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 |
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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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. 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. This work is published under https://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>The author(s) 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c406t-97d3623033249ebfe0333aa50df2bf541cfc0216a88e2ce908cc8b693bc75f123</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893580/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893580/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,725,778,782,883,27911,27912,53778,53780</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33613115$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liu, Yuhui</creatorcontrib><creatorcontrib>Shi, Chengjian</creatorcontrib><creatorcontrib>He, Zheng</creatorcontrib><creatorcontrib>Zhu, Feng</creatorcontrib><creatorcontrib>Wang, Min</creatorcontrib><creatorcontrib>He, Ruizhi</creatorcontrib><creatorcontrib>Zhao, Chunle</creatorcontrib><creatorcontrib>Shi, Xiuhui</creatorcontrib><creatorcontrib>Zhou, Min</creatorcontrib><creatorcontrib>Pan, Shutao</creatorcontrib><creatorcontrib>Gao, Yang</creatorcontrib><creatorcontrib>Li, Xu</creatorcontrib><creatorcontrib>Qin, Renyi</creatorcontrib><title>Inhibition of PI3K/AKT signaling via ROS regulation is involved in Rhein-induced apoptosis and enhancement of oxaliplatin sensitivity in pancreatic cancer cells</title><title>International journal of biological sciences</title><addtitle>Int J Biol Sci</addtitle><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.</description><subject>1-Phosphatidylinositol 3-kinase</subject><subject>AKT protein</subject><subject>Anthraquinones - pharmacology</subject><subject>Anthraquinones - therapeutic use</subject><subject>Antibodies</subject><subject>Anticancer properties</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Apoptosis</subject><subject>Cancer</subject><subject>Cancer therapies</subject><subject>Caspase</subject><subject>Cell cycle</subject><subject>Cell Line, Tumor</subject><subject>Cell proliferation</subject><subject>Chemotherapy</subject><subject>Combined treatment</subject><subject>Cytochrome</subject><subject>Deactivation</subject><subject>Drug resistance</subject><subject>Drug Resistance, Neoplasm - drug effects</subject><subject>Drug Screening Assays, Antitumor</subject><subject>Drug Synergism</subject><subject>Drugs</subject><subject>Flow cytometry</subject><subject>G1 phase</subject><subject>Humans</subject><subject>Inactivation</subject><subject>Kinases</subject><subject>Mitochondria</subject><subject>N-Acetyl-L-cysteine</subject><subject>Natural products</subject><subject>Oxaliplatin</subject><subject>Oxaliplatin - therapeutic use</subject><subject>Pancreatic cancer</subject><subject>Pancreatic Neoplasms - drug therapy</subject><subject>Pancreatic Neoplasms - metabolism</subject><subject>Pheochromocytoma cells</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>Phytotherapy</subject><subject>Proteins</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Reactive oxygen species</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>Reagents</subject><subject>Research Paper</subject><subject>Rheum</subject><subject>Rhubarb</subject><subject>Sensitivity enhancement</subject><subject>Side effects</subject><subject>Tumors</subject><issn>1449-2288</issn><issn>1449-2288</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><recordid>eNpdkd1KHTEUhYNU1Nre-AAS6I0URvMzP8mNIGLbg4Ji7XXIZPack8OcZExmBn2bPmozakW9yib7y9oreyF0QMlxRQtyYtd1PM5lQfMttEfzXGaMCfHpTb2LPse4JoSXhSA7aJfzknJKiz30d-FWtraD9Q77Ft8s-OXJ2eUdjnbpdGfdEk9W49vr3zjAcuz0E2gjtm7y3QRNKvDtCqzLrGtGky507_vBx8Ro12BwK-0MbMANs75_SKL9LONwBBfT4MkOj7NKn7gAqWOwmZ8EbKDr4he03eouwteXcx_9-XFxd_4ru7r-uTg_u8pMTsohk1XDS8YJ5yyXULeQKq51QZqW1W2RU9MawmiphQBmQBJhjKhLyWtTFS1lfB-dPuv2Y72BxiTDQXeqD3ajw6Py2qr3HWdXauknVQnJ01aTwNGLQPD3I8RBbWycv6Ad-DGq5CtFwURVJvTbB3Ttx5D2nahCCi6FzGdH358pE3yMAdpXM5SoOXg1B6-egk_w4Vv7r-j_pPk_C9-s1w</recordid><startdate>20210101</startdate><enddate>20210101</enddate><creator>Liu, Yuhui</creator><creator>Shi, Chengjian</creator><creator>He, Zheng</creator><creator>Zhu, Feng</creator><creator>Wang, Min</creator><creator>He, Ruizhi</creator><creator>Zhao, Chunle</creator><creator>Shi, Xiuhui</creator><creator>Zhou, Min</creator><creator>Pan, Shutao</creator><creator>Gao, Yang</creator><creator>Li, Xu</creator><creator>Qin, Renyi</creator><general>Ivyspring International Publisher Pty Ltd</general><general>Ivyspring International Publisher</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QL</scope><scope>7QO</scope><scope>7U9</scope><scope>8FD</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20210101</creationdate><title>Inhibition of PI3K/AKT signaling via ROS regulation is involved in Rhein-induced apoptosis and enhancement of oxaliplatin sensitivity in pancreatic cancer cells</title><author>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</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c406t-97d3623033249ebfe0333aa50df2bf541cfc0216a88e2ce908cc8b693bc75f123</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>1-Phosphatidylinositol 3-kinase</topic><topic>AKT protein</topic><topic>Anthraquinones - pharmacology</topic><topic>Anthraquinones - therapeutic use</topic><topic>Antibodies</topic><topic>Anticancer properties</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Apoptosis</topic><topic>Cancer</topic><topic>Cancer therapies</topic><topic>Caspase</topic><topic>Cell cycle</topic><topic>Cell Line, Tumor</topic><topic>Cell proliferation</topic><topic>Chemotherapy</topic><topic>Combined treatment</topic><topic>Cytochrome</topic><topic>Deactivation</topic><topic>Drug resistance</topic><topic>Drug Resistance, Neoplasm - drug effects</topic><topic>Drug Screening Assays, Antitumor</topic><topic>Drug Synergism</topic><topic>Drugs</topic><topic>Flow cytometry</topic><topic>G1 phase</topic><topic>Humans</topic><topic>Inactivation</topic><topic>Kinases</topic><topic>Mitochondria</topic><topic>N-Acetyl-L-cysteine</topic><topic>Natural products</topic><topic>Oxaliplatin</topic><topic>Oxaliplatin - therapeutic use</topic><topic>Pancreatic cancer</topic><topic>Pancreatic Neoplasms - drug therapy</topic><topic>Pancreatic Neoplasms - metabolism</topic><topic>Pheochromocytoma cells</topic><topic>Phosphatidylinositol 3-Kinases - metabolism</topic><topic>Phytotherapy</topic><topic>Proteins</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Reactive oxygen species</topic><topic>Reactive Oxygen Species - metabolism</topic><topic>Reagents</topic><topic>Research Paper</topic><topic>Rheum</topic><topic>Rhubarb</topic><topic>Sensitivity enhancement</topic><topic>Side effects</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Liu, Yuhui</creatorcontrib><creatorcontrib>Shi, Chengjian</creatorcontrib><creatorcontrib>He, Zheng</creatorcontrib><creatorcontrib>Zhu, Feng</creatorcontrib><creatorcontrib>Wang, Min</creatorcontrib><creatorcontrib>He, Ruizhi</creatorcontrib><creatorcontrib>Zhao, Chunle</creatorcontrib><creatorcontrib>Shi, Xiuhui</creatorcontrib><creatorcontrib>Zhou, Min</creatorcontrib><creatorcontrib>Pan, Shutao</creatorcontrib><creatorcontrib>Gao, Yang</creatorcontrib><creatorcontrib>Li, Xu</creatorcontrib><creatorcontrib>Qin, Renyi</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>International journal of biological sciences</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Liu, Yuhui</au><au>Shi, Chengjian</au><au>He, Zheng</au><au>Zhu, Feng</au><au>Wang, Min</au><au>He, Ruizhi</au><au>Zhao, Chunle</au><au>Shi, Xiuhui</au><au>Zhou, Min</au><au>Pan, Shutao</au><au>Gao, Yang</au><au>Li, Xu</au><au>Qin, Renyi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of PI3K/AKT signaling via ROS regulation is involved in Rhein-induced apoptosis and enhancement of oxaliplatin sensitivity in pancreatic cancer cells</atitle><jtitle>International journal of biological sciences</jtitle><addtitle>Int J Biol Sci</addtitle><date>2021-01-01</date><risdate>2021</risdate><volume>17</volume><issue>2</issue><spage>589</spage><epage>602</epage><pages>589-602</pages><issn>1449-2288</issn><eissn>1449-2288</eissn><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
. 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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