61%, correspondently). The FACS analysis has shown that both colon and prostate spheroids contained minority cell populations with high levels of expression of Oct4, Sox2, c-Myc and Nanog, which are essential for stem cell pluripotency and self-renewal. Single administration of the SB-T-1214 at concentration 0.01-0.1 μg/ml for 48 hr not only induced growth inhibition and apoptotic cell death in these two types of cancer spheroids in 3D culture, but also mediated massive inhibition of the stem cell-related genes and significant down-regulation of the pluripotency gene expression. PCR array and FACS data were confirmed with western blotting. Importantly, viable cells that survived this treatment regimen were no longer able to induce secondary floating spheroids and exhibited significant morphological abnormalities.

Summay: We report here that a new-generation taxoid SB-T-1214 possesses significant activity against colon and prostate cancer spheroids induced by and enriched with drug resistant tumorigenic cell populations and efficiently inhibited expression of the majority of stem cell-related genes.

Conclusion: Our data indicates that the long-term efficacy of the SB-T-1214 against several drug resistant tumors in vivo may be explained by down-regulation of multiple stem cell-related genes in the tumorigenic cell population, in addition to its known efficacy as a mitotic poison against proliferating cancer cells.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3331.