Int J Biol Sci 2021; 17(2):589-602. doi:10.7150/ijbs.49514

Research Paper

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

Yuhui Liu1*, Chengjian Shi1*, Zheng He2*, Feng Zhu1, Min Wang1, Ruizhi He1, Chunle Zhao1, Xiuhui Shi1, Min Zhou1, Shutao Pan1, Yang Gao1, Xu Li1✉, Renyi Qin1✉

1. Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
2. Department of General Surgery, Shiyan People's Hospital of Bao'an Distict, Shenzhen, Guangdong, China.
* These authors contributed equally to this work.

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Citation:
Liu Y, Shi C, He Z, Zhu F, Wang M, He R, Zhao C, Shi X, Zhou M, Pan S, Gao Y, Li X, Qin R. Inhibition of PI3K/AKT signaling via ROS regulation is involved in Rhein-induced apoptosis and enhancement of oxaliplatin sensitivity in pancreatic cancer cells. Int J Biol Sci 2021; 17(2):589-602. doi:10.7150/ijbs.49514. Available from https://www.ijbs.com/v17p0589.htm

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Abstract

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.

Keywords: Pancreatic cancer, Rhein, PI3K/AKT pathway, Reactive oxygen species, Apoptosis, Oxaliplatin