Curcumin targets FOLFOX-surviving colon cancer cells via inhibition of EGFRs and IGF-1R.
Curcumin targets FOLFOX-surviving colon cancer cells via inhibition of EGFRs and IGF-1R.
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发表时间：
2010-02
影响因子：
2
通讯作者：
B. Patel;D. Gupta;Althea A Elliott;V. Sengupta;Yingjie Yu;A. Majumdar
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作者：
B. Patel;D. Gupta;Althea A Elliott;V. Sengupta;Yingjie Yu;A. Majumdar
姜黄素(二阿魏酰甲烷)没有明显的毒性，可抑制致癌的启动、促进和进展。5-氟尿嘧啶(5-FU)或5-FU联合奥沙利铂(FOLFOX)仍然是结直肠癌化疗药物的主干，但会产生不完全反应，导致细胞(化疗存活细胞)存活，从而可能导致癌症复发。因此，目前的研究是为了检查在FOLFOX中添加姜黄素是否是化疗存活细胞的更好的治疗策略。用FOLFOX处理结肠癌HCT-116和HT-29细胞48小时后，细胞存活率为60-70%，伴随着胰岛素样生长因子-1受体(IGF-1R)的显著激活，表皮生长因子受体(EGFR)、v-erb-b2红细胞性白血病病毒癌基因同源物2(HER-2)以及v-AKT小鼠胸腺瘤病毒癌基因同源物1(AKT)、环氧合酶-2(COX-2)和细胞周期蛋白-D1(Cyclin-d1)的表达轻微到中度增加。然而，继续给予FOLFOX 48h的姜黄素显著降低了这些细胞的存活率，并伴随着EGFR、HER-2、IGF-1R和AKT的激活以及COX-2和Cyclin-D1的表达减少。更重要的是，EGFR酪氨酸激酶抑制剂Gefitinib或相应的si-RNA抑制IGF-1R的表达导致化疗存活的HCT-116细胞的生长抑制30%-60%。然而，单独使用姜黄素比吉非替尼和IGF-1R si-RNA更有效地介导了对化疗存活的HCT-116细胞的生长抑制作用，而在姜黄素中加入FOLFOX并不能增加姜黄素的生长抑制作用。我们的数据表明，在常规化疗方案中加入姜黄素可能是防止化疗耐药结肠癌细胞出现的有效策略。
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.