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姜黄素通过抑制表皮生长因子受体和胰岛素样生长因子-1 受体靶向 FOLFOX 存活的结肠癌细胞。

Curcumin targets FOLFOX-surviving colon cancer cells via inhibition of EGFRs and IGF-1R.

机构信息

Department of Veterans Affairs Medical Center, Karmanos Cancer Center, Wayne State University, Detroit, MI 48201, USA.

出版信息

Anticancer Res. 2010 Feb;30(2):319-25.

Abstract

Curcumin (diferuloylmethane), which has no discernible toxicity, inhibits initiation, promotion and progression of carcinogenesis. 5-Fluorouracil (5-FU) or 5-FU plus oxaliplatin (FOLFOX) remains the backbone of colorectal cancer chemotherapeutics, but produces an incomplete response resulting in survival of cells (chemo-surviving cells) that may lead to cancer recurrence. The present investigation was, therefore, undertaken to examine whether addition of curcumin to FOLFOX is a superior therapeutic strategy for chemo-surviving cells. Forty-eight-hour treatment of colon cancer HCT-116 and HT-29 cells with FOLFOX resulted in 60-70% survival, accompanied by a marked activation of insulin like growth factor-1 receptor (IGF-1R) and minor to moderate increase in epidermal growth factor receptor (EGFR), v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (HER-2) as well as v-akt murine thymoma viral oncogene homolog 1 (AKT), cyclooxygenase-2 (COX-2) and cyclin-D1. However, inclusion of curcumin to continued FOLFOX treatment for another 48 h greatly reduced the survival of these cells, accompanied by a concomitant reduction in activation of EGFR, HER-2, IGF-1R and AKT, as well as expression of COX-2 and cyclin-D1. More importantly, EGFR tyrosine kinase inhibitor gefitinib or attenuation of IGF-1R expression by the corresponding si-RNA caused a 30-60% growth inhibition of chemo-surviving HCT-116 cells. However, curcumin alone was found to be more effective than both gefitinib and IGF-1R si-RNA mediated growth inhibition of chemo-surviving HCT-116 cells and addition of FOLFOX to curcumin did not increase the growth inhibitory effect of curcumin. Our data suggest that inclusion of curcumin in conventional chemotherapeutic regimens could be an effective strategy to prevent the emergence of chemoresistant colon cancer cells.

摘要

姜黄素(二芳基甲烷)无毒,能抑制致癌作用的起始、促进和发展。5-氟尿嘧啶(5-FU)或 5-FU 加奥沙利铂(FOLFOX)仍是结直肠癌化疗的基础,但产生不完全反应,导致细胞(化疗存活细胞)存活,这可能导致癌症复发。因此,本研究旨在探讨在 FOLFOX 中加入姜黄素是否是化疗存活细胞的更佳治疗策略。用 FOLFOX 对结肠癌细胞 HCT-116 和 HT-29 进行 48 小时处理,导致 60-70%的细胞存活,同时胰岛素样生长因子-1 受体(IGF-1R)明显激活,表皮生长因子受体(EGFR)、v-erb-b2 红细胞白血病病毒致癌基因同源物 2(HER-2)以及 v-akt 鼠胸腺瘤病毒致癌基因同源物 1(AKT)、环氧化酶-2(COX-2)和细胞周期蛋白-D1 中度增加。然而,在继续用 FOLFOX 治疗 48 小时的过程中加入姜黄素,大大降低了这些细胞的存活率,同时 EGFR、HER-2、IGF-1R 和 AKT 的激活以及 COX-2 和 cyclin-D1 的表达也相应减少。更重要的是,表皮生长因子受体酪氨酸激酶抑制剂吉非替尼或用相应的 si-RNA 减弱 IGF-1R 的表达,导致化疗存活的 HCT-116 细胞的生长抑制率为 30-60%。然而,与吉非替尼和 IGF-1R si-RNA 介导的化疗存活的 HCT-116 细胞生长抑制相比,姜黄素单独使用更有效,并且向姜黄素中添加 FOLFOX 不会增加姜黄素的生长抑制作用。我们的数据表明,将姜黄素纳入常规化疗方案可能是防止耐药结肠癌细胞出现的有效策略。

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