Hypomethylating agents synergize with irinotecan to improve response to chemotherapy in colorectal cancer cells.
Hypomethylating agents synergize with irinotecan to improve response to chemotherapy in colorectal cancer cells.
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DOI：
10.1371/journal.pone.0176139
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Ahuja N
中科院分区：
文献类型：
--
作者：
Sharma A;Vatapalli R;Abdelfatah E;Wyatt McMahon K;Kerner Z;A Guzzetta A;Singh J;Zahnow C;B Baylin S;Yerram S;Hu Y;Azad N;Ahuja N
结直肠癌(CRC)是美国癌症死亡的第二大原因。在转移的环境中，大多数患者对最初的治疗有反应，但最终产生耐药性并取得进展。在这项研究中，我们测试了这样一种假设，即用表观遗传疗法启动会使先前对后续化疗药物耐药的CRC细胞系变得敏感。当多个CRC细胞系首次暴露于500 NM的DNA去甲基化试剂5-氮杂胞苷(AZA)体外，然后在未经处理的NOD-SCID小鼠中建立体内异种移植瘤；在CRC治疗中常用的药物对细胞毒性化疗有增强的反应。对于伊立替康(IRI)，通过增殖(IC50)和锚定非依赖细胞生长软琼脂试验评估，生长减少了16-62倍。对于耐药的HCT116细胞株和体内的结直肠癌移植瘤，AZA联合IRI再次显示出这种协同效应，显著改善了小鼠的生存和肿瘤消退。全基因组表达将细胞黏附和DNA修复途径的变化与上述反应相关联。测试这一概念的1/2阶段临床试验已经在进行中，测试这一概念在耐IRI、转移性结直肠癌(NCT01896856)中的临床疗效。
Colorectal cancer (CRC) is the second leading cause of cancer death in the United States. In the metastatic setting, the majority of patients respond to initial therapies but eventually develop resistance and progress. In this study, we test the hypothesis that priming with epigenetic therapy sensitizes CRC cell lines, which were previously resistant to subsequent chemotherapeutic agents. When multiple CRC cell lines are first exposed to 500 nM of the DNA demethylating agent, 5-aza-cytidine (AZA) in-vitro, and the cells then established as in-vivo xenografts in untreated NOD-SCID mice; there is an enhanced response to cytotoxic chemotherapy with agents commonly used in CRC treatment. For irinotecan (IRI), growth diminished by 16–62 fold as assessed, by both proliferation (IC50) and anchorage independent cell growth soft agar assays. Treatment of resistant HCT116 cell line along with in-vivo, for CRC line xenografts, AZA plus IRI again exhibits this synergistic response with significant improvement in survival and tumor regression in the mice. Genome-wide expression correlates changes in pathways for cell adhesion and DNA repair with the above responses. A Phase 1/2 clinical trial testing this concept is already underway testing the clinical efficacy of this concept in IRI resistant, metastatic CRC (NCT01896856).