Combined Treatment of Tanshinone I and Epirubicin Revealed Enhanced Inhibition of Hepatocellular Carcinoma by Targeting PI3K/AKT/HIF-1[alpha]

Background: Epirubicin (EADM) is a common chemotherapeutic agent in hepatocellular carcinoma (HCC). The accumulation of hypoxia-inducible factor-1[alpha] (HIF-1[alpha]) is an important cause of drug resistance to EADM in HCC. Tanshinone I (Tan I) is an agent with promising anti-cancer effects alone...

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Veröffentlicht in:Drug design, development and therapy development and therapy, 2022-09, Vol.16, p.3197
Hauptverfasser: Zhao, Jiali, Lin, En, Cai, Chaonong, Zhang, Manyao, Li, Decheng, Cai, Shanglin, Zeng, Guifang, Yin, Zeren, Wang, Bo, Li, Peiping, Hong, Xiaopeng, Chen, Jiafan, Zou, Baojia, Li, Jian
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container_title Drug design, development and therapy
container_volume 16
creator Zhao, Jiali
Lin, En
Cai, Chaonong
Zhang, Manyao
Li, Decheng
Cai, Shanglin
Zeng, Guifang
Yin, Zeren
Wang, Bo
Li, Peiping
Hong, Xiaopeng
Chen, Jiafan
Zou, Baojia
Li, Jian
description Background: Epirubicin (EADM) is a common chemotherapeutic agent in hepatocellular carcinoma (HCC). The accumulation of hypoxia-inducible factor-1[alpha] (HIF-1[alpha]) is an important cause of drug resistance to EADM in HCC. Tanshinone I (Tan I) is an agent with promising anti-cancer effects alone or with other drugs. Some tanshinones mediate HIF-1[alpha] regulation via PI3K/AKT. However, the role of Tan I combined with EADM to reduce the resistance of HCC to EADM has not been investigated. Therefore, this study aimed to investigate the combined use of Tan I and EADM in HCC and the underlying mechanism of PI3K/AKT/HIF-1[alpha]. Methods: HCC cells were treated with Tan I, EADM, or the combined treatment for 48 hrs. Cell transfection was used to construct HIF-1[alpha] overexpression HCC stable cells. Cell viability, colony formation, and flow cytometric assays were used to detect the viability, proliferation, and apoptosis in HCC cells. Synergism between Tan I and EADM were tested by calculating the Bliss synergy score, positive excess over bliss additivism (EOBA), and the combination index (CI). Western blotting analyses were used to detect the levels of [beta]-actin, HIF-1[alpha], PI3K p1 10[alpha], p-Akt Thr308, Cleaved Caspase-3, and Cleaved Caspase-9. Toxicity parameters were used to evaluate the safety of the combination in mice. The xenograft model of mice was built by HCC stable cell lines, which was administrated with Tan I, EADM, or a combination of them for 8 weeks. Immunohistochemistry staining (IHC) was used to assess tumor apoptosis in mouse models. Results: Hypoxia could upregulate HIF-1[alpha] to induce drug resistance in HCC cancer cells. The combination of Tan I and EADM was synergistic. Although Tan I or EADM alone could inhibit HCC cancer cells, the combination of them could further enhance the cytotoxicity and growth inhibition by targeting the PI3K/AKT/HIF-1[alpha] signaling pathway. Furthermore, Tan I and EADM synergistically reversed HIF-1[alpha]-mediated drug resistance to inhibit HCC. The results of toxicity parameters showed that the combination was safe in mice. Meanwhile, animal models showed that Tan I not only improved the anti-tumor effect of EADM, but also reduced the drug reactions of EADM-induced weight loss. Conclusion: Our results suggested that Tan I could effectively improve the anti-tumor effect of EADM, and synergize EADM to reverse HIF-1[alpha] mediated resistance via targeting PI3K/AKT/HIF-1[alpha] signaling pathwa
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The accumulation of hypoxia-inducible factor-1[alpha] (HIF-1[alpha]) is an important cause of drug resistance to EADM in HCC. Tanshinone I (Tan I) is an agent with promising anti-cancer effects alone or with other drugs. Some tanshinones mediate HIF-1[alpha] regulation via PI3K/AKT. However, the role of Tan I combined with EADM to reduce the resistance of HCC to EADM has not been investigated. Therefore, this study aimed to investigate the combined use of Tan I and EADM in HCC and the underlying mechanism of PI3K/AKT/HIF-1[alpha]. Methods: HCC cells were treated with Tan I, EADM, or the combined treatment for 48 hrs. Cell transfection was used to construct HIF-1[alpha] overexpression HCC stable cells. Cell viability, colony formation, and flow cytometric assays were used to detect the viability, proliferation, and apoptosis in HCC cells. Synergism between Tan I and EADM were tested by calculating the Bliss synergy score, positive excess over bliss additivism (EOBA), and the combination index (CI). Western blotting analyses were used to detect the levels of [beta]-actin, HIF-1[alpha], PI3K p1 10[alpha], p-Akt Thr308, Cleaved Caspase-3, and Cleaved Caspase-9. Toxicity parameters were used to evaluate the safety of the combination in mice. The xenograft model of mice was built by HCC stable cell lines, which was administrated with Tan I, EADM, or a combination of them for 8 weeks. Immunohistochemistry staining (IHC) was used to assess tumor apoptosis in mouse models. Results: Hypoxia could upregulate HIF-1[alpha] to induce drug resistance in HCC cancer cells. The combination of Tan I and EADM was synergistic. Although Tan I or EADM alone could inhibit HCC cancer cells, the combination of them could further enhance the cytotoxicity and growth inhibition by targeting the PI3K/AKT/HIF-1[alpha] signaling pathway. Furthermore, Tan I and EADM synergistically reversed HIF-1[alpha]-mediated drug resistance to inhibit HCC. The results of toxicity parameters showed that the combination was safe in mice. Meanwhile, animal models showed that Tan I not only improved the anti-tumor effect of EADM, but also reduced the drug reactions of EADM-induced weight loss. Conclusion: Our results suggested that Tan I could effectively improve the anti-tumor effect of EADM, and synergize EADM to reverse HIF-1[alpha] mediated resistance via targeting PI3K/AKT/HIF-1[alpha] signaling pathway. Keywords: hepatocellular carcinoma, epirubicin, Tanshinone I, HIF-1[alpha], resistance</description><identifier>ISSN: 1177-8881</identifier><identifier>EISSN: 1177-8881</identifier><identifier>DOI: 10.2147/DDDT.S360691</identifier><language>eng</language><publisher>Dove Medical Press Limited</publisher><subject>Analysis ; Antimitotic agents ; Antineoplastic agents ; Cancer ; Chemotherapy ; Drug resistance ; Hepatoma ; Immunohistochemistry ; Measuring instruments ; Muscle proteins</subject><ispartof>Drug design, development and therapy, 2022-09, Vol.16, p.3197</ispartof><rights>COPYRIGHT 2022 Dove Medical Press Limited</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,781,785,865,27929,27930</link.rule.ids></links><search><creatorcontrib>Zhao, Jiali</creatorcontrib><creatorcontrib>Lin, En</creatorcontrib><creatorcontrib>Cai, Chaonong</creatorcontrib><creatorcontrib>Zhang, Manyao</creatorcontrib><creatorcontrib>Li, Decheng</creatorcontrib><creatorcontrib>Cai, Shanglin</creatorcontrib><creatorcontrib>Zeng, Guifang</creatorcontrib><creatorcontrib>Yin, Zeren</creatorcontrib><creatorcontrib>Wang, Bo</creatorcontrib><creatorcontrib>Li, Peiping</creatorcontrib><creatorcontrib>Hong, Xiaopeng</creatorcontrib><creatorcontrib>Chen, Jiafan</creatorcontrib><creatorcontrib>Zou, Baojia</creatorcontrib><creatorcontrib>Li, Jian</creatorcontrib><title>Combined Treatment of Tanshinone I and Epirubicin Revealed Enhanced Inhibition of Hepatocellular Carcinoma by Targeting PI3K/AKT/HIF-1[alpha]</title><title>Drug design, development and therapy</title><description>Background: Epirubicin (EADM) is a common chemotherapeutic agent in hepatocellular carcinoma (HCC). The accumulation of hypoxia-inducible factor-1[alpha] (HIF-1[alpha]) is an important cause of drug resistance to EADM in HCC. Tanshinone I (Tan I) is an agent with promising anti-cancer effects alone or with other drugs. Some tanshinones mediate HIF-1[alpha] regulation via PI3K/AKT. However, the role of Tan I combined with EADM to reduce the resistance of HCC to EADM has not been investigated. Therefore, this study aimed to investigate the combined use of Tan I and EADM in HCC and the underlying mechanism of PI3K/AKT/HIF-1[alpha]. Methods: HCC cells were treated with Tan I, EADM, or the combined treatment for 48 hrs. Cell transfection was used to construct HIF-1[alpha] overexpression HCC stable cells. Cell viability, colony formation, and flow cytometric assays were used to detect the viability, proliferation, and apoptosis in HCC cells. Synergism between Tan I and EADM were tested by calculating the Bliss synergy score, positive excess over bliss additivism (EOBA), and the combination index (CI). Western blotting analyses were used to detect the levels of [beta]-actin, HIF-1[alpha], PI3K p1 10[alpha], p-Akt Thr308, Cleaved Caspase-3, and Cleaved Caspase-9. Toxicity parameters were used to evaluate the safety of the combination in mice. The xenograft model of mice was built by HCC stable cell lines, which was administrated with Tan I, EADM, or a combination of them for 8 weeks. Immunohistochemistry staining (IHC) was used to assess tumor apoptosis in mouse models. Results: Hypoxia could upregulate HIF-1[alpha] to induce drug resistance in HCC cancer cells. The combination of Tan I and EADM was synergistic. Although Tan I or EADM alone could inhibit HCC cancer cells, the combination of them could further enhance the cytotoxicity and growth inhibition by targeting the PI3K/AKT/HIF-1[alpha] signaling pathway. Furthermore, Tan I and EADM synergistically reversed HIF-1[alpha]-mediated drug resistance to inhibit HCC. The results of toxicity parameters showed that the combination was safe in mice. Meanwhile, animal models showed that Tan I not only improved the anti-tumor effect of EADM, but also reduced the drug reactions of EADM-induced weight loss. Conclusion: Our results suggested that Tan I could effectively improve the anti-tumor effect of EADM, and synergize EADM to reverse HIF-1[alpha] mediated resistance via targeting PI3K/AKT/HIF-1[alpha] signaling pathway. Keywords: hepatocellular carcinoma, epirubicin, Tanshinone I, HIF-1[alpha], resistance</description><subject>Analysis</subject><subject>Antimitotic agents</subject><subject>Antineoplastic agents</subject><subject>Cancer</subject><subject>Chemotherapy</subject><subject>Drug resistance</subject><subject>Hepatoma</subject><subject>Immunohistochemistry</subject><subject>Measuring instruments</subject><subject>Muscle proteins</subject><issn>1177-8881</issn><issn>1177-8881</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid/><recordid>eNptkFFLwzAUhYMoOKdv_oCA4Fu3JmnT9nF0mysbKNo3kXGTpW2kTUabCf4I_7MZ-jBB7sM9XM534B6Ebkk4oSRKpvP5vJy8MB7yjJyhESFJEqRpSs5P9CW6Gob3MOSM03CEvnLbCW3UDpe9Atcp47CtcAlmaLSxRuECg9nhxV73B6GlNvhZfShoPbEwDRjpRWEaLbTT1hzZldqDs1K17aGFHufQe8p2gMWnz-1r5bSp8VPB1tPZupyuimVAXqHdN_B2jS4qaAd187vHqFwuynwVbB4finy2Ceos5QGotAKZMAFJBTQmQpJMABeMCpkRxqMIMprGWRwxCUQkRHFPRFzFPI6hAjZGdz-xtf9jq01lXQ-y04PczhLKaBQSzr1r8o_Lz051WvpqKu3vf4D7E6DxJblmsO3hWMxwavwGZb2BsQ</recordid><startdate>20220930</startdate><enddate>20220930</enddate><creator>Zhao, Jiali</creator><creator>Lin, En</creator><creator>Cai, Chaonong</creator><creator>Zhang, Manyao</creator><creator>Li, Decheng</creator><creator>Cai, Shanglin</creator><creator>Zeng, Guifang</creator><creator>Yin, Zeren</creator><creator>Wang, Bo</creator><creator>Li, Peiping</creator><creator>Hong, Xiaopeng</creator><creator>Chen, Jiafan</creator><creator>Zou, Baojia</creator><creator>Li, Jian</creator><general>Dove Medical Press Limited</general><scope/></search><sort><creationdate>20220930</creationdate><title>Combined Treatment of Tanshinone I and Epirubicin Revealed Enhanced Inhibition of Hepatocellular Carcinoma by Targeting PI3K/AKT/HIF-1[alpha]</title><author>Zhao, Jiali ; Lin, En ; Cai, Chaonong ; Zhang, Manyao ; Li, Decheng ; Cai, Shanglin ; Zeng, Guifang ; Yin, Zeren ; Wang, Bo ; Li, Peiping ; Hong, Xiaopeng ; Chen, Jiafan ; Zou, Baojia ; Li, Jian</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-g986-ae8fac73ba7fa251bc19ba6b32bc913644a92859543ca1b71e6e8f46e5655afa3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Analysis</topic><topic>Antimitotic agents</topic><topic>Antineoplastic agents</topic><topic>Cancer</topic><topic>Chemotherapy</topic><topic>Drug resistance</topic><topic>Hepatoma</topic><topic>Immunohistochemistry</topic><topic>Measuring instruments</topic><topic>Muscle proteins</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhao, Jiali</creatorcontrib><creatorcontrib>Lin, En</creatorcontrib><creatorcontrib>Cai, Chaonong</creatorcontrib><creatorcontrib>Zhang, Manyao</creatorcontrib><creatorcontrib>Li, Decheng</creatorcontrib><creatorcontrib>Cai, Shanglin</creatorcontrib><creatorcontrib>Zeng, Guifang</creatorcontrib><creatorcontrib>Yin, Zeren</creatorcontrib><creatorcontrib>Wang, Bo</creatorcontrib><creatorcontrib>Li, Peiping</creatorcontrib><creatorcontrib>Hong, Xiaopeng</creatorcontrib><creatorcontrib>Chen, Jiafan</creatorcontrib><creatorcontrib>Zou, Baojia</creatorcontrib><creatorcontrib>Li, Jian</creatorcontrib><jtitle>Drug design, development and therapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhao, Jiali</au><au>Lin, En</au><au>Cai, Chaonong</au><au>Zhang, Manyao</au><au>Li, Decheng</au><au>Cai, Shanglin</au><au>Zeng, Guifang</au><au>Yin, Zeren</au><au>Wang, Bo</au><au>Li, Peiping</au><au>Hong, Xiaopeng</au><au>Chen, Jiafan</au><au>Zou, Baojia</au><au>Li, Jian</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Combined Treatment of Tanshinone I and Epirubicin Revealed Enhanced Inhibition of Hepatocellular Carcinoma by Targeting PI3K/AKT/HIF-1[alpha]</atitle><jtitle>Drug design, development and therapy</jtitle><date>2022-09-30</date><risdate>2022</risdate><volume>16</volume><spage>3197</spage><pages>3197-</pages><issn>1177-8881</issn><eissn>1177-8881</eissn><abstract>Background: Epirubicin (EADM) is a common chemotherapeutic agent in hepatocellular carcinoma (HCC). The accumulation of hypoxia-inducible factor-1[alpha] (HIF-1[alpha]) is an important cause of drug resistance to EADM in HCC. Tanshinone I (Tan I) is an agent with promising anti-cancer effects alone or with other drugs. Some tanshinones mediate HIF-1[alpha] regulation via PI3K/AKT. However, the role of Tan I combined with EADM to reduce the resistance of HCC to EADM has not been investigated. Therefore, this study aimed to investigate the combined use of Tan I and EADM in HCC and the underlying mechanism of PI3K/AKT/HIF-1[alpha]. Methods: HCC cells were treated with Tan I, EADM, or the combined treatment for 48 hrs. Cell transfection was used to construct HIF-1[alpha] overexpression HCC stable cells. Cell viability, colony formation, and flow cytometric assays were used to detect the viability, proliferation, and apoptosis in HCC cells. Synergism between Tan I and EADM were tested by calculating the Bliss synergy score, positive excess over bliss additivism (EOBA), and the combination index (CI). Western blotting analyses were used to detect the levels of [beta]-actin, HIF-1[alpha], PI3K p1 10[alpha], p-Akt Thr308, Cleaved Caspase-3, and Cleaved Caspase-9. Toxicity parameters were used to evaluate the safety of the combination in mice. The xenograft model of mice was built by HCC stable cell lines, which was administrated with Tan I, EADM, or a combination of them for 8 weeks. Immunohistochemistry staining (IHC) was used to assess tumor apoptosis in mouse models. Results: Hypoxia could upregulate HIF-1[alpha] to induce drug resistance in HCC cancer cells. The combination of Tan I and EADM was synergistic. Although Tan I or EADM alone could inhibit HCC cancer cells, the combination of them could further enhance the cytotoxicity and growth inhibition by targeting the PI3K/AKT/HIF-1[alpha] signaling pathway. Furthermore, Tan I and EADM synergistically reversed HIF-1[alpha]-mediated drug resistance to inhibit HCC. The results of toxicity parameters showed that the combination was safe in mice. Meanwhile, animal models showed that Tan I not only improved the anti-tumor effect of EADM, but also reduced the drug reactions of EADM-induced weight loss. Conclusion: Our results suggested that Tan I could effectively improve the anti-tumor effect of EADM, and synergize EADM to reverse HIF-1[alpha] mediated resistance via targeting PI3K/AKT/HIF-1[alpha] signaling pathway. Keywords: hepatocellular carcinoma, epirubicin, Tanshinone I, HIF-1[alpha], resistance</abstract><pub>Dove Medical Press Limited</pub><doi>10.2147/DDDT.S360691</doi></addata></record>
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subjects Analysis
Antimitotic agents
Antineoplastic agents
Cancer
Chemotherapy
Drug resistance
Hepatoma
Immunohistochemistry
Measuring instruments
Muscle proteins
title Combined Treatment of Tanshinone I and Epirubicin Revealed Enhanced Inhibition of Hepatocellular Carcinoma by Targeting PI3K/AKT/HIF-1[alpha]
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