Department of Chemistry and Biochemistry, Faculty of Medicine, University of Rijeka, Rijeka, 51000, Croatia.
Department of Microbiology and Parasitology, Faculty of Medicine, University of Rijeka, Rijeka, 51000, Croatia.
Phytother Res. 2018 Jun;32(6):1090-1097. doi: 10.1002/ptr.6048. Epub 2018 Feb 8.
Carvacrol has been shown to possess anticancer activity, but the mechanism is unknown, as well as the possibility of interaction with anticancer drugs. The aim of this study was to investigate the role of mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling in carvacrol-induced human cervical cancer HeLa cell cytotoxicity. In addition, we studied sensitization of HeLa cells to cisplatin (CP) by carvacrol. Both carvacrol and CP showed dose-dependent cytotoxicity against HeLa cells and activated ERK1/2. The MEK inhibitor PD325901 suppressed ERK expression and further increased cytotoxicity of carvacrol but increased viability of CP-treated cells by modulating apoptosis. The MEK inhibitor also increased microtubule-associated protein 1A/1B-light chain 3 beta expression in CP treatment. Cotreatment with CP and carvacrol resulted in increased viability of the cancer cells compared with CP treatment, which was associated with the suppression of apoptosis. MEK inhibition decreased the cell viability, without changes in apoptosis. Concomitantly, carvacrol increased CP-induced expression of light chain 3 beta, which was enhanced by MEK inhibition. The results of the current study suggest the opposite role of ERK1/2 in carvacrol and CP-induced HeLa cell cytotoxicity. Interestingly, carvacrol induced CP resistance in HeLa cells through ERK1/2-independent suppression of apoptosis and ERK1/2-dependent modulation of autophagy.
香芹酚具有抗癌活性，但作用机制尚不清楚，也不清楚其与抗癌药物相互作用的可能性。本研究旨在探讨丝裂原活化蛋白激酶激酶（MEK）/细胞外信号调节激酶（ERK）信号通路在香芹酚诱导人宫颈癌 HeLa 细胞毒性中的作用。此外，我们研究了香芹酚对顺铂（CP）的 HeLa 细胞增敏作用。香芹酚和 CP 均对 HeLa 细胞表现出剂量依赖性细胞毒性，并激活 ERK1/2。MEK 抑制剂 PD325901 抑制 ERK 表达，进一步增加香芹酚的细胞毒性，但通过调节细胞凋亡增加 CP 处理细胞的活力。MEK 抑制剂还增加了 CP 处理时微管相关蛋白 1A/1B-轻链 3β的表达。与 CP 处理相比，CP 和香芹酚联合处理可增加癌细胞的活力，这与细胞凋亡的抑制有关。MEK 抑制降低了细胞活力，而不改变细胞凋亡。同时，香芹酚增加了 CP 诱导的 LC3β表达，MEK 抑制增强了这一表达。本研究结果表明 ERK1/2 在香芹酚和 CP 诱导的 HeLa 细胞毒性中发挥相反的作用。有趣的是，香芹酚通过 ERK1/2 非依赖性抑制细胞凋亡和 ERK1/2 依赖性调节自噬诱导 HeLa 细胞对 CP 的耐药性。
