Department of Clinical and Molecular Medicine, Sapienza University of Rome, Piazza Sassari 3, 00161 Rome, Italy; Department of Surgery "Pietro Valdoni", Sapienza University of Rome, Via Antonio Scarpa 14, 00161 Rome, Italy.
Toxicol In Vitro. 2013 Dec;27(8):2256-63. doi: 10.1016/j.tiv.2013.09.020. Epub 2013 Oct 2.
Cigarette smoking is implicated in the development of colon cancer. Furthermore, nicotine increases cell proliferation and inhibits apoptosis through α7-nicotinic acetylcholine receptor (α7-nAChR) activation in human colon carcinoma cells. An open issue is whether nicotine interfere with colorectal cancer pharmacological treatment, by inhibiting drug-mediated apoptosis. To assess this hypothesis, we evaluated nicotine effect on Caco-2 and HCT-8 colon cancer cells, treated with 5-Fluorouracil (5-FU) and Camptothecin (CPT), chemotherapeutics commonly utilized as adjuvant treatment of colon cancer. Nicotine decreased anti-proliferative and pro-apoptotic effects exerted by chemotherapeutics on both cell lines. These effects partially reverted by exposure to α-bungarotoxin (α-BTX), an inhibitor of α7-nAChR. Nicotine addition to Caco-2 and HCT-8, treated with 5-FU or CPT, decreased the cleavage of substrate of caspase 3 and 7, poly-ADP-ribose polymerase (PARP). Moreover, P-ERK/ERK ratio was modified by nicotine addition to 5-FU and CPT treated cells in an opposite manner. However, when co-administrating PD98059, an ERK phosphorylation inhibitor, an increased apoptosis was observed. In Caco-2 and HCT-8 nicotine reverted 5-FU and CPT apoptotic effects through AKT phosphorylation, as demonstrated by apoptotic increase in presence of LY294002, an AKT phosphorylation inhibitor. Nicotine interfered with colorectal cancer pharmacological treatment in vitro by inhibiting apoptosis induced by chemotherapeutic drugs. Nicotine anti-apoptotic effects were exerted through ERK and AKT pathway activation.
吸烟与结肠癌的发生有关。此外，尼古丁通过激活人结肠癌细胞中的α7-烟碱型乙酰胆碱受体（α7-nAChR），增加细胞增殖并抑制细胞凋亡。一个悬而未决的问题是，尼古丁是否通过抑制药物介导的细胞凋亡来干扰结直肠癌的药物治疗。为了评估这一假说，我们评估了尼古丁对 Caco-2 和 HCT-8 结肠癌细胞的影响，这些细胞用氟尿嘧啶（5-FU）和喜树碱（CPT）处理，这两种化疗药物常用于结直肠癌的辅助治疗。尼古丁降低了这两种细胞系中化疗药物的抗增殖和促凋亡作用。这些作用部分被α-银环蛇毒素（α-BTX）逆转，α-BTX 是α7-nAChR 的抑制剂。当将尼古丁添加到用 5-FU 或 CPT 处理的 Caco-2 和 HCT-8 中时，尼古丁降低了 caspase 3 和 7 的底物裂解，多聚 ADP-核糖聚合酶（PARP）。此外，尼古丁的添加以相反的方式改变了用 5-FU 和 CPT 处理的细胞中 P-ERK/ERK 比值。然而，当共同给予 ERK 磷酸化抑制剂 PD98059 时，观察到细胞凋亡增加。在 Caco-2 和 HCT-8 中，尼古丁通过 AKT 磷酸化逆转 5-FU 和 CPT 的凋亡作用，如在 AKT 磷酸化抑制剂 LY294002 存在下观察到的凋亡增加所证明的那样。尼古丁通过抑制化疗药物诱导的细胞凋亡，在体外干扰结直肠癌的药物治疗。尼古丁的抗凋亡作用是通过 ERK 和 AKT 通路的激活来发挥的。
