Multiple studies are currently targeting dysregulated cancer cell metabolism with distinct combinations of inhibitors. In this study, we evaluated in pancreatic cancer cells metformin, which blocks oxidative phosphorylation, in combination with α-cyano-4-hydroxycinnamate, which has been reported to inhibit the export of lactate from the cytosol. The combination of metformin with α-cyano-4-hydroxycinnamate had a major inhibitory effect on the migration of 6606PDA cells. Monotherapy with α-cyano-4-hydroxycinnamate and especially the combination with metformin also caused significant inhibition of cell proliferation and induced cell death. α-cyano-4-hydroxycinnamate in combination with metformin reduced the export of lactate significantly, whereas α-cyano-4-hydroxycinnamate monotherapy only modestly influenced lactate export. None of these two drugs inhibited the expression of distinct glycolytic enzymes. Interestingly, α-cyano-4-hydroxycinnamate rather inhibited the ERK and very strongly stimulated the p38 signaling pathway in 6606PDA as well as in 7265PDA cells. In addition, the inhibition of the p38 signaling pathway by PH-797804 partially reversed the effect of α-cyano-4-hydroxycinnamate on cell apoptosis in both cell lines. We conclude that α-cyano-4-hydroxycinnamate monotherapy and especially the combinatorial therapy with metformin has strong anti-cancerous effects. α-cyano-4-hydroxycinnamate causes cancer cell apoptosis by a novel mechanism for this drug, namely the stimulation of the p38 signaling pathway.

目前，有多种研究针对具有不同抑制剂组合的癌细胞代谢失调。在这项研究中，我们评估了在胰腺癌细胞中二甲双胍与α-氰基-4-羟基肉桂酸酯的结合，该物质可阻止氧化磷酸化作用，据报道，α-氰基-4-羟基肉桂酸酯可抑制乳酸从细胞质中的输出。二甲双胍与α-氰基-4-羟基肉桂酸酯的组合对6606PDA细胞的迁移具有主要的抑制作用。α-氰基-4-羟基肉桂酸酯的单一疗法，尤其是与二甲双胍的联合疗法，也显着抑制细胞增殖并诱导细胞死亡。α-氰基-4-羟基肉桂酸酯与二甲双胍联用显着降低了乳酸盐的出口，而α-氰基-4-羟基肉桂酸酯的单药治疗仅适度影响了乳酸盐的出口。这两种药物均未抑制不同糖酵解酶的表达。有趣的是，α-氰基-4-羟基肉桂酸酯反而会抑制ERK，并非常强烈地刺激6606PDA和7265PDA细胞中的p38信号通路。此外，PH-797804对p38信号通路的抑制可部分逆转α-氰基-4-羟基肉桂酸酯对两种细胞系中细胞凋亡的影响。我们得出的结论是，α-氰基-4-羟基肉桂酸酯单药治疗，尤其是二甲双胍的联合治疗具有很强的抗癌作用。α-氰基-4-羟基肉桂酸酯通过这种药物的新机制（即刺激p38信号通路）引起癌细胞凋亡。α-氰基-4-羟基肉桂酸酯反而会抑制ERK，并非常强烈地刺激6606PDA和7265PDA细胞中的p38信号通路。此外，PH-797804对p38信号通路的抑制可部分逆转α-氰基-4-羟基肉桂酸酯对两种细胞系中细胞凋亡的影响。我们得出的结论是，α-氰基-4-羟基肉桂酸酯单药治疗，尤其是二甲双胍的联合治疗具有很强的抗癌作用。α-氰基-4-羟基肉桂酸酯通过这种药物的新机制（即刺激p38信号通路）引起癌细胞凋亡。α-氰基-4-羟基肉桂酸酯反而会抑制ERK，并非常强烈地刺激6606PDA和7265PDA细胞中的p38信号通路。此外，PH-797804对p38信号通路的抑制可部分逆转α-氰基-4-羟基肉桂酸酯对两种细胞系中细胞凋亡的影响。我们得出的结论是，α-氰基-4-羟基肉桂酸酯单药治疗，尤其是二甲双胍的联合治疗具有很强的抗癌作用。α-氰基-4-羟基肉桂酸酯通过这种药物的新机制（即刺激p38信号通路）引起癌细胞凋亡。我们得出的结论是，α-氰基-4-羟基肉桂酸酯单药治疗，尤其是二甲双胍的联合治疗具有很强的抗癌作用。α-氰基-4-羟基肉桂酸酯通过这种药物的新机制（即刺激p38信号通路）引起癌细胞凋亡。我们得出的结论是，α-氰基-4-羟基肉桂酸酯单药治疗，尤其是二甲双胍的联合治疗具有很强的抗癌作用。α-氰基-4-羟基肉桂酸酯通过这种药物的新机制（即刺激p38信号通路）引起癌细胞凋亡。