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
Medical Sciences, Indiana University School of Medicine, Bloomington, Indiana.
Astex Pharmaceuticals Inc., Dublin, California.
Clin Cancer Res. 2014 Dec 15;20(24):6504-16. doi: 10.1158/1078-0432.CCR-14-1553. Epub 2014 Oct 14.
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.
研究SGI-110作为卵巢癌“化学增敏剂”的作用，并评估其对卵巢癌中因DNA甲基化而沉默的肿瘤抑制基因（TSG）和化疗反应相关基因的影响。
使用多种卵巢癌细胞系进行体外和体内铂再敏化研究。通过焦磷酸测序和逆转录聚合酶链反应（RT-PCR）测量SGI-110作用下DNA甲基化以及TSG和其他癌症相关基因表达水平的变化。
我们在体外证明，SGI-110使一系列铂耐药卵巢癌细胞对顺铂（CDDP）重新敏感，并诱导TSG、分化相关基因以及卵巢癌顺铂耐药假定驱动基因的显著去甲基化和重新表达。在体内，单独使用SGI-110或与CDDP联合使用耐受性良好，并在卵巢癌异种移植模型中诱导抗肿瘤作用。焦磷酸测序分析证实，SGI-110在体内引起整体（LINE1）和基因特异性低甲基化，包括TSG（RASSF1A）、卵巢癌顺铂耐药的假定驱动基因（MLH1和ZIC1）、分化相关基因（HOXA10和HOXA11）以及转录因子（STAT5B）。此外，通过电感耦合等离子体质谱分析DNA加合物形成和顺铂诱导的DNA损伤修复来测量，SGI-110增加了CDDP在卵巢癌细胞中诱导的DNA损伤。
这些结果有力地支持了对铂耐药卵巢癌低甲基化策略的进一步研究。具体而言，SGI-110与传统和/或靶向治疗联合在这种情况下值得进一步开发。
