The histone deacetylase inhibitor PXD101 increases the efficacy of irinotecan in in vitro and in vivo colon cancer models
The histone deacetylase inhibitor PXD101 increases the efficacy of irinotecan in in vitro and in vivo colon cancer models
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DOI：
10.1007/s00280-010-1495-6
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发表时间：
2011-08-01
影响因子：
3
通讯作者：
Kim, Tae Won
中科院分区：
文献类型：
--
作者：
Na, Young-Soon;Jung, Kyung-Ah;Kim, Tae Won
组蛋白去乙酰化酶抑制剂（HDACIs），如PXD 101和辛二酰苯胺异羟肟酸，抑制肿瘤细胞的增殖并刺激肿瘤细胞的凋亡。在几种癌症中观察到化疗或放疗与HDACI联合使用时的有效性增强。本研究采用PXD 101和/或伊立替康的活性形式SN-38处理HCT 116和HT 29结肠癌细胞，观察PXD 101联合伊立替康对结肠癌的抗肿瘤作用。评价了用这些组合处理的HCT 116和HT 29异种移植物的抗肿瘤作用。[F-18]FLT-PET用于检测PXD 101和伊立替康在结肠癌中的早期反应。PXD 101和SN 38对HCT 116和HT 29细胞具有剂量依赖性的抗增殖活性，并且当联合使用时产生协同作用。在异种移植小鼠中，PXD 101与伊立替康联合显著抑制肿瘤生长，而不引起附加毒性。联合治疗对异种移植肿瘤的凋亡作用大于伊立替康单药治疗。[F-18]FLT-PET成像显示，在接受PXD 101和伊立替康联合给药的携带HCT 116异种移植物的小鼠的肿瘤中，[F-18]FLT摄取降低64%，表明胸苷激酶1（TK 1）活性降低。这些结果得到了Western印迹分析的支持，显示肿瘤胸苷激酶1蛋白水平的降低，表明[F-18]FLT-PET可用于非侵入性检测对这些药物的早期反应。这些数据表明，PXD 101增加了伊立替康在体外和体内结肠癌模型中的细胞毒活性，并表明这些药物组合应在结肠癌治疗中进行探索。
Histone deacetylase inhibitors (HDACIs), such as PXD101 and suberoylanilide hydroxamic acid, inhibit proliferation and stimulate apoptosis of tumor cells. The enhanced effectiveness of chemotherapy or radiotherapy when combined with HDACIs has been observed in several cancers. In this study, we investigated the antitumor effect of PXD101 combined with irinotecan in colon cancer.HCT116 and HT29 colon cancer cells for cell viability assay were treated with PXD101 and/or SN-38, the active form of irinotecan. Antitumor effects of HCT116 and HT29 xenografts treated with these combinations were evaluated. [F-18]FLT-PET was used to detect early responses to PXD101 and irinotecan in colon cancer.PXD101 and SN38 possessed dose-dependent antiproliferative activity against HCT116 and HT29 cells and exerted a synergistic effect when used in combination. In xenografted mice, PXD101 in combination with irinotecan dramatically inhibited tumor growth without causing additive toxicity. Apoptotic effects on xenograft tumors were greater with combined treatment than with irinotecan alone. [F-18]FLT-PET imaging revealed a 64% decrease in [F-18]FLT uptake in tumors of HCT116 xenograft-bearing mice treated with a combination of PXD101 and irinotecan, indicating a decrease in thymidine kinase 1 (TK1) activity. These results were supported by Western blot analyses showing a decrease in tumor thymidine kinase 1 protein levels, suggesting that [F-18]FLT-PET can be used to non-invasively detect early responses to these agents.These data show that PXD101 increases the cytotoxic activity of irinotecan in in vitro and in vivo colon cancer models and suggest these agent combinations should be explored in the treatment of colon cancer.