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

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 pharmacolog...

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Veröffentlicht in:International journal of biological sciences 2021-01, Vol.17 (2), p.589-602
Hauptverfasser: Liu, Yuhui, Shi, Chengjian, He, Zheng, Zhu, Feng, Wang, Min, He, Ruizhi, Zhao, Chunle, Shi, Xiuhui, Zhou, Min, Pan, Shutao, Gao, Yang, Li, Xu, Qin, Renyi
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container_issue 2
container_start_page 589
container_title International journal of biological sciences
container_volume 17
creator Liu, Yuhui
Shi, Chengjian
He, Zheng
Zhu, Feng
Wang, Min
He, Ruizhi
Zhao, Chunle
Shi, Xiuhui
Zhou, Min
Pan, Shutao
Gao, Yang
Li, Xu
Qin, Renyi
description 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 . 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.
doi_str_mv 10.7150/ijbs.49514
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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 . 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.</description><identifier>ISSN: 1449-2288</identifier><identifier>EISSN: 1449-2288</identifier><identifier>DOI: 10.7150/ijbs.49514</identifier><identifier>PMID: 33613115</identifier><language>eng</language><publisher>Australia: Ivyspring International Publisher Pty Ltd</publisher><subject>1-Phosphatidylinositol 3-kinase ; AKT protein ; Anthraquinones - pharmacology ; Anthraquinones - therapeutic use ; Antibodies ; Anticancer properties ; Antineoplastic Agents - therapeutic use ; Apoptosis ; Cancer ; Cancer therapies ; Caspase ; Cell cycle ; Cell Line, Tumor ; Cell proliferation ; Chemotherapy ; Combined treatment ; Cytochrome ; Deactivation ; Drug resistance ; Drug Resistance, Neoplasm - drug effects ; Drug Screening Assays, Antitumor ; Drug Synergism ; Drugs ; Flow cytometry ; G1 phase ; Humans ; Inactivation ; Kinases ; Mitochondria ; N-Acetyl-L-cysteine ; Natural products ; Oxaliplatin ; Oxaliplatin - therapeutic use ; Pancreatic cancer ; Pancreatic Neoplasms - drug therapy ; Pancreatic Neoplasms - metabolism ; Pheochromocytoma cells ; Phosphatidylinositol 3-Kinases - metabolism ; Phytotherapy ; Proteins ; Proto-Oncogene Proteins c-akt - metabolism ; Reactive oxygen species ; Reactive Oxygen Species - metabolism ; Reagents ; Research Paper ; Rheum ; Rhubarb ; Sensitivity enhancement ; Side effects ; Tumors</subject><ispartof>International journal of biological sciences, 2021-01, Vol.17 (2), p.589-602</ispartof><rights>The author(s).</rights><rights>2021. 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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. 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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 . 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.</abstract><cop>Australia</cop><pub>Ivyspring International Publisher Pty Ltd</pub><pmid>33613115</pmid><doi>10.7150/ijbs.49514</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record>
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subjects 1-Phosphatidylinositol 3-kinase
AKT protein
Anthraquinones - pharmacology
Anthraquinones - therapeutic use
Antibodies
Anticancer properties
Antineoplastic Agents - therapeutic use
Apoptosis
Cancer
Cancer therapies
Caspase
Cell cycle
Cell Line, Tumor
Cell proliferation
Chemotherapy
Combined treatment
Cytochrome
Deactivation
Drug resistance
Drug Resistance, Neoplasm - drug effects
Drug Screening Assays, Antitumor
Drug Synergism
Drugs
Flow cytometry
G1 phase
Humans
Inactivation
Kinases
Mitochondria
N-Acetyl-L-cysteine
Natural products
Oxaliplatin
Oxaliplatin - therapeutic use
Pancreatic cancer
Pancreatic Neoplasms - drug therapy
Pancreatic Neoplasms - metabolism
Pheochromocytoma cells
Phosphatidylinositol 3-Kinases - metabolism
Phytotherapy
Proteins
Proto-Oncogene Proteins c-akt - metabolism
Reactive oxygen species
Reactive Oxygen Species - metabolism
Reagents
Research Paper
Rheum
Rhubarb
Sensitivity enhancement
Side effects
Tumors
title 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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