Several natural products have been demonstrated to both enhance the anti-tumor efficacy and alleviate the side effects of conventional chemotherapy drugs. Rhein, a main constituent of the Chinese herb rhubarb, has been shown to induce apoptosis in various cancer types. However, the exact pharmacological mechanisms controlling the influence of Rhein on chemotherapy drug effects in pancreatic cancer (PC) remain largely undefined. In this study, we found that Rhein inhibited the growth and proliferation of PC cells through G1 phase cell cycle arrest. Moreover, Rhein induced caspase-dependent mitochondrial apoptosis of PC cells through inactivation of the PI3K/AKT pathway. Combination treatment of Rhein and oxaliplatin synergistically enhanced apoptosis of PC cells through increased generation of intracellular reactive oxygen species (ROS) and inactivation of the PI3K/AKT pathway. Pre-treatment with the ROS scavenger N-acetyl-L-cysteine attenuated the combined treatment-induced apoptosis and restored the level of phosphorylated AKT, indicating that ROS is an upstream regulator of the PI3K/AKT pathway. The combination therapy also exhibited stronger anti-tumor effects compared with single drug treatments in vivo. Taken together, these data demonstrate that Rhein can induce apoptosis and enhance the oxaliplatin sensitivity of PC cells, suggesting that Rhein may be an effective strategy to overcome drug resistance in the chemotherapeutic treatment of PC.

中文翻译：

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通过ROS调节抑制PI3K/AKT信号参与大黄酸诱导的胰腺癌细胞凋亡和奥沙利铂敏感性的增强

几种天然产物已被证明既能增强抗肿瘤功效，又能减轻常规化疗药物的副作用。大黄酸是中草药大黄的主要成分，已被证明可诱导多种癌症类型的细胞凋亡。然而，控制大黄酸对胰腺癌 (PC) 化疗药物作用影响的确切药理学机制在很大程度上仍未确定。在本研究中，我们发现大黄酸通过 G1 期细胞周期阻滞抑制 PC 细胞的生长和增殖。此外，Rhein 通过 PI3K/AKT 通路的失活诱导 PC 细胞的半胱天冬酶依赖性线粒体凋亡。大黄酸和奥沙利铂的联合治疗通过增加细胞内活性氧 (ROS) 的产生和 PI3K/AKT 通路的失活协同增强 PC 细胞的凋亡。用 ROS 清除剂 N-乙酰-L-半胱氨酸预处理减弱了联合治疗诱导的细胞凋亡并恢复了磷酸化 AKT 的水平，表明 ROS 是 PI3K/AKT 通路的上游调节剂。与单一药物治疗相比，联合治疗也表现出更强的抗肿瘤作用体内。综上所述，这些数据表明大黄酸可以诱导 PC 细胞凋亡并增强其对奥沙利铂的敏感性，表明大黄酸可能是克服 PC 化疗耐药的有效策略。