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Inhibition of PI3K/AKT signaling via ROS regulation is involved in Rhein-induced apoptosis and enhancement of oxaliplatin sensitivity in pancreatic cancer cells

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单位: [1]Huazhong Univ Sci & Technol,Affiliated Tongji Hosp,Tongji Med Coll,Dept Biliary Pancreat Surg,1095 Jiefang Ave,Wuhan 430030,Hubei,Peoples R China [2]Shiyan Peoples Hosp Baoan Distict, Dept Gen Surg, Shenzhen, Guangdong, Peoples R China
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关键词: Pancreatic cancer Rhein PI3K/AKT pathway Reactive oxygen species Apoptosis Oxaliplatin

摘要:
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.

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出版当年[2020]版:
大类 | 2 区 生物
小类 | 3 区 生化与分子生物学
最新[2025]版:
大类 | 1 区 生物学
小类 | 2 区 生化与分子生物学
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出版当年[2019]版:
Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
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Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

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第一作者单位: [1]Huazhong Univ Sci & Technol,Affiliated Tongji Hosp,Tongji Med Coll,Dept Biliary Pancreat Surg,1095 Jiefang Ave,Wuhan 430030,Hubei,Peoples R China
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