We studied the interactions between gum Arabic and select catecholic compounds like caffeic acid, chlorogenic acid and catechol. We observed that GA is capable of promoting the auto-oxidation of the above-mentioned compounds into darkly colored pigments without the addition of redox-sensitive cations. Gum Arabic appeared to be unique among polysaccharide-based materials as many other types of polysaccharides promote the oxidation of the above-mentioned compounds only in the presence of redox cations like Fe 2+ or Cu 2+. RP-HPLC and SEC chromatographic techniques were employed to monitor the reactions and to observe the formation of high molecular mass, pigmented materials from gum Arabic and all three catecholic compounds. FT-IR spectroscopic analysis revealed that, despite their darkly colored appearances, the gum Arabic/pigment materials synthesized contain mostly gum Arabic and very little pigment. As chlorogenic acid is an ester of caffeic acid, we studied the capacity of gum Arabic to promote ester hydrolysis using acetylsalicylic acid as the model compound. We observed that gum Arabic did promote the hydrolysis of acetylsalicylic acid into salicylic acid. However, in all our experiments involving the pigment formation between gum Arabic and chlorogenic acid, we did not observe any evidence that chlorogenic acid was hydrolyzed leading to the release of caffeic acid during these reactions. In addition, we observed that heat treatment of gum Arabic did not affect its pro-oxidizing capability, but it did negatively affect its capability to hydrolyze salicylic acid. Thus, these two types of chemical reactivity present in the gum Arabic material may be associated with different components of the gum Arabic material.

Ovarian cancer is the deadliest gynecologic malignancy. Current options for treating platinum-resistant disease are limited by drug choices and toxicities. Epigenetic therapy is emerging as a strategy for reversing tumor resistance and a recent encouraging clinical trial in platinum-resistant ovarian cancer suggests a potential unique application in ovarian cancer. The epigenetic drugs histone deacetylase inhibitors (HDACi) and DNA methyltransferase inhibitors (DNMTi) cause chromatin relaxation and multiple anti-tumor effects on cell growth, cell cycle, cell death and deregulation of DNA damage response and repair (DDR) pathways. Among HDACi we have tested in a panel of ovarian cancer cells, the depsipeptide FK228 exerts the most potent growth inhibitory effects in the majority of cells. Therefore, we aimed to determine whether the combination of FK228 and the DNMTi 5-azacytadine (AZA) can re-sensitize ovarian cancer cells to cisplatin more effectively than either agent alone. We found that FK228 synergized with low doses of the DNMTi 5-azacytadine (AZA) in SRB cell growth assays in vitro, and that low dose combinations of the drugs enhanced the growth inhibitory effects of cisplatin. Similar effects were observed when ovarian cancer cells were grown as xenografts in immunocompromised mice in vivo. Furthermore, a key DDR sensor, phosphorylated gamma-H2AX (pH2AX) activation was associated with the enhanced cytotoxic effects of the combination of the epigenetics and may be a marker of response. In conclusion, we have identified a novel combination of epigenetic drugs that can re-sensitize ovarian cancer cells to cisplatin treatment, at least in part through stimulation of pH2AX. Targeting DDR pathways in DDR-deficient ovarian cancer cells with low dose epigenetic drugs represents a promising strategy in ovarian cancer treatment. Citation Format: Andrew Wilson, Lanzi Sinaise, Jade M. Readus, Michelle Park, Anum S. Lalani, Jeanette Saskowski, Dineo Khabele. Combination low dose 5-azacytidine (AZA) and romidepsin (FK228) therapy re-sensitizes ovarian cancer cells to cisplatin. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1016. doi:10.1158/1538-7445.AM2013-1016