Fang, FangMunck, JoanneTang, JessicaTaverna, PietroWang, YinuMiller, David F. B.Pilrose, JayChoy, GavinAzab, MohammadPawelczak, Katherine S.VanderVere-Carozza, PamelaWagner, MichaelLyons, JohnMatei, DanielaTurchi, John J.Nephew, Kenneth P.2017-01-042017-01-042014-12-15Fang, F., Munck, J., Tang, J., Taverna, P., Wang, Y., Miller, D. F. B., … Nephew, K. P. (2014). The novel, small molecule DNA methylation inhibitor SGI-110 as an ovarian cancer chemosensitizer. Clinical Cancer Research : An Official Journal of the American Association for Cancer Research, 20(24), 6504–6516. http://doi.org/10.1158/1078-0432.CCR-14-15531078-0432https://hdl.handle.net/1805/11770PURPOSE: To investigate SGI-110 as a "chemosensitizer" in ovarian cancer and to assess its effects on tumor suppressor genes (TSG) and chemoresponsiveness-associated genes silenced by DNA methylation in ovarian cancer. EXPERIMENTAL DESIGN: Several ovarian cancer cell lines were used for in vitro and in vivo platinum resensitization studies. Changes in DNA methylation and expression levels of TSG and other cancer-related genes in response to SGI-110 were measured by pyrosequencing and RT-PCR. RESULTS: We demonstrate in vitro that SGI-110 resensitized a range of platinum-resistant ovarian cancer cells to cisplatin (CDDP) and induced significant demethylation and reexpression of TSG, differentiation-associated genes, and putative drivers of ovarian cancer cisplatin resistance. In vivo, SGI-110 alone or in combination with CDDP was well tolerated and induced antitumor effects in ovarian cancer xenografts. Pyrosequencing analyses confirmed that SGI-110 caused both global (LINE1) and gene-specific hypomethylation in vivo, including TSGs (RASSF1A), proposed drivers of ovarian cancer cisplatin resistance (MLH1 and ZIC1), differentiation-associated genes (HOXA10 and HOXA11), and transcription factors (STAT5B). Furthermore, DNA damage induced by CDDP in ovarian cancer cells was increased by SGI-110, as measured by inductively coupled plasma-mass spectrometry analysis of DNA adduct formation and repair of cisplatin-induced DNA damage. CONCLUSIONS: These results strongly support further investigation of hypomethylating strategies in platinum-resistant ovarian cancer. Specifically, SGI-110 in combination with conventional and/or targeted therapeutics warrants further development in this setting.en-USPublisher PolicyAzacitidineanalogs & derivativesDNA Methylationdrug effectsDrug Resistance, NeoplasmgeneticsOvarian NeoplasmspathologyArticle