Jeong Soyeon, Kim Dae Yeong, Kang Sang Hee, Yun Hye Kyeong, Kim Jung Lim, Kim Bo Ram, Park Seong Hye, Na Yoo Jin, Jo Min Jee, Jeong Yoon A, Kim Bu Gyeom, Lee Dae-Hee, Oh Sang Cheul
Department of Oncology, Korea University Guro Hospital, Korea University College of Medicine, Seoul 08308, Korea.
Graduate School of Medicine, College of Medicine, Korea University, Seoul 08308, Korea.
Cancers (Basel). 2019 Jul 14;11(7):982. doi: 10.3390/cancers11070982.
Oxaliplatin is an anticancer drug administered to colorectal cancer (CRC) patients in combination with 5-fluorouracil and antibodies (bevacizumab and cetuximab), thereby significantly improving the survival rate of CRC. However, due to various side effects associated with the above treatment strategy, the need for combinatorial therapeutic strategies has emerged. Based on the demand for new combinatorial therapies and the known antitumor effects of the omega-3 polyunsaturated fatty acid, docosahexaenoic acid (DHA), we investigated the Oxaliplatin and DHA combination for its effect. Our results indicated that DHA further enhanced Oxaliplatin-induced cell viability and autophagic cell death, in vitro and in vivo. Oxaliplatin and DHA also increased the expression of Sestrin 2 (SESN2) and endoplasmic reticulum (ER) stress related C/EBP homologous protein (CHOP). Additionally, treatment with Oxaliplatin and DHA enhanced the binding of CHOP to the promotor region of SESN2, increasing SESN2 expression. These results suggested that DHA enhanced Oxaliplatin-induced reduction in cell viability and increase in autophagy via activating SESN2 and increasing ER stress. Thus, SESN2 may be an effective preclinical target for CRC treatment.
奥沙利铂是一种抗癌药物，用于治疗结直肠癌（CRC）患者，通常与5-氟尿嘧啶及抗体（贝伐单抗和西妥昔单抗）联合使用，从而显著提高结直肠癌患者的生存率。然而，由于上述治疗策略存在各种副作用，因此出现了对联合治疗策略的需求。基于对新型联合疗法的需求以及ω-3多不饱和脂肪酸二十二碳六烯酸（DHA）已知的抗肿瘤作用，我们研究了奥沙利铂与DHA联合使用的效果。我们的结果表明，在体外和体内，DHA进一步增强了奥沙利铂诱导的细胞活力和自噬性细胞死亡。奥沙利铂和DHA还增加了Sestrin 2（SESN2）和内质网（ER）应激相关的C/EBP同源蛋白（CHOP）的表达。此外，用奥沙利铂和DHA处理增强了CHOP与SESN2启动子区域的结合，增加了SESN2的表达。这些结果表明，DHA通过激活SESN2和增加内质网应激增强了奥沙利铂诱导的细胞活力降低和自噬增加。因此，SESN2可能是结直肠癌治疗的一个有效的临床前靶点。
