The novel, small-molecule DNA methylation inhibitor SGI-110 as an ovarian cancer chemosensitizer

• Published in: Clinical cancer research 2014-12, Vol.20 (24), p.6504-6516
• Main Authors: Fang, Fang, Munck, Joanne, Tang, Jessica, Taverna, Pietro, Wang, Yinu, Miller, David F B, Pilrose, Jay, Choy, Gavin, Azab, Mohammad, Pawelczak, Katherine S, VanderVere-Carozza, Pamela, Wagner, Michael, Lyons, John, Matei, Daniela, Turchi, John J, Nephew, Kenneth P
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacology; Azacitidine - administration & dosage; Azacitidine - analogs & derivatives; Azacitidine - pharmacology; Cell Line, Tumor; Cisplatin - administration & dosage; Cisplatin - pharmacology; Disease Models, Animal; DNA Adducts; DNA Methylation - drug effects; Drug Resistance, Neoplasm - genetics; Epigenesis, Genetic; Female; Gene Expression Regulation, Neoplastic - drug effects; Gene Silencing; Histones - metabolism; Humans; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Tumor Burden - drug effects; Xenograft Model Antitumor Assays
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-14-1553

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. 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. 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. 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.