Liu Fang, Lv Rong-Bin, Liu Yan, Hao Qian, Liu Shu-Jie, Zheng Yuan-Yuan, Li Cui, Zhu Cheng, Wang Min
Department of Geriatric Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, People's Republic of China.
Department of Gastroenterology, Taian City Central Hospital, Taian, Shandong 271000, People's Republic of China.
Onco Targets Ther. 2020 Jun 3;13:4957-4969. doi: 10.2147/OTT.S246706. eCollection 2020.
Both salinomycin (SAL) and sulforaphane (SFN) exert their antitumorigenic effects in various types of cancer We investigated whether combining salinomycin (SAL, an antibiotic ionophore) with sulforaphane (SFN, a phytochemical) exerted synergistic antiproliferative and proapoptotic activities in colorectal cancer (CRC) cells in vitro and in vivo by evaluating the proliferative and apoptotic responses of two CRC cell lines.
The combination index (CI) was calculated using the Chou-Talalay method, and the effects of the synergistic combination (CI<1) of lower doses of SAL and SFN were selected for further studies. Anti-tumor effect of the combination of SAL and SFN was tested both in vitro and in vivo.
Cotreatment effectively inhibited proliferation, migration and invasion and enhanced apoptosis. The xenograft model also showed similar results. Furthermore, we evaluated the molecular mechanism behind SAL- and SFN-mediated CRC cell apoptosis. The combination treatment induced apoptosis in Caco-2 and CX-1 cells by inhibiting the PI3K/Akt pathway, which increased the expression of the tumor suppressor protein p53. The treatment also decreased the expression of the survival protein Bcl-2 and increased the expression of the proapoptotic protein Bax, which increased the Bax/Bcl-2 ratio, as well as enhanced poly ADP-ribose polymerase (PARP) cleavage. Upon inhibiting the PI3K/Akt pathway with LY294002 prior to cotreatment, we detected enhanced PARP cleavage compared to that in the cotreatment only group.
We investigated whether the combination of SAL and SFN had antiproliferative and proapoptotic effects in CRC cells both in vitro and in vivo. Cotreatment also significantly decreased migration and invasion compared to that of the control and SAL or SFN monotherapies. This novel combination of SAL and SFN might provide a potential strategy to treat CRC.
盐霉素（SAL）和萝卜硫素（SFN）在多种癌症中均发挥其抗肿瘤作用。我们通过评估两种结直肠癌细胞系的增殖和凋亡反应，研究了将盐霉素（一种抗生素离子载体）与萝卜硫素（一种植物化学物质）联合使用是否在体外和体内对结直肠癌（CRC）细胞发挥协同抗增殖和促凋亡活性。
采用Chou-Talalay法计算联合指数（CI），并选择低剂量SAL和SFN的协同组合（CI<1）的效果进行进一步研究。在体外和体内测试SAL和SFN联合的抗肿瘤作用。
联合处理有效抑制了增殖、迁移和侵袭，并增强了凋亡。异种移植模型也显示了类似的结果。此外，我们评估了SAL和SFN介导的CRC细胞凋亡背后的分子机制。联合处理通过抑制PI3K/Akt途径诱导Caco-2和CX-1细胞凋亡，这增加了肿瘤抑制蛋白p53的表达。该处理还降低了存活蛋白Bcl-2的表达，增加了促凋亡蛋白Bax的表达，从而增加了Bax/Bcl-2比值，并增强了聚ADP-核糖聚合酶（PARP）的切割。在联合处理前用LY294002抑制PI3K/Akt途径后，与仅联合处理组相比，我们检测到PARP切割增强。
我们研究了SAL和SFN联合在体外和体内对CRC细胞是否具有抗增殖和促凋亡作用。与对照组以及SAL或SFN单一疗法相比，联合处理还显著降低了迁移和侵袭。SAL和SFN的这种新型联合可能为治疗CRC提供一种潜在策略。
