Nautiyal Jyoti, Kanwar Shailender S, Yu Yingjie, Majumdar Adhip Pn
Veterans Affairs Medical Center, Wayne State University, Detroit, MI 48201, USA.
J Mol Signal. 2011 Jul 20;6:7. doi: 10.1186/1750-2187-6-7.
Metastatic colorectal cancer remains a serious health concern with poor patient survival. Although 5-Fluorouracil (5-FU) or 5-FU plus oxaliplatin (FOLFOX) is the standard therapy for colorectal cancer, it has met with limited success. Recurrence of the tumor after chemotherapy could partly be explained by the enrichment of the chemo-resistant sub-population of cancer stem cells (CSCs) that possess the ability for self-renewal and differentiation into different lineages in the tumor. Therefore development of therapeutic strategies that target CSCs for successful treatment of this malignancy is warranted. The current investigation was undertaken to examine the effectiveness of the combination therapy of dasatinib (a Src inhibitor) and curcumin (a dietary agent with pleiotropic effect) in inhibiting the growth and other properties of carcinogenesis of chemo-resistant colon cancer cells that are enriched in CSCs sub-population. Remnants of spontaneous adenomas from APCMin +/- mice treated with dasatinib and/or curcumin were analyzed for several cancer stem cell markers (ALDH, CD44, CD133 and CD166). Human colon cancer cells HCT-116 (p53 wild type; K-ras mutant) and HT-29 (p53 mutant; K-ras wild type) were used to generate FOLFOX resistant (referred to as CR) cells. The effectiveness of the combination therapy in inhibiting growth, invasive potential and stemness was examined in colon cancer CR cells. The residual tumors from APCMin +/- mice treated with dasatinib and/or curcumin showed 80-90% decrease in the expression of the CSC markers ALDH, CD44, CD133, CD166. The colon cancer CR cells showed a higher expression of CSCs markers, cell invasion potential and ability to form colonospheres, compared to the corresponding parental cells. The combination therapy of dasatinib and curcumin demonstrated synergistic interactions in CR HCT-116 and CR HT-29 cells, as determined by Calcusyn analysis. The combinatorial therapy inhibited cellular growth, invasion and colonosphere formation and also reduced CSC population as evidenced by the decreased expression of CSC specific markers: CD133, CD44, CD166 and ALDH. Our data suggest that the combination therapy of dasatinib and curcumin may be a therapeutic strategy for re-emergence of chemo-resistant colon cancer by targeting CSC sub-population.
转移性结直肠癌仍然是一个严重的健康问题，患者生存率较低。尽管5-氟尿嘧啶（5-FU）或5-FU联合奥沙利铂（FOLFOX）是结直肠癌的标准治疗方法，但成效有限。化疗后肿瘤复发的部分原因可能是具有自我更新能力并能分化为肿瘤中不同谱系的化疗耐药性癌症干细胞（CSCs）亚群增多。因此，有必要开发针对CSCs的治疗策略，以成功治疗这种恶性肿瘤。目前的研究旨在检验达沙替尼（一种Src抑制剂）和姜黄素（一种具有多种效应的膳食剂）联合治疗对抑制富含CSCs亚群的化疗耐药性结肠癌细胞生长及致癌作用其他特性的有效性。对用达沙替尼和/或姜黄素治疗的APCMin+/-小鼠的自发性腺瘤残余物进行了几种癌症干细胞标志物（醛脱氢酶、CD44、CD133和CD166）分析。用人结肠癌细胞HCT-116（p53野生型；K-ras突变型）和HT-29（p53突变型；K-ras野生型）生成FOLFOX耐药（称为CR）细胞。在结肠癌CR细胞中检测了联合治疗对抑制生长、侵袭潜能和干性的有效性。用达沙替尼和/或姜黄素治疗的APCMin+/-小鼠的残余肿瘤显示，癌症干细胞标志物醛脱氢酶、CD44、CD133、CD166的表达降低了80%-90%。与相应的亲本细胞相比，结肠癌CR细胞显示出更高的癌症干细胞标志物表达、细胞侵袭潜能和形成结肠球的能力。通过Calcusyn分析确定，达沙替尼和姜黄素联合治疗在CR HCT-116和CR HT-29细胞中表现出协同相互作用。联合治疗抑制了细胞生长、侵袭和结肠球形成，并且还减少了癌症干细胞群体，这通过癌症干细胞特异性标志物CD133、CD44、CD166和醛脱氢酶表达的降低得到证明。我们的数据表明，达沙替尼和姜黄素联合治疗可能是一种通过靶向癌症干细胞亚群来治疗化疗耐药性结肠癌复发的治疗策略。
