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

Fang Fang, Joanne Munck, Jessica Tang, Pietro Taverna, Yinu Wang, David F.B. Miller, Jay Pilrose, Gavin Choy, Mohammad Azab, Katherine S. Pawelczak, Pamela VanderVere-Carozza, Michael Wagner, John Lyons, Daniela Matei, John J. Turchi, Kenneth P. Nephew

Research output: Contribution to journalArticle

58 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)6504-6516
Number of pages13
JournalClinical Cancer Research
Volume20
Issue number24
DOIs
StatePublished - Dec 15 2014

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Fang, F., Munck, J., Tang, J., Taverna, P., Wang, Y., Miller, D. F. B., Pilrose, J., Choy, G., Azab, M., Pawelczak, K. S., VanderVere-Carozza, P., Wagner, M., Lyons, J., Matei, D., Turchi, J. J., & Nephew, K. P. (2014). The novel, small-molecule DNA methylation inhibitor SGI-110 as an ovarian cancer chemosensitizer. Clinical Cancer Research, 20(24), 6504-6516. https://doi.org/10.1158/1078-0432.CCR-14-1553