Protein Kinase B Inactivation Is Associated with Magnolol-Enhanced Therapeutic Efficacy of Sorafenib in Hepatocellular Carcinoma In Vitro and In Vivo
Although sorafenib, an oral multikinase inhibitor, was approved as a treatment drug of advance hepatocellular carcinoma (HCC), treatment efficacy still requires improvement. Searching for the adjuvant reagent for enhancing sorafenib efficacy remains as a critical issue. Sorafenib has been proved to...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2019-12-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/12/1/87 |
| _version_ | 1797726311531151360 |
|---|---|
| author | Jiann-Hwa Chen I-Tsang Chiang Fei-Ting Hsu |
| author_facet | Jiann-Hwa Chen I-Tsang Chiang Fei-Ting Hsu |
| author_sort | Jiann-Hwa Chen |
| collection | DOAJ |
| description | Although sorafenib, an oral multikinase inhibitor, was approved as a treatment drug of advance hepatocellular carcinoma (HCC), treatment efficacy still requires improvement. Searching for the adjuvant reagent for enhancing sorafenib efficacy remains as a critical issue. Sorafenib has been proved to suppress extracellular signal-regulated kinases (ERK) in HCC; however, protein kinase B (AKT) was not affected by it. Targeting AKT in combination with sorafenib could be an important breakthrough point of HCC treatment. Many herbal compounds and composite formulas have been shown to enhance anti-HCC activity of sorafenib. Magnolol is a bioactive compound extracted from the bark of the <i>Magnolia officinalis</i> and has been shown to induce apoptosis and inhibit cell invasion in HCC in vitro. However, whether magnolol sensitizes HCC to sorafenib is ambiguous. In this study, we indicated that magnolol significantly enhanced sorafenib-diminished tumor cell growth, expression of anti-apoptotic proteins, and migration/invasion ability compared to sorafenib alone. Magnolol significantly boosted sorafenib-induced extrinsic/intrinsic dependent apoptosis pathways in HCC. Notably sorafenib could not reduce protein level of AKT (Ser473), but expression of AKT (Ser473) was significantly decreased by magnolol or magnolol combined with sorafenib. LY294002 as specific AKT inhibitor was used to confirm that AKT inactivation may promote anticancer effect of sorafenib. Taken together, AKT inhibition is associated with magnolol-enhanced the therapeutic effect of sorafenib in HCC. We suggested magnolol as the potential adjuvant which may enhance therapeutic benefits of sorafenib in patients with HCC. |
| first_indexed | 2024-03-12T10:43:47Z |
| format | Article |
| id | doaj.art-9a9dd8f3d51c43b38f564be0adfa2ccb |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T10:43:47Z |
| publishDate | 2019-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-9a9dd8f3d51c43b38f564be0adfa2ccb2023-09-02T07:50:06ZengMDPI AGCancers2072-66942019-12-011218710.3390/cancers12010087cancers12010087Protein Kinase B Inactivation Is Associated with Magnolol-Enhanced Therapeutic Efficacy of Sorafenib in Hepatocellular Carcinoma In Vitro and In VivoJiann-Hwa Chen0I-Tsang Chiang1Fei-Ting Hsu2Department of Emergency Medicine, Cathay General Hospital, Taipei 280, TaiwanDepartment of Radiation Oncology, Show Chwan Memorial Hospital, Changhua 500, TaiwanDepartment of Biological Science and Technology, China Medical University, Taichung 404, TaiwanAlthough sorafenib, an oral multikinase inhibitor, was approved as a treatment drug of advance hepatocellular carcinoma (HCC), treatment efficacy still requires improvement. Searching for the adjuvant reagent for enhancing sorafenib efficacy remains as a critical issue. Sorafenib has been proved to suppress extracellular signal-regulated kinases (ERK) in HCC; however, protein kinase B (AKT) was not affected by it. Targeting AKT in combination with sorafenib could be an important breakthrough point of HCC treatment. Many herbal compounds and composite formulas have been shown to enhance anti-HCC activity of sorafenib. Magnolol is a bioactive compound extracted from the bark of the <i>Magnolia officinalis</i> and has been shown to induce apoptosis and inhibit cell invasion in HCC in vitro. However, whether magnolol sensitizes HCC to sorafenib is ambiguous. In this study, we indicated that magnolol significantly enhanced sorafenib-diminished tumor cell growth, expression of anti-apoptotic proteins, and migration/invasion ability compared to sorafenib alone. Magnolol significantly boosted sorafenib-induced extrinsic/intrinsic dependent apoptosis pathways in HCC. Notably sorafenib could not reduce protein level of AKT (Ser473), but expression of AKT (Ser473) was significantly decreased by magnolol or magnolol combined with sorafenib. LY294002 as specific AKT inhibitor was used to confirm that AKT inactivation may promote anticancer effect of sorafenib. Taken together, AKT inhibition is associated with magnolol-enhanced the therapeutic effect of sorafenib in HCC. We suggested magnolol as the potential adjuvant which may enhance therapeutic benefits of sorafenib in patients with HCC.https://www.mdpi.com/2072-6694/12/1/87magnololsorafenibakthepatocellular carcinoma |
| spellingShingle | Jiann-Hwa Chen I-Tsang Chiang Fei-Ting Hsu Protein Kinase B Inactivation Is Associated with Magnolol-Enhanced Therapeutic Efficacy of Sorafenib in Hepatocellular Carcinoma In Vitro and In Vivo Cancers magnolol sorafenib akt hepatocellular carcinoma |
| title | Protein Kinase B Inactivation Is Associated with Magnolol-Enhanced Therapeutic Efficacy of Sorafenib in Hepatocellular Carcinoma In Vitro and In Vivo |
| title_full | Protein Kinase B Inactivation Is Associated with Magnolol-Enhanced Therapeutic Efficacy of Sorafenib in Hepatocellular Carcinoma In Vitro and In Vivo |
| title_fullStr | Protein Kinase B Inactivation Is Associated with Magnolol-Enhanced Therapeutic Efficacy of Sorafenib in Hepatocellular Carcinoma In Vitro and In Vivo |
| title_full_unstemmed | Protein Kinase B Inactivation Is Associated with Magnolol-Enhanced Therapeutic Efficacy of Sorafenib in Hepatocellular Carcinoma In Vitro and In Vivo |
| title_short | Protein Kinase B Inactivation Is Associated with Magnolol-Enhanced Therapeutic Efficacy of Sorafenib in Hepatocellular Carcinoma In Vitro and In Vivo |
| title_sort | protein kinase b inactivation is associated with magnolol enhanced therapeutic efficacy of sorafenib in hepatocellular carcinoma in vitro and in vivo |
| topic | magnolol sorafenib akt hepatocellular carcinoma |
| url | https://www.mdpi.com/2072-6694/12/1/87 |
| work_keys_str_mv | AT jiannhwachen proteinkinasebinactivationisassociatedwithmagnololenhancedtherapeuticefficacyofsorafenibinhepatocellularcarcinomainvitroandinvivo AT itsangchiang proteinkinasebinactivationisassociatedwithmagnololenhancedtherapeuticefficacyofsorafenibinhepatocellularcarcinomainvitroandinvivo AT feitinghsu proteinkinasebinactivationisassociatedwithmagnololenhancedtherapeuticefficacyofsorafenibinhepatocellularcarcinomainvitroandinvivo |