英国学者发现吉西他滨联合鱼油脂肪乳靶向治疗胰腺癌作用机制

　　胰腺癌长期以来都是一种预后不良的疾病，科学家们正不断寻求替代策略以提高治疗效果。其中，ω-3脂肪酸已经显示临床获益，科学家们正在研究其作用机制。

　　2016年6月，德国《分子营养与食品研究》正式发表英国莱斯特大学皇家医院、莱斯特总医院的体外研究报告，探讨了吉西他滨联合鱼油脂肪乳靶向治疗胰腺癌的作用机制。

　　该研究采用细胞增殖测定、流式细胞计量、细胞侵袭测定、酶联免疫吸附测定（ELISA）和蛋白质印迹法分析了ω-3脂肪酸联合吉西他滨的效果。

　　结果发现，含有二十二碳六烯酸（DHA）和二十碳五烯酸（EPA）的力保鱼优（ω-3鱼油中/长链脂肪乳注射液）联合吉西他滨可抑制胰腺癌和胰腺星状细胞生长，胰腺星状细胞表现最为敏感。

　　胰腺星状细胞在胰腺纤维化的过程中起关键作用，而胰腺癌最为主要的病理学特点就是纤维化变性。在肿瘤三维球状模型中，胰腺星状细胞和胰腺癌细胞的侵袭力受到吉西他滨联合力保鱼优的抑制。在器官型共培养模型中，胰腺星状细胞参与癌细胞侵袭，而单用力保鱼优即可降低其侵袭能力。

　　此外，在增殖和侵袭信号转导中，血小板源生长因子（PDGF）是关键的细胞因子，并且是胰腺癌细胞与相邻基质之间相互作用的关键调节因子。PDGF为糖蛋白二聚体，有A和B两种不同形式，可组合为AA、AB和BB等结构。在癌细胞和胰腺星状细胞中，PDGF-BB的分泌可被力保鱼优联合吉西他滨完全抑制。

　　因此，力保鱼优联合吉西他滨，在体外具有抗增殖和抗侵袭的效果，胰腺星状细胞对此联合疗法表现出最高敏感性。

Mol Nutr Food Res. 2016 Jun;60(6):1437-47.

Targeting pancreatic cancer using a combination of gemcitabine with the omega-3 polyunsaturated fatty acid emulsion, Lipidem.

Haqq J, Howells LM, Garcea G, Dennison AR.

Department of Cancer Studies, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, University of Leicester, Leicester, United Kingdom.

Department of Hepatobiliary Surgery, Leicester General Hospital, Leicester, United Kingdom.

SCOPE: Pancreatic cancer remains a disease of poor prognosis, with alternate strategies being sought to improve therapeutic efficacy. Omega-3 fatty acids have shown clinical benefit, and mechanisms of action are under investigation.

METHODS/RESULTS: Proliferation assays, flow cytometry, invasion assays, ELISA and western blotting were used to investigate efficacy of omega-3 fatty acids alone and in combination with gemcitabine. The docosahexanoic acid (DHA)/eicosapentanoic acid (EPA) combination, Lipidem, in combination with gemcitabine inhibited growth in pancreatic cancer and pancreatic stellate cell (PSC) lines, with PSCs exhibiting greatest sensitivity to this combination. Invasion of pancreatic cancer cells and PSCs in a 3D spheroid model, was inhibited by combination of gemcitabine with Lipidem. PSCs were required for cancer cell invasion in an organotypic co-culture model, with invasive capacity reduced by Lipidem alone. Platelet-derived growth factor (PDGF) is a key cytokine in pro-proliferative and invasion signalling, and thus a critical regulator of interactions between pancreatic cancer cells and adjacent stroma. Platelet-derived growth factor (PDGF-BB) secretion was completely inhibited by the combination of Lipidem with gemcitabine in cancer cells and PSCs.

CONCLUSION: Lipidem in combination with gemcitabine, has anti-proliferative and anti-invasive efficacy in vitro, with pancreatic stellate cells exhibiting the greatest sensitivity to this combination.

KEYWORDS: Fishoil; Pancreatic cancer; Pancreatic stellate cells; Platelet-derived growth factor; Polyunsaturated fatty acids

PMID: 26603273

DOI: 10.1002/mnfr.201500755