Fang Feng-Qi, Guo Hui-Shu, Zhang Jie, Ban Li-Ying, Liu Ji-Wei, Yu Pei-Yao
Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China.
Central Laboratory, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China.
Mol Med Rep. 2015 Dec;12(6):8062-70. doi: 10.3892/mmr.2015.4451. Epub 2015 Oct 16.
The present study demonstrated the anti-tumor effects of the quinoline derivative [5-(3-chloro-oxo-4-phenyl-cyclobutyl)-quinoli-8-yl-oxy] acetic acid hydrazide (CQAH) against colorectal carcinoma. Substantial apoptotic effects of CQAH on HCT116 and LoVo human colon cancer cell lines were observed. Apoptosis was identified based on cell morphological characteristics, including cell shrinkage and chromatin condensation as well as Annexin V/propidium iodide double staining followed by flow cytometric analysis and detection of apoptosis-associated proteins by western blot analysis. CQAH induced caspase-3 and PARP cleavage, reduced the expression of the anti-apoptotic proteins myeloid cell leukemia-1 and B-cell lymphoma (Bcl) extra large protein and elevated the expression of the pro-apoptotic protein Bcl-2 homologous antagonist killer. In addition, pharmacological inhibition of c-Jun N-terminal kinase (JNK), but not extracellular signal-regulated kinase or p38, significantly reduced CQAH-mediated cell death as well as cleavage of caspase-3 and PARP. Co-treatment of CQAH with the commercial chemotherapeutics 5-fluorouracil and camptothecin-11 significantly improved their efficacies. Comparison of the apoptotic effects of CQAH with those of two illustrated structure-activity associations for this compound type, indicating that substitution at position-4 of the azetidine phenyl ring is pivotal for inducing apoptosis. In conclusion, the results of the present study indicated CQAH and its analogues are potent candidate drugs for the treatment of colon carcinoma.
本研究证明了喹啉衍生物[5-(3-氯-氧代-4-苯基-环丁基)-喹啉-8-基-氧基]乙酸酰肼(CQAH)对结直肠癌的抗肿瘤作用。观察到CQAH对HCT116和LoVo人结肠癌细胞系有显著的凋亡作用。根据细胞形态学特征鉴定凋亡，包括细胞皱缩和染色质浓缩，以及膜联蛋白V/碘化丙啶双染色，随后进行流式细胞术分析，并通过蛋白质印迹分析检测凋亡相关蛋白。CQAH诱导半胱天冬酶-3和聚(ADP-核糖)聚合酶(PARP)裂解，降低抗凋亡蛋白髓样细胞白血病-1和B细胞淋巴瘤(Bcl)超大蛋白的表达，并提高促凋亡蛋白Bcl-2同源拮抗剂杀手的表达。此外，c-Jun氨基末端激酶(JNK)的药理学抑制，而非细胞外信号调节激酶或p38，显著降低了CQAH介导的细胞死亡以及半胱天冬酶-3和PARP的裂解。CQAH与商业化疗药物5-氟尿嘧啶和喜树碱-11联合治疗显著提高了它们的疗效。将CQAH的凋亡作用与该化合物类型的两个所示结构-活性关联的凋亡作用进行比较，表明氮杂环丁烷苯环4位的取代对于诱导凋亡至关重要。总之，本研究结果表明CQAH及其类似物是治疗结肠癌的有效候选药物。
