Veterans Affairs Medical Center, Wayne State University, Detroit, Michigan 48201, USA.
Pharm Res. 2011 Apr;28(4):827-38. doi: 10.1007/s11095-010-0336-y. Epub 2010 Dec 14.
Recurrence of colon cancer, which affects nearly 50% of patients treated by conventional therapeutics, is thought to be due to re-emergence of chemotherapy-resistant cancer stem/stem-like cells (CSCs). Therefore, development of therapeutic strategies for targeted elimination of CSCs would be a novel strategy. The current study examines whether difluorinated-curcumin (CDF), a novel analog of the dietary ingredient of curcumin, in combination with 5-fluorouracil and oxaliplatin (5-FU + Ox), the mainstay of colon cancer chemotherapeutic, would be effective in eliminating colon CSCs.
Multiple methodologies that include real-time RT-PCR, Western blot, MTT assay, caspase-3 activity, colonosphere formation, Hoechst-33342 dye exclusion and NF-κB-ELISA were used.
We observed that CDF together with 5-FU + Ox were more potent than curcumin in reducing CD44 and CD166 in chemo-resistant colon cancer cells, accompanied by inhibition of growth, induction of apoptosis and disintegration of colonospheres. These changes were associated with down-regulation of the membrane transporter ABCG2 and attenuation of EGFR, IGF-1R, and NF-κB signaling consistent with inactivation of β-catenin, COX-2, c-Myc and Bcl-xL and activation of the pro-apoptotic Bax.
Our results suggest that CDF together with the conventional chemotherapeutics could be an effective treatment strategy for preventing the emergence of chemo-resistant colon cancer cells by eliminating CSCs.
复发的结肠癌影响了近 50%接受传统疗法治疗的患者，据认为是由于化疗耐药的癌症干细胞/干细胞样细胞（CSCs）重新出现。因此，开发针对 CSCs 的靶向消除治疗策略将是一种新策略。本研究探讨了二氟代姜黄素（CDF），一种姜黄素膳食成分的新型类似物，与氟尿嘧啶和奥沙利铂（5-FU+Ox）联合使用，作为结肠癌化疗的主要药物，是否能有效消除结肠 CSCs。
采用实时 RT-PCR、Western blot、MTT 测定、caspase-3 活性、结肠球体形成、Hoechst-33342 染料排除和 NF-κB-ELISA 等多种方法。
我们观察到 CDF 与 5-FU+Ox 联合使用比姜黄素更能降低耐药结肠癌细胞中 CD44 和 CD166 的表达，同时抑制生长、诱导凋亡和破坏结肠球体。这些变化与膜转运蛋白 ABCG2 的下调以及 EGFR、IGF-1R 和 NF-κB 信号的衰减有关，与β-catenin、COX-2、c-Myc 和 Bcl-xL 的失活以及促凋亡 Bax 的激活一致。
我们的结果表明，CDF 与常规化疗药物联合使用可能是一种有效的治疗策略，通过消除 CSCs 来预防化疗耐药结肠癌细胞的出现。
