Yu Tianqi, Ganapathy Suthakar, Shen Ling, Peng Bo, Kim Sung-Hoon, Makriyannis Alexandros, Chen Changyan
The Center for Drug Discovery, Northeastern University, Boston, MA, USA.
Cancer Molecular Targeted Herbal Research Center, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea.
Oncotarget. 2018 Jan 4;9(5):6308-6319. doi: 10.18632/oncotarget.23918. eCollection 2018 Jan 19.
Side effects of anti-cancer drugs are always challenging for effective cancer treatments. The polysaccharides extracted from (PLGL) have been widely used in treating cancers. However, the mechanism by which PLGL antagonizes cancerous growth has not been fully investigated. The current study demonstrated that human colon cancer HCT116 and HT29 cells became highly susceptible to cell death when being co-treated with PLGL and low dose of camptothecin11 (CPT11, a topoisomerase inhibitor-based drug), the efficacy of which was comparable as that generated by the high dose of CPT11. However, the co-treatment, unlike high doses of CPT11, was not cytotoxic to the control immortalized colon Caco-2 cells. The co-treatment caused high percentages of the colon cancer cells to accumulate in S phase of the cell cycle, which was also seen in the same cells received the high dose of CPT11 treatment. Chk1 was phosphorylated, and then rapidly degraded in the cancer cells treated with the high dose of CPT11 or co-treatment, but not in the cells treated with PLGL alone or low doses of CPT11. PLGL appeared enhancing CPT11 inhibitory effect on topoisomerase, and Chk1 degradatopm in the cancer cells. Furthermore, cyclin E (clnE) became unstable at the transcription level in co-treated or PLGL-treated colon cancer cells. The data suggested that PLGL functions in two ways to achieve its lethal synergy with CPT11 in colon cancer cells. Our findings are of potential significance as PLGL represents a promising medicine for overcoming the side effects of CPT11 and perhaps also for improving other CPTs-based regimens.
抗癌药物的副作用一直是有效治疗癌症的一大挑战。从（PLGL）中提取的多糖已被广泛用于治疗癌症。然而，PLGL拮抗癌性生长的机制尚未得到充分研究。目前的研究表明，当人结肠癌细胞HCT116和HT29细胞与PLGL和低剂量的喜树碱11（CPT11，一种基于拓扑异构酶抑制剂的药物）联合处理时，它们对细胞死亡变得高度敏感，其疗效与高剂量CPT11产生的疗效相当。然而，与高剂量CPT11不同，联合处理对对照永生化结肠Caco-2细胞没有细胞毒性。联合处理导致高比例的结肠癌细胞在细胞周期的S期积累，这在接受高剂量CPT11处理的相同细胞中也可见。在接受高剂量CPT11或联合处理的癌细胞中，Chk1被磷酸化，然后迅速降解，但在单独用PLGL或低剂量CPT11处理的细胞中则没有。PLGL似乎增强了CPT11对拓扑异构酶的抑制作用以及癌细胞中Chk1的降解。此外，在联合处理或PLGL处理的结肠癌细胞中，细胞周期蛋白E（clnE）在转录水平变得不稳定。数据表明，PLGL通过两种方式发挥作用，以在结肠癌细胞中与CPT11实现致命的协同作用。我们的发现具有潜在意义，因为PLGL代表了一种有前景的药物，可用于克服CPT11的副作用，也许还可用于改善其他基于CPT的治疗方案。
