Abstract 5444: Polyamine-based HAT inhibitors as therapy sensitizers

Histone acetylation plays an important role in regulating chromatin structure and is tightly controlled through the actions of histone acetyltransferases (HAT) and histone deacetylases (HDAC). Deregulation of either HAT or HDAC activity can affect chromatin remodeling needed to carry out its functions and contribute to cancer. While HATs are potential targets for anticancer therapeutics, the development of effective HAT inhibitors has been slow. We have examined the cellular effects of an S-substituted coenzyme A (CoA) inhibitor of histone acetylation, consisting of spermidine (Spd) linked to the S-terminus of CoA through a thioglycolic acid linkage (adduct abbreviated as Spd-CoA), as well as the effects of a truncated Spd-CoA derivative lacking the negatively charged portion of the CoA moiety. While exposure of cancer cells to Spd-CoA has little effect on cell viability, it causes a rapid inhibition of specific acetylated lysines, H3-K9 and H3-K56. That inhibition correlates with a transient arrest of DNA synthesis, a transient delay in S-phase progression, and an inhibition of nucleotide excision repair and DNA double strand break repair. Furthermore, Spd-CoA synergizes with a variety of commonly used DNA damaging chemotherapeutic agents, cisplatin (Platinol TM ) and 5-fluorouracil, camptothecin, as well as UV-C radiation to induce cancer cell killing. This suggests that a common mechanism, relevant to DNA damage, underlies the ability of histone acetylation inhibition to synergize with drugs and radiation. Normal human fibroblasts and epithelial cells are not sensitized to DNA damage by Spd-CoA due to a barrier to uptake, indicating that this differential uptake can be exploited to achieve cancer cell-specific sensitization. Furthermore, therapy sensitization occurs in both p53-null cancer cells and in cancer cells expressing wild-type p53, indicating that p53-mediated apoptosis is not required. The truncated Spd-CoA derivative displays similar but enhanced chemosensitization effects, suggesting that this class of inhibitors may be amenable to further refinement and have considerable clinical potential as a novel class of potent therapy sensitizers applicable to a broad range of conventional cancer treatments, particularly to reduce therapy toxicity and reverse therapy resistance. 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 5444.