Rani Isha, Sharma Bhoomika, Kumar Sandeep, Kaur Satinder, Agnihotri Navneet
Department of Biochemistry, Panjab University, Chandigarh, India.
Tumour Biol. 2017 Mar;39(3):1010428317695019. doi: 10.1177/1010428317695019.
5-Fluorouracil has been considered as a cornerstone therapy for colorectal cancer; however, it suffers from low therapeutic response rate and severe side effects. Therefore, there is an urgent need to increase the clinical efficacy of 5-fluorouracil. Recently, fish oil rich in n-3 polyunsaturated fatty acids has been reported to chemosensitize tumor cells to anti-cancer drugs. This study is designed to understand the underlying mechanisms of synergistic effect of fish oil and 5-fluorouracil by evaluation of tumor cell-associated markers such as apoptosis and DNA damage. The colon cancer was developed by administration of N,N-dimethylhydrazine dihydrochloride and dextran sulfate sodium salt. Further these animals were treated with 5-fluorouracil, fish oil, or a combination of both. In carcinogen-treated animals, a decrease in DNA damage and apoptotic index was observed. There was also a decrease in the expression of Fas, FasL, caspase 8, and Bax, and an increase in Bcl-2. In contrast, administration of 5-fluorouracil and fish oil as an adjuvant increased both DNA damage and apoptotic index by activation of both extrinsic and intrinsic apoptotic pathways as compared to the other groups. The increased pro-apoptotic effect by synergism of 5-fluorouracil and fish oil may be attributed to the incorporation of n-3 polyunsaturated fatty acids in membrane, which alters membrane fluidity in cancer cells. In conclusion, this study highlights that the induction of apoptotic pathway by fish oil may increase the susceptibility of tumors to chemotherapeutic regimens.
5-氟尿嘧啶一直被视为结直肠癌的基石疗法；然而，它存在治疗反应率低和严重副作用的问题。因此，迫切需要提高5-氟尿嘧啶的临床疗效。最近，据报道富含n-3多不饱和脂肪酸的鱼油可使肿瘤细胞对抗癌药物产生化学增敏作用。本研究旨在通过评估凋亡和DNA损伤等肿瘤细胞相关标志物，了解鱼油与5-氟尿嘧啶协同作用的潜在机制。通过给予盐酸N，N-二甲基肼和葡聚糖硫酸钠诱导结肠癌。进一步对这些动物用5-氟尿嘧啶、鱼油或两者的组合进行治疗。在致癌物处理的动物中，观察到DNA损伤和凋亡指数降低。Fas、FasL、半胱天冬酶8和Bax的表达也降低，而Bcl-2表达增加。相比之下，与其他组相比，联合使用5-氟尿嘧啶和鱼油作为佐剂可通过激活外源性和内源性凋亡途径增加DNA损伤和凋亡指数。5-氟尿嘧啶与鱼油协同作用增加的促凋亡作用可能归因于n-3多不饱和脂肪酸掺入细胞膜，从而改变癌细胞的膜流动性。总之，本研究强调鱼油诱导凋亡途径可能会增加肿瘤对化疗方案的敏感性。
