Department of Veterans Affairs Medical Center, Wayne State University, Detroit, MI 48201, USA.
Transl Oncol. 2009 Dec;2(4):321-8. doi: 10.1593/tlo.09193.
5-Fluorouracil (5-FU) or 5-FU plus oxaliplatin (FOLFOX) remains the backbone of colorectal cancer chemotherapeutics but with limited success. This could partly be due to the enrichment of cancer stem cells (CSCs) that are resistant to conventional chemotherapy. Therefore, validation of a nontoxic agent that can either cause reversal of chemoresistance or promote the killing of CSCs would be highly desirable. The current study examines whether curcumin, the major active ingredient of turmeric, either alone or together with FOLFOX, would be an effective strategy to eliminate colon CSCs. Exposure of colon cancer HCT-116 or HT-29 cells to FOLFOX that inhibited their growth led to the enrichment of CSC phenotype as evidenced by increased proportion of CD133-, CD44-, and/or CD166-positive cells and epidermal growth factor receptor (EGFR) levels. Treatment of FOLFOX-surviving colon cancer cells with either curcumin alone or together with FOLFOX resulted in a marked reduction in CSCs, as evidenced by the decreased expression of CD44 and CD166 as well as EGFR and by their ability to form anchorage-dependent colonies. They also caused disintegration of colonospheres. Increased expression of EGFR in FOLFOX-surviving cells could be attributed to hypomethylation of the EGFR promoter, whereas an opposite phenomenon was observed when the FOLFOX-surviving cells were treated with curcumin and/or FOLFOX. These changes were accompanied by parallel alterations in the levels of DNA methyltransferase 1. In conclusion, our data suggest that curcumin by itself or together with the conventional chemotherapeutic could be an effective treatment strategy for preventing the emergence of chemoresistant colon cancer cells by reducing/eliminating CSCs.
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的基础，但疗效有限。这可能部分是由于癌症干细胞（CSCs）的富集，这些细胞对常规化疗有抵抗力。因此，验证一种非毒性药物，既能逆转耐药性，又能促进 CSCs 的杀伤，将是非常理想的。本研究探讨了姜黄素（姜黄的主要活性成分）单独或与 FOLFOX 联合使用是否是消除结肠 CSCs 的有效策略。暴露于 FOLFOX 可抑制其生长的结肠癌细胞 HCT-116 或 HT-29 导致 CSC 表型的富集，这表现为 CD133+、CD44+和/或 CD166+细胞和表皮生长因子受体（EGFR）水平的增加。单独用姜黄素或与 FOLFOX 一起处理 FOLFOX 存活的结肠癌细胞，导致 CSCs 明显减少，这表现为 CD44 和 CD166 以及 EGFR 的表达减少，以及它们形成锚定依赖性集落的能力降低。它们还导致结肠球体的解体。FOLFOX 存活细胞中 EGFR 的高表达可归因于 EGFR 启动子的低甲基化，而当 FOLFOX 存活细胞用姜黄素和/或 FOLFOX 处理时，观察到相反的现象。这些变化伴随着 DNA 甲基转移酶 1 水平的平行变化。总之，我们的数据表明，姜黄素本身或与常规化疗联合使用可能是一种有效的治疗策略，通过减少/消除 CSCs 来预防耐药性结肠癌细胞的出现。
