Abstract 4721: Adaptation to histone deacetylase inhibitors attenuates cancer cell growth

Abstract

Abstract Histone deacetylase (HDAC) inhibitors, such as SAHA (suberoylanilude hydroxamic acid) inhibit the growth of multiple cancer cell lines in vitro, and human tumor xenografts in vivo. SAHA has recently been approved for the treatment of human T cell lymphomas and is in clinical trials for a number of other different malignancies. HDAC inhibitors lead to increased acetylation of multiple cellular proteins, including histones, and lead to major changes in cellular gene expression, however the precise mechanisms of their therapeutic effects are not known. HDAC inhibitors have been reported to have multiple effects on different cancer cell lines, ranging from induction of differentiation to induction of apoptosis, DNA damage, senescence, and autophagy. We hypothesized that chronic treatment of malignant cells with HDAC inhibitors, through changes in the program of cancer cell gene expression, would induce differentiation and senescence, and attenuate the malignant phenotype. We have treated a subclone of the SW480 colon cancer cells (S3 cells) with step-wise increasing amounts of SAHA. Chronic treatment with SAHA resulted in adaptation of S3 cells to SAHA, associated with marked decrease in cell growth and tumorigenicity in nude mice. In addition to slow growth, SAHA-adapted SW480 cells (designated SH80), exhibit features of differentiation including gland formation and increased intestinal alkaline phosphatase production (IAP), and increased cell size, associated with multiple nuclei and polyploidy. Interestingly, decreased growth rate and increased expression of alkaline phosphatase were seen even following drug withdrawal, suggesting that drug-adaptation resulted in a relatively stable phenotype. Frequent expression of senescence-associated β-galactosidase was observed in SH80 cells, particularly in giant cells and cell clusters, suggesting on-going senescence. Increased expression of p21 RNA and protein, previously suggested to contribute to the growth inhibition effect of HDAC inhibitors, was observed in the SH80 cells. SH80 cells also exhibited changes in the expression of several microRNAs previously implicated in oncogenesis, suggesting that altered expression of these miRs might contribute to the attenuated malignant phenotype in SH80 cells. These data suggest adaptation of colon cancer cells to HDAC inhibitor therapy may attenuate key aspects of the malignant phenotype, and offer a new therapeutic approach to the long-term control of cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4721. doi:1538-7445.AM2012-4721