Department of Gastrointestinal Surgery, Shunde Hospital, Southern Medical University, Shunde, Guangdong 528300, P.R. China.
Department of General Surgery, Heping Hospital Affiliated with Changzhi Medical College, Changzhi, Shanxi 046000, P.R. China.
Int J Oncol. 2018 Sep;53(3):1343-1353. doi: 10.3892/ijo.2018.4461. Epub 2018 Jun 29.
Resistance to conventional chemotherapeutic agents, including irinotecan (CPT‑11), 5-fluorouracil and capecitabine is a major cause for therapeutic failure in patients with colorectal cancer (CRC). Increasing evidence has demonstrated that cancer cells exhibiting stem cell-like characteristics are associated with the development of resistance to chemotherapeutic agents. As a plant polyphenol, curcumin has been demonstrated to have the ability to ameliorate resistance of CRC to chemotherapeutic agents, but the associations among curcumin, cancer stem cells (CSCs) and chemoresistance of CRC remain unclear. The present study established a CPT‑11-resistant colon cancer cell line, LoVo/CPT‑11 cells, and detected the expression levels of CSC identification markers [cluster of differentiation (CD)44, CD133, epithelial cell adhesion molecule (EpCAM) and CD24] in parental cells and CPT‑11-resistant cells. It was revealed that the expression levels of the colon CSC markers in LoVo/CPT‑11 cells were significantly higher compared those in parental cells at the mRNA and protein level. The effect of curcumin on the chemoresistance to CPT‑11 and the expression levels of CSC identification markers in LoVo/CPT‑11 cells separately treated with curcumin and CPT‑11 were further investigated. The results revealed that curcumin significantly attenuated chemoresistance to CPT‑11, and treatment with curcumin resulted in a significant reduction of the expression levels of CSC identification markers. Furthermore, a tumor sphere formation assay was used to enrich colon CSCs from LoVo/CPT‑11 cells, and demonstrated that curcumin efficiently diminished the traits of colon CSCs, as evidenced by the inability to form tumor spheres, the reduction in the expression of CSC identification markers, and apoptosis-induced effects on sphere-forming cells treated with curcumin alone or in combination with CPT‑11. Altogether, the present data demonstrated that curcumin attenuated resistance to chemotherapeutic drugs through induction of apoptosis of CSCs among colon cancer cells. These findings may provide novel evidence for the therapeutic application of curcumin in CRC intervention.
对包括伊立替康（CPT-11）、5-氟尿嘧啶和卡培他滨在内的常规化疗药物的耐药性是结直肠癌（CRC）患者治疗失败的主要原因。越来越多的证据表明，表现出干细胞样特征的癌细胞与对化疗药物的耐药性的发展有关。作为一种植物多酚，姜黄素已被证明能够改善 CRC 对化疗药物的耐药性，但姜黄素、癌症干细胞（CSC）和 CRC 化疗耐药性之间的关联尚不清楚。本研究建立了 CPT-11 耐药结肠癌细胞系 LoVo/CPT-11 细胞，并检测了亲本细胞和 CPT-11 耐药细胞中 CSC 鉴定标志物[CD44、CD133、上皮细胞黏附分子（EpCAM）和 CD24]的表达水平。结果显示，LoVo/CPT-11 细胞中结肠 CSC 标志物的表达水平在 mRNA 和蛋白水平上均明显高于亲本细胞。进一步研究了姜黄素对 LoVo/CPT-11 细胞对 CPT-11 的耐药性以及单独用姜黄素和 CPT-11 处理后 CSC 鉴定标志物表达水平的影响。结果表明，姜黄素显著减弱了对 CPT-11 的耐药性，用姜黄素处理后，CSC 鉴定标志物的表达水平显著降低。此外，还使用肿瘤球形成实验从 LoVo/CPT-11 细胞中富集结肠 CSCs，并证明姜黄素能够有效削弱结肠 CSCs 的特性，表现为无法形成肿瘤球、CSC 鉴定标志物表达减少，以及单独用姜黄素或与 CPT-11 联合处理球形成细胞时诱导凋亡的作用。综上所述，本研究数据表明，姜黄素通过诱导结肠癌细胞中的 CSCs 凋亡来减弱对化疗药物的耐药性。这些发现可能为姜黄素在 CRC 干预中的治疗应用提供新的证据。
