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 Turchi, Kenneth Nephew

Research output: Contribution to journalArticle

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

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DNA Methylation
Ovarian Neoplasms
Cisplatin
Platinum
Tumor Suppressor Genes
Genes
DNA Damage
SGI-110
DNA Adducts
Neoplasm Genes
Heterografts
DNA Repair
Mass Spectrometry
Research Design
Transcription Factors
Cell Line
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

The novel, small-molecule DNA methylation inhibitor SGI-110 as an ovarian cancer chemosensitizer. / 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; Nephew, Kenneth.

In: Clinical Cancer Research, Vol. 20, No. 24, 15.12.2014, p. 6504-6516.

Research output: Contribution to journalArticle

Fang, F, Munck, J, Tang, J, Taverna, P, Wang, Y, Miller, DFB, Pilrose, J, Choy, G, Azab, M, Pawelczak, KS, VanderVere-Carozza, P, Wagner, M, Lyons, J, Matei, D, Turchi, J & Nephew, K 2014, 'The novel, small-molecule DNA methylation inhibitor SGI-110 as an ovarian cancer chemosensitizer', Clinical Cancer Research, vol. 20, no. 24, pp. 6504-6516. https://doi.org/10.1158/1078-0432.CCR-14-1553
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 ; Nephew, Kenneth. / The novel, small-molecule DNA methylation inhibitor SGI-110 as an ovarian cancer chemosensitizer. In: Clinical Cancer Research. 2014 ; Vol. 20, No. 24. pp. 6504-6516.
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AU - Fang, Fang

AU - Munck, Joanne

AU - Tang, Jessica

AU - Taverna, Pietro

AU - Wang, Yinu

AU - Miller, David F B

AU - Pilrose, Jay

AU - Choy, Gavin

AU - Azab, Mohammad

AU - Pawelczak, Katherine S.

AU - VanderVere-Carozza, Pamela

AU - Wagner, Michael

AU - Lyons, John

AU - Matei, Daniela

AU - Turchi, John

AU - Nephew, Kenneth

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N2 - 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.

AB - 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.

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