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

F Fang, J Munck, J Tang, P Taverna, Y Wang… - Clinical cancer …, 2014 - AACR
F Fang, J Munck, J Tang, P Taverna, Y Wang, DFB Miller, J Pilrose, G Choy, M Azab…
Clinical cancer research, 2014AACR
Purpose: 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 …
Abstract
Purpose: 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. Clin Cancer Res; 20(24); 6504–16. ©2014 AACR.
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