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

doi:10.1158/1078-0432.CCR-14-1553

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

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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 language	English (US)
Pages (from-to)	6504-6516
Number of pages	13
Journal	Clinical Cancer Research
Volume	20
Issue number	24
DOIs	https://doi.org/10.1158/1078-0432.CCR-14-1553
State	Published - Dec 15 2014

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General Medicine

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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

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, JJ & Nephew, KP 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

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

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.",

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

note = "Publisher Copyright: {\textcopyright} 2014 AACR.",

year = "2014",

month = dec,

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doi = "10.1158/1078-0432.CCR-14-1553",

language = "English (US)",

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pages = "6504--6516",

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T1 - The novel, small-molecule DNA methylation inhibitor SGI-110 as an ovarian cancer chemosensitizer

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 J.

AU - Nephew, Kenneth P.

PY - 2014/12/15

Y1 - 2014/12/15

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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DO - 10.1158/1078-0432.CCR-14-1553

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AN - SCOPUS:84919769943

SN - 1078-0432

VL - 20

SP - 6504

EP - 6516

JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 24

ER -

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

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