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Shahrokhi H, Asili J, Tayarani-Najaran Z, Boozari M. Signaling pathways behind the biological effects of tanshinone IIA for the prevention of cancer and cardiovascular diseases. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-03857-x. [PMID: 39937254 DOI: 10.1007/s00210-025-03857-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Accepted: 01/24/2025] [Indexed: 02/13/2025]
Abstract
Tanshinone IIA (Tan IIA) is a well-known fat-soluble diterpenoid found in Salvia miltiorrhiza, recognized for its various biological effects. The molecular signaling pathways of Tan IIA have been investigated in different diseases, including the anti-inflammatory, hepatoprotective, renoprotective, neuroprotective effects, and fibrosis prevention. This article provides a brief overview of the signaling pathways related to anti-cancer and cardioprotective effects of Tan IIA. It shows that Tan IIAs anti-cancer ability has good expectation through multiplicity mechanisms affecting various aspects' tumor biology. The major pathways involved in its anti-cancer effects include inhibition of PI3/Akt, MAPK, and p53/p21 signaling which leads to enhancement of immune responses and increased radiation sensitivity. Some essential pathways responsible for cardioprotective effects induced by Tan IIA are PI3/AKT activation, MAPK, and SIRT1 promoting protection against ischemia/reperfusion injury in myocardial cells as well as inhibiting pathological remodeling processes. Finally, the article underscores the complex and specific signaling pathways influenced by Tan IIA. The PI3/Akt and MAPK pathways play critical roles in the anti-cancer and cardioprotective effects of Tan IIA. Particularly, Tan IIA suppresses the proliferation of malignancies in cancerous cells but stimulates protective mechanisms in normal cardiovascular cells. These findings highlight the importance of investigating molecular signaling pathways in evaluating the therapeutic potential of natural products. Studying about signaling pathways is vital in understanding the therapeutic aspects of Tan IIA and its derivatives as anti-cancer and cardio-protective agents. Further research is necessary to understand these complex mechanisms.
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Affiliation(s)
- Homa Shahrokhi
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Javad Asili
- Department of Pharmacognosy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Zahra Tayarani-Najaran
- Medical Toxicology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Motahareh Boozari
- Department of Pharmacognosy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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Shinhmar S, Schaf J, Lloyd Jones K, Pardo OE, Beesley P, Williams RSB. Developing a Tanshinone IIA Memetic by Targeting MIOS to Regulate mTORC1 and Autophagy in Glioblastoma. Int J Mol Sci 2024; 25:6586. [PMID: 38928292 PMCID: PMC11204349 DOI: 10.3390/ijms25126586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Revised: 06/05/2024] [Accepted: 06/11/2024] [Indexed: 06/28/2024] Open
Abstract
Tanshinone IIA (T2A) is a bioactive compound that provides promise in the treatment of glioblastoma multiforme (GBM), with a range of molecular mechanisms including the inhibition of the mechanistic target of rapamycin complex 1 (mTORC1) and the induction of autophagy. Recently, T2A has been demonstrated to function through sestrin 2 (SESN) to inhibit mTORC1 activity, but its possible impact on autophagy through this pathway has not been investigated. Here, the model system Dictyostelium discoideum and GBM cell lines were employed to investigate the cellular role of T2A in regulating SESN to inhibit mTORC1 and activate autophagy through a GATOR2 component MIOS. In D. discoideum, T2A treatment induced autophagy and inhibited mTORC1 activity, with both effects lost upon the ablation of SESN (sesn-) or MIOS (mios-). We further investigated the targeting of MIOS to reproduce this effect of T2A, where computational analysis identified 25 novel compounds predicted to strongly bind the human MIOS protein, with one compound (MIOS inhibitor 3; Mi3) reducing cell proliferation in two GBM cells. Furthermore, Mi3 specificity was demonstrated through the loss of potency in the D. discoideum mios- cells regarding cell proliferation and the induction of autophagy. In GBM cells, Mi3 treatment also reduced mTORC1 activity and induced autophagy. Thus, a potential T2A mimetic showing the inhibition of mTORC1 and induction of autophagy in GBM cells was identified.
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Affiliation(s)
- Sonia Shinhmar
- Centre for Biomedical Sciences, School of Biological Sciences, Royal Holloway University of London, Egham TW20 0EX, UK; (S.S.); (J.S.); (K.L.J.); (P.B.)
| | - Judith Schaf
- Centre for Biomedical Sciences, School of Biological Sciences, Royal Holloway University of London, Egham TW20 0EX, UK; (S.S.); (J.S.); (K.L.J.); (P.B.)
| | - Katie Lloyd Jones
- Centre for Biomedical Sciences, School of Biological Sciences, Royal Holloway University of London, Egham TW20 0EX, UK; (S.S.); (J.S.); (K.L.J.); (P.B.)
| | - Olivier E. Pardo
- Division of Cancer, Department of Surgery and Cancer, Imperial College London, London SW7 2AZ, UK;
| | - Philip Beesley
- Centre for Biomedical Sciences, School of Biological Sciences, Royal Holloway University of London, Egham TW20 0EX, UK; (S.S.); (J.S.); (K.L.J.); (P.B.)
| | - Robin S. B. Williams
- Centre for Biomedical Sciences, School of Biological Sciences, Royal Holloway University of London, Egham TW20 0EX, UK; (S.S.); (J.S.); (K.L.J.); (P.B.)
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Kang T, Qin X, Chen Y, Yang Q. Systematic investigation of Radix Salviae for treating diabetic peripheral neuropathy disease based on network Pharmacology. World J Diabetes 2024; 15:945-957. [PMID: 38766429 PMCID: PMC11099361 DOI: 10.4239/wjd.v15.i5.945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 02/07/2024] [Accepted: 03/13/2024] [Indexed: 05/10/2024] Open
Abstract
BACKGROUND Diabetic peripheral neuropathy (DPN) is a debilitating complication of diabetes mellitus with limited available treatment options. Radix Salviae, a traditional Chinese herb, has shown promise in treating DPN, but its therapeutic mech-anisms have not been systematically investigated. AIM Radix Salviae (Danshen in pinin), a traditional Chinese medicine (TCM), is widely used to treat DPN in China. However, the mechanism through which Radix Salviae treats DPN remains unclear. Therefore, we aimed to explore the mechanism of action of Radix Salviae against DPN using network pharmacology. METHODS The active ingredients and target genes of Radix Salviae were screened using the TCM pharmacology database and analysis platform. The genes associated with DPN were obtained from the Gene Cards and OMIM databases, a drug-com-position-target-disease network was constructed, and a protein-protein inter-action network was subsequently constructed to screen the main targets. Gene Ontology (GO) functional annotation and pathway enrichment analysis were performed via the Kyoto Encyclopedia of Genes and Genomes (KEGG) using Bioconductor. RESULTS A total of 56 effective components, 108 targets and 4581 DPN-related target genes of Radix Salviae were screened. Intervention with Radix Salviae for DPN mainly involved 81 target genes. The top 30 major targets were selected for enrichment analysis of GO and KEGG pathways. CONCLUSION These results suggested that Radix Salviae could treat DPN by regulating the AGE-RAGE signaling pathway and the PI3K-Akt signaling pathway. Therefore, Danshen may affect DPN by regulating inflammation and apoptosis.
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Affiliation(s)
- Tao Kang
- Department of Neurology, Shaanxi Provincial People’s Hospital, Xi'an 710068, Shaanxi Province, China
| | - Xiao Qin
- Department of Neurology, Shaanxi Provincial People’s Hospital, Xi'an 710068, Shaanxi Province, China
| | - Yan Chen
- Department of Neurology, Shaanxi Provincial People’s Hospital, Xi'an 710068, Shaanxi Province, China
| | - Qian Yang
- Department of Neurology, Shaanxi Provincial People’s Hospital, Xi'an 710068, Shaanxi Province, China
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Jiang Y, Bi Y, Zhou L, Zheng S, Jian T, Chen J. Tanshinone IIA inhibits proliferation and migration by downregulation of the PI3K/Akt pathway in small cell lung cancer cells. BMC Complement Med Ther 2024; 24:68. [PMID: 38297301 PMCID: PMC10829381 DOI: 10.1186/s12906-024-04363-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Accepted: 01/17/2024] [Indexed: 02/02/2024] Open
Abstract
BACKGROUND Small cell lung cancer (SCLC) is the most malignant lung cancer type. Due to the high rates of metastasis and drug resistance, effective therapeutic strategies remain lacking. Tanshinone IIA (Tan IIA) has been reported to exhibit anti-tumor activity. Therefore, this study investigated the ability and underlying mechanism of Tan IIA to inhibit the metastasis and proliferation of SCLC. METHODS H1688 and H446 cells were treated in vitro with Tan IIA (0, 1, 2 and 4 µM) or LY294002 (10 µM) for 24, 48, 72 h. H1688 and H446 cell migration was evaluated in wound healing and transwell migration assays. RNA-sequencing helped assess gene expression. BALB/c nude mice were injected with H1688 cells and treated with the Tan IIA group (10 mg/kg/day) or a control. Expression of E-cadherin, vimentin and PI3K/Akt signaling pathway proteins in tumors and H1688 was investigated by immunohistochemical analysis and western blot. RESULTS Tan IIA inhibited H1688 and H446 cell proliferation without inducing apoptosis and suppressed H1688 and H446 cell migration. E-cadherin expression was increased, while vimentin expression was reduced after administration of Tan IIA. RNA-sequencing revealed that some genes related with the PI3K/Akt signaling pathway were altered using Tan IIA treatment. Furthermore, western blot helped detect PI3K and p-Akt expression was also reduced by Tan IIA treatment. Tan IIA inhibited tumor growth in vivo. Moreover, Tan IIA increased tumoral expression of E-cadherin accompanied by PI3K and p-Akt downregulation. CONCLUSION Tan IIA suppresses SCLC proliferation and metastasis by inhibiting the PI3K/Akt signaling pathway, thereby highlighting the potential of Tan IIA as a new and relatively safe drug candidate to treat SCLC.
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Affiliation(s)
- Yuxin Jiang
- School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, No. 481 Binwen Road, Binjiang District, Hangzhou, 310053, Zhejiang, China
| | - Yanli Bi
- Department of Clinical Laboratorial Examination, Air Force Hangzhou Special Service Recuperation Center Sanatorium Area 3, Hangzhou, Zhejiang, China
| | - Lingjie Zhou
- School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, No. 481 Binwen Road, Binjiang District, Hangzhou, 310053, Zhejiang, China
| | - Senwen Zheng
- School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, No. 481 Binwen Road, Binjiang District, Hangzhou, 310053, Zhejiang, China
| | - Tingting Jian
- School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, No. 481 Binwen Road, Binjiang District, Hangzhou, 310053, Zhejiang, China
| | - Jian Chen
- School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, No. 481 Binwen Road, Binjiang District, Hangzhou, 310053, Zhejiang, China.
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Zhang P, Liu W, Wang Y. The mechanisms of tanshinone in the treatment of tumors. Front Pharmacol 2023; 14:1282203. [PMID: 37964867 PMCID: PMC10642231 DOI: 10.3389/fphar.2023.1282203] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Accepted: 10/18/2023] [Indexed: 11/16/2023] Open
Abstract
Tanshinone is a lipophilic compound that is present in traditional Chinese medicine and is derived from the roots of Salvia miltiorrhiza (Danshen). It has been proven to be highly effective in combating tumors in various parts of the body, including liver carcinoma, gastric cancer, ovarian cancer, cervix carcinoma, breast cancer, colon cancer, and prostate cancer. Tanshinone can efficiently prevent the reproduction of cancerous cells, induce cell death, and inhibit the spread of cancerous cells, which are mainly involved in the PI3K/Akt signaling pathway, NF-κB pathway, Bcl-2 family, Caspase cascades, MicroRNA, MAPK signaling pathway, p21, STAT3 pathway, miR30b-P53-PTPN11/SHP2 axis, β-catenin, and Skp2. However, the properties and mechanisms of tanshinone's anti-tumor effects remain unclear currently. Thus, this study aims to review the research progress on tumor prevention and mechanisms of tanshinone to gain new perspectives for further development and clinical application of tanshinone.
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Affiliation(s)
- Pengyu Zhang
- The Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Wendi Liu
- School of Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yuan Wang
- Department of Histology and Embryology, Shandong University of Traditional Chinese Medicine, Jinan, China
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Sah DK, Arjunan A, Lee B, Jung YD. Reactive Oxygen Species and H. pylori Infection: A Comprehensive Review of Their Roles in Gastric Cancer Development. Antioxidants (Basel) 2023; 12:1712. [PMID: 37760015 PMCID: PMC10525271 DOI: 10.3390/antiox12091712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 08/14/2023] [Accepted: 08/30/2023] [Indexed: 09/29/2023] Open
Abstract
Gastric cancer (GC) is the fifth most common cancer worldwide and makes up a significant component of the global cancer burden. Helicobacter pylori (H. pylori) is the most influential risk factor for GC, with the International Agency for Research on Cancer classifying it as a Class I carcinogen for GC. H. pylori has been shown to persist in stomach acid for decades, causing damage to the stomach's mucosal lining, altering gastric hormone release patterns, and potentially altering gastric function. Epidemiological studies have shown that eliminating H. pylori reduces metachronous cancer. Evidence shows that various molecular alterations are present in gastric cancer and precancerous lesions associated with an H. pylori infection. However, although H. pylori can cause oxidative stress-induced gastric cancer, with antioxidants potentially being a treatment for GC, the exact mechanism underlying GC etiology is not fully understood. This review provides an overview of recent research exploring the pathophysiology of H. pylori-induced oxidative stress that can cause cancer and the antioxidant supplements that can reduce or even eliminate GC occurrence.
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Affiliation(s)
| | | | - Bora Lee
- Department of Biochemistry, Chonnam National University Medical School, Seoyang Ro 264, Jeonnam, Hwasun 58128, Republic of Korea; (D.K.S.); (A.A.)
| | - Young Do Jung
- Department of Biochemistry, Chonnam National University Medical School, Seoyang Ro 264, Jeonnam, Hwasun 58128, Republic of Korea; (D.K.S.); (A.A.)
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Xie W, An L, Liu Z, Wang X, Fu X, Ma J. Therapeutic Effect of Polaprezinc on Reflux Esophagitis in the Rat Model. Dig Dis Sci 2023:10.1007/s10620-023-07990-6. [PMID: 37335414 DOI: 10.1007/s10620-023-07990-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 05/24/2023] [Indexed: 06/21/2023]
Abstract
BACKGROUND/AIMS To explore the protective effects and therapeutic mechanism of Esomeprazole (PPI), polaprezinc granule (PZ), and PPI + PZ on reflux esophagitis (RE) in the rat model. METHODS Wistar rats were randomly divided into 9 groups, which contain the control group, the acid cessation group (0.7% HCl, Q3D × 4), and the acid persistence group (0.7% HCl, Q3D × 11). PPI was administered by gavage at 8 mg·kg-1 body weight and PZ was administered by gavage at 120 mg·kg-1 body weight once a day for 15 days. The gastric cardia tissue of the feeding tube was observed under the light microscope, and the levels of interleukin-8 (IL-8) and prostaglandin E2 (PGE2) were measured by ELISA. The expression of EGFR, Akt, p-Akt, and p-mTOR was detected by Western blot. RESULTS The ELISA results showed that the levels of IL-8 and PGE2 were significantly increased in the model group, but decreased in all groups after treatment. In the acid cessation group, PZ treatment had the most significant effect on reducing IL-8 levels and PPI + PZ treatment had the most significant effect on reducing PGE2 levels. In the acid persistence group, the PPI treatment had the most significant effect on reducing the levels of IL-8 and PGE2, and the PZ treatment could also significantly reduce their levels, close to the normal value. Western blot results showed that the expression of PI3K/Akt/mTOR pathway protein was increased in the model group, while its expression was decreased after treatment. CONCLUSIONS Polaprezinc has a significant therapeutic effect on RE in rats, which can reduce the levels of IL-8 and PGE2 and downregulate the expression of PI3K/Akt/mTOR signal pathway protein. The efficacy of polaprezinc in the treatment of reflux esophagitis is comparable to that of PPI, and the combination of them is more effective in the reflux esophagitis treatment.
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Affiliation(s)
- Wenbo Xie
- National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, 130000, China
| | - Lu An
- National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, 130000, China
| | - Zhaoyang Liu
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Xindi Wang
- Liaoning University of Traditional Chinese Medicine, Shenyang, 110000, Liaoning Province, China
| | - Xueqi Fu
- National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, 130000, China
| | - Junfeng Ma
- National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, 130000, China.
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Tiwari A, Tiwari V, Sharma A, Singh D, Singh Rawat M, Virmani T, Virmani R, Kumar G, Kumar M, Alhalmi A, Noman OM, Mothana RA, Alali M. Tanshinone-I for the treatment of uterine fibroids: Molecular docking, simulation, and density functional theory investigations. Saudi Pharm J 2023; 31:1061-1076. [PMID: 37250358 PMCID: PMC10209546 DOI: 10.1016/j.jsps.2023.05.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Accepted: 05/01/2023] [Indexed: 05/31/2023] Open
Abstract
Uterine fibroids (UF), most prevalent gynecological disorder, require surgery when symptomatic. It is estimated that between 25 and 35 percent of women wait until the symptoms have worsened like extended heavy menstrual bleeding and severe pelvic pain. These UF may be reduced in size through various methods such as medical or surgical intervention. Progesterone (prog) is a crucial hormone that restores the endometrium and controls uterine function. In the current study, 28 plant-based molecules are identified from previous literature and docked onto the prog receptors with 1E3K and 2OVH. Tanshinone-I has shown the best docking score against both proteins. The synthetic prog inhibitor Norethindrone Acetate is used as a standard to evaluate the docking outcomes. The best compound, tanshinone-I, was analyzed using molecular modeling and DFT. The RMSD for the 1E3K protein-ligand complex ranged from 0.10 to 0.42 Å, with an average of 0.21 Å and a standard deviation (SD) of 0.06, while the RMSD for the 2OVH protein-ligand complex ranged from 0.08 to 0.42 Å, with an average of 0.20 Å and a SD of 0.06 showing stable interaction. In principal component analysis, the observed eigen values of HPR-Tanshinone-I fluctuate between -1.11 to 1.48 and -1.07 to 1.25 for PC1 and PC2, respectively (1E3K), and the prog-tanshinone-I complex shows eigen values of -38.88 to -31.32 and -31.32 to 35.87 for PC1 and PC2, respectively (2OVH), which shows Tanshinone-I forms a stable protein-ligand complex with 1E3K in comparison to 2OVH. The Free Energy Landscape (FEL) analysis shows the Gibbs free energy in the range of 0 to 8 kJ/mol for Tanshinone-I with 1E3K and 0 to 14 kJ/mol for Tanshinone-I with the 2OVH complex. The DFT calculation reveals ΔE value of 2.8070 eV shows tanshinone-I as a stable compound. 1E3K modulates the prog pathway, it may have either an agonistic or antagonistic effect on hPRs. Tanshinone-I can cause ROS, apoptosis, autophagy (p62 accumulation), up-regulation of inositol requiring protein-1, enhancer-binding protein homologous protein, p-c-Jun N-terminal kinase (p-JNK), and suppression of MMPs. Bcl-2 expression can change LC3I to LC3II and cause apoptosis through Beclin-1 expression.
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Affiliation(s)
- Abhishek Tiwari
- Department of Pharmacy, Pharmacy Academy, IFTM University, Lodhipur-Rajpur, Moradabad 244102, India
| | - Varsha Tiwari
- Department of Pharmacy, Pharmacy Academy, IFTM University, Lodhipur-Rajpur, Moradabad 244102, India
| | - Ajay Sharma
- Delhi Pharmaceutical Sciences and Research University, Pushp Vihar, New Delhi 110017, India
| | - Deependra Singh
- University Institute of Pharmacy, Pt. Ravi Shankar Shukla University, Raipur, Chhattisgarh, India
| | - Manju Singh Rawat
- University Institute of Pharmacy, Pt. Ravi Shankar Shukla University, Raipur, Chhattisgarh, India
| | - Tarun Virmani
- School of Pharmaceutical Sciences, MVN University, Palwal, Haryana 121105, India
| | - Reshu Virmani
- School of Pharmaceutical Sciences, MVN University, Palwal, Haryana 121105, India
| | - Girish Kumar
- School of Pharmaceutical Sciences, MVN University, Palwal, Haryana 121105, India
| | - Manish Kumar
- School of Pharmaceutical Sciences, CT University, Ludhiana- 142024 Punjab, India
| | - Abdulsalam Alhalmi
- Department of Pharmaceutical Sciences, College of Pharmacy, Aden University, Aden, Yemen
| | - Omar M. Noman
- Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Ramzi A. Mothana
- Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Mohammad Alali
- Institute of Pharmacy, Clinical Pharmacy, University of Greifswald, Friedrich-Ludwig-Jahn-Str. 17, 17489 Greifswald, Germany
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Islam R, Zhao L, Zhang X, Liu LZ. MiR-218-5p/EGFR Signaling in Arsenic-Induced Carcinogenesis. Cancers (Basel) 2023; 15:1204. [PMID: 36831545 PMCID: PMC9954652 DOI: 10.3390/cancers15041204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Accepted: 02/11/2023] [Indexed: 02/17/2023] Open
Abstract
BACKGROUND Arsenic is a well-known carcinogen inducing lung, skin, bladder, and liver cancer. Abnormal epidermal growth factor receptor (EGFR) expression is common in lung cancer; it is involved in cancer initiation, development, metastasis, and treatment resistance. However, the underlying mechanism for arsenic-inducing EGFR upregulation remains unclear. METHODS RT-PCR and immunoblotting assays were used to detect the levels of miR-218-5p and EGFR expression. The Luciferase assay was used to test the transcriptional activity of EGFR mediated by miR-218-5p. Cell proliferation, colony formation, wound healing, migration assays, tube formation assays, and tumor growth assays were used to study the function of miR-218-5p/EGFR signaling. RESULTS EGFR and miR-218-5p were dramatically upregulated and downregulated in arsenic-induced transformed (As-T) cells, respectively. MiR-218-5p acted as a tumor suppressor to inhibit cell proliferation, migration, colony formation, tube formation, tumor growth, and angiogenesis. Furthermore, miR-218-5p directly targeted EGFR by binding to its 3'-untranslated region (UTR). Finally, miR-218-5p exerted its antitumor effect by inhibiting its direct target, EGFR. CONCLUSION Our study highlights the vital role of the miR-218-5p/EGFR signaling pathway in arsenic-induced carcinogenesis and angiogenesis, which may be helpful for the treatment of lung cancer induced by chronic arsenic exposure in the future.
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Affiliation(s)
| | | | | | - Ling-Zhi Liu
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
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The Regulatory Effects of Traditional Chinese Medicine on Ferroptosis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:4578381. [PMID: 36193068 PMCID: PMC9526626 DOI: 10.1155/2022/4578381] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 09/01/2022] [Indexed: 11/17/2022]
Abstract
Traditional Chinese medicine (TCM) has significantly contributed to protecting human health and promoting the progress of world civilization. A total of 2,711 TCMs are included in the 2020 version of the Chinese Pharmacopoeia, which is an integral part of the world’s medical resources. Tu Youyou and her team discovered and purified artemisinin. And their contributions made the values and advantageous effects of TCM more and more recognized by the international community. There has been a lot of studies on TCM to treat diseases through antioxidant mechanisms, the reports on the new mechanisms beyond antioxidants of TCM has also increased year by year. Recently, many TCMs appear to have significant effects in regulating ferroptosis. Ferroptosis is an iron-dependent, non-apoptotic, regulated cell death characterized by intracellular lipid peroxide accumulation and oxidative membrane damage. Recently, accumulating studies have demonstrated that numerous organ injuries and pathophysiological process of many diseases are companied with ferroptosis, such as cancer, neurodegenerative disease, acute renal injury, arteriosclerosis, diabetes, and ischemia-reperfusion injury. This work mainly introduces dozens of TCMs that can regulate ferroptosis and their possible mechanisms and targets.
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Li W, Huang T, Xu S, Che B, Yu Y, Zhang W, Tang K. Molecular Mechanism of Tanshinone against Prostate Cancer. Molecules 2022; 27:molecules27175594. [PMID: 36080361 PMCID: PMC9457553 DOI: 10.3390/molecules27175594] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 08/18/2022] [Accepted: 08/22/2022] [Indexed: 11/16/2022] Open
Abstract
Prostate cancer (PCa) is the most common malignant tumor of the male urinary system in Europe and America. According to the data in the World Cancer Report 2020, the incidence rate of PCa ranks second in the prevalence of male malignant tumors and varies worldwide between regions and population groups. Although early PCa can achieve good therapeutic results after surgical treatment, due to advanced PCa, it can adapt and tolerate androgen castration-related drugs through a variety of mechanisms. For this reason, it is often difficult to achieve effective therapeutic results in the treatment of advanced PCa. Tanshinone is a new fat-soluble phenanthraquinone compound derived from Salvia miltiorrhiza that can play a therapeutic role in different cancers, including PCa. Several studies have shown that Tanshinone can target various molecular pathways of PCa, including the signal transducer and activator of transcription 3 (STAT3) pathway, androgen receptor (AR) pathway, phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway, and mitogen-activated protein kinase (MAPK) pathway, which will affect the release of pro-inflammatory cytokines and affect cell proliferation, apoptosis, tumor metabolism, genomic stability, and tumor drug resistance. Thus, the occurrence and development of PCa cells are inhibited. In this review, we summarized the in vivo and in vitro evidence of Tanshinone against prostate cancer and discussed the effect of Tanshinone on nuclear factor kappa-B (NF-κB), AR, and mTOR. At the same time, we conducted a network pharmacology analysis on the four main components of Tanshinone to further screen the possible targets of Tanshinone against prostate cancer and provide ideas for future research.
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Zhang W, Liu C, Li J, Lu Y, Li H, Zhuang J, Ren X, Wang M, Sun C. Tanshinone IIA: New Perspective on the Anti-Tumor Mechanism of A Traditional Natural Medicine. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2022; 50:209-239. [PMID: 34983327 DOI: 10.1142/s0192415x22500070] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
The search for natural and efficacious antineoplastic drugs, with minimal toxicity and side effects, is an important part of antitumor drug research and development. Tanshinone IIA is the most evaluated lipophilic active component of Salvia miltiorrhiza. Tanshinone IIA is a path-breaking traditional drug applied in cardiovascular treatment. It has also been found that tanshinone IIA plays an important role in the digestive, respiratory and circulatory systems, as well as in other tumor diseases. Tanshinone IIA significantly inhibits the proliferation of several types of tumors, blocks the cell cycle, induces apoptosis and autophagic death, in addition to inhibiting cell migration and invasion. Among these, the regulation of tumor-cell apoptosis signaling pathways is the key breakthrough point in several modes of antitumor therapy. The PI3K/AKT/MTOR signaling pathway and the JNK pathway are the key pathways for tanshinone IIA to induce tumor cell apoptosis. In addition to glycolysis, reactive oxygen species and signal transduction all play an active role with the participation of tanshinone IIA. Endogenous apoptosis is considered the main mechanism of tumor apoptosis induced by tanshinone IIA. Multiple pathways and targets play a role in the process of endogenous apoptosis. Tanshinone IIA can protect chemotherapy drugs, which is mainly reflected in the protection of the side effects of chemotherapy drugs, such as neurotoxicity and inhibition of the hematopoietic system. Tanshinone IIA also has a certain regulatory effect on tumor angiogenesis, which is mainly manifested in the control of hypoxia. Our findings indicated that tanshinone IIA is an effective treatment agent in the cardiovascular field and plays a significant role in antitumor therapeutics. This paper reviews the pharmacological potential and inhibitory effect of tanshinone IIA on cancer. It is greatly anticipated that tanshinone IIA will be employed as an adjuvant in the treatment of various cancers.
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Affiliation(s)
- Wenfeng Zhang
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250014, P. R. China.,School of Traditional Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau, P. R. China
| | - Cun Liu
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250014, P. R. China
| | - Jie Li
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250014, P. R. China
| | - Yiping Lu
- Integrated Traditional Chinese and Western Medicine Center, Department of Medicine, Qingdao University, Qingdao Shandong 266000, P. R. China
| | - Huayao Li
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250014, P. R. China
| | - Jing Zhuang
- Department of Oncology, Weifang Traditional Chinese Medicine Hospital, Weifang, Shandong 261041, P. R. China
| | - Xin Ren
- Clinical Medical Colleges, Weifang Medical University, Weifang, Shandong 261000, P. R. China
| | - Mengmeng Wang
- Clinical Medical Colleges, Weifang Medical University, Weifang, Shandong 261000, P. R. China
| | - Changgang Sun
- Department of Oncology, Weifang Traditional Chinese Medicine Hospital, Weifang, Shandong 261041, P. R. China.,Qingdao Academy of Chinese Medical Sciences, Shandong University of Traditional Chinese Medicine, Qingdao, P. R. China
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13
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Ni H, Ruan G, Sun C, Yang X, Miao Z, Li J, Chen Y, Qin H, Liu Y, Zheng L, Xing Y, Xi T, Li X. Tanshinone IIA inhibits gastric cancer cell stemness through inducing ferroptosis. ENVIRONMENTAL TOXICOLOGY 2022; 37:192-200. [PMID: 34661962 DOI: 10.1002/tox.23388] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 09/27/2021] [Accepted: 10/03/2021] [Indexed: 05/16/2023]
Abstract
Tanshinone IIA is the active constituent extracted from Salvia Miltiorrhza. Numerous studies have shown that Tanshinone IIA could inhibit tumor proliferation and metastasis, including gastric cancer. However, the effect of Tanshinone IIA on gastric cancer cell stemness stays unclear. Here, we found that Tanshinone IIA could reduce gastric cancer cell stemness through detecting spheroid-forming, flow cytometry analysis, and the expression of stemness markers (OCT3/4, ALDH1A1, and CD44). Mechanistically, Tanshinone IIA increased the level of lipid peroxides and decreased glutathione level in gastric cancer cells, both of which are the markers of ferroptosis. Similarly, ferroptosis inducers (erastin, sulfasalazine, and sorafenib) reduced gastric cancer cell stemness. Additionally, the inhibitory effects of Tanshinone IIA on GC cell stemness were reversed by ferroptosis inhibitor (Fer-1) or overexpression of SLC7A11, which is a critical ferroptosis inhibitor. Therefore, we revealed that Tanshinone IIA inhibited the stemness of gastric cancer cells partly through inducing ferroptosis.
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Affiliation(s)
- Haiwei Ni
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, China
| | - Guojing Ruan
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, China
| | - Cheng Sun
- Department of Pharmacy, the Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Xuan Yang
- Department of Pharmacy, Huai'an Third People's Hospital, Huai'an, China
| | - Zhenyan Miao
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, China
| | - Jifei Li
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, China
| | - Ying Chen
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, China
| | - Hai Qin
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, China
| | - Yichen Liu
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, China
| | - Lufeng Zheng
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, China
| | - Yingying Xing
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, China
| | - Tao Xi
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, China
| | - Xiaoman Li
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
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14
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Wu Q, Yin CH, Li Y, Cai JQ, Yang HY, Huang YY, Zheng YX, Xiong K, Yu HL, Lu AP, Wang KX, Guan DG, Chen YP. Detecting Critical Functional Ingredients Group and Mechanism of Xuebijing Injection in Treating Sepsis. Front Pharmacol 2021; 12:769190. [PMID: 34938184 PMCID: PMC8687625 DOI: 10.3389/fphar.2021.769190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 11/04/2021] [Indexed: 11/13/2022] Open
Abstract
Sepsis is a systemic inflammatory reaction caused by various infectious or noninfectious factors, which can lead to shock, multiple organ dysfunction syndrome, and death. It is one of the common complications and a main cause of death in critically ill patients. At present, the treatments of sepsis are mainly focused on the controlling of inflammatory response and reduction of various organ function damage, including anti-infection, hormones, mechanical ventilation, nutritional support, and traditional Chinese medicine (TCM). Among them, Xuebijing injection (XBJI) is an important derivative of TCM, which is widely used in clinical research. However, the molecular mechanism of XBJI on sepsis is still not clear. The mechanism of treatment of "bacteria, poison and inflammation" and the effects of multi-ingredient, multi-target, and multi-pathway have still not been clarified. For solving this issue, we designed a new systems pharmacology strategy which combines target genes of XBJI and the pathogenetic genes of sepsis to construct functional response space (FRS). The key response proteins in the FRS were determined by using a novel node importance calculation method and were condensed by a dynamic programming strategy to conduct the critical functional ingredients group (CFIG). The results showed that enriched pathways of key response proteins selected from FRS could cover 95.83% of the enriched pathways of reference targets, which were defined as the intersections of ingredient targets and pathogenetic genes. The targets of the optimized CFIG with 60 ingredients could be enriched into 182 pathways which covered 81.58% of 152 pathways of 1,606 pathogenetic genes. The prediction of CFIG targets showed that the CFIG of XBJI could affect sepsis synergistically through genes such as TAK1, TNF-α, IL-1β, and MEK1 in the pathways of MAPK, NF-κB, PI3K-AKT, Toll-like receptor, and tumor necrosis factor signaling. Finally, the effects of apigenin, baicalein, and luteolin were evaluated by in vitro experiments and were proved to be effective in reducing the production of intracellular reactive oxygen species in lipopolysaccharide-stimulated RAW264.7 cells, significantly. These results indicate that the novel integrative model can promote reliability and accuracy on depicting the CFIGs in XBJI and figure out a methodological coordinate for simplicity, mechanism analysis, and secondary development of formulas in TCM.
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Affiliation(s)
- Qi- Wu
- Department of Burns, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Chuan-Hui Yin
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Guangdong Province Key Laboratory of Single Cell Technology and Application, Southern Medical University, Guangzhou, China
| | - Yi Li
- Department of Radiology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jie-Qi Cai
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Guangdong Province Key Laboratory of Single Cell Technology and Application, Southern Medical University, Guangzhou, China
| | - Han-Yun Yang
- The First Clinical Medical College of Southern Medical University, Guangzhou, China
| | - Ying-Ying Huang
- Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yi-Xu Zheng
- Department of Ophthalmology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Ke Xiong
- Department of Ophthalmology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Hai-Lang Yu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Guangdong Province Key Laboratory of Single Cell Technology and Application, Southern Medical University, Guangzhou, China
| | - Ai-Ping Lu
- Institute of Integrated Bioinformedicine and Translational Science, Hong Kong Baptist University, Kowloon Tong, Hong Kong China
| | - Ke-Xin Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,National Key Clinical Specialty/Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Neurosurgery Institute, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Dao-Gang Guan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Guangdong Province Key Laboratory of Single Cell Technology and Application, Southern Medical University, Guangzhou, China
| | - Yu-Peng Chen
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Guangdong Province Key Laboratory of Single Cell Technology and Application, Southern Medical University, Guangzhou, China
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15
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Guo Y, Wang FF, Xiang B, Ma HB, Gong YP. Tanshinone IIA potentiates the efficacy of imatinib by regulating the AKT-MDM2-P53 signaling pathway in Philadelphia chromosome-positive acute lymphoblastic leukemia. Oncol Lett 2021; 23:7. [PMID: 34820006 PMCID: PMC8607239 DOI: 10.3892/ol.2021.13125] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Accepted: 07/15/2021] [Indexed: 02/05/2023] Open
Abstract
Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is triggered by breakpoint cluster region-abelson leukemia virus (BCR/ABL) kinase. Targeting BCR/ABL kinase with tyrosine kinase inhibitors combined with chemotherapy is the standard first-line therapy for Ph+ ALL. Imatinib and dasatinib are the preferred agents for the treatment of Ph+ ALL. Dasatinib treatment can induce a faster and deeper remission than imatinib treatment; however, the side effects of dasatinib, especially the cardiovascular side effects, are markedly greater than those of imatinib. Patients will benefit from treatments that improve the efficacy of imatinib without increasing its side effects. The present study revealed that tanshinone IIA markedly potentiated the cytotoxic and apoptotic induction effects of imatinib by regulating the AKT-MDM2-P53 signaling pathway and inhibiting the anti-apoptotic proteins BCL2 and MCL1 apoptosis regulator, BCL2 family member in Ph+ ALL cell lines. In vitro studies, MTT assay, flow cytometry, western blotting and reverse transcription-quantitative PCR were performed in the present study to detect cell viability, cell apoptosis, protein expression and gene expression, respectively. In a Ph+ ALL mouse model, imatinib combined with tanshinone IIA also exhibited a synergistic effect on the reduction in leukemia burden without increasing the toxic side effects of imatinib. These results demonstrated that imatinib combined with tanshinone IIA might be a promising treatment strategy for patients with Ph+ ALL.
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Affiliation(s)
- Yong Guo
- Department of Hematology, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Fang-Fang Wang
- Hematology Research Laboratory, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Bing Xiang
- Department of Hematology, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Hong-Bing Ma
- Department of Hematology, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yu-Ping Gong
- Department of Hematology, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, P.R. China
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16
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Zhong C, Lin Z, Ke L, Shi P, Li S, Huang L, Lin X, Yao H. Recent Research Progress (2015-2021) and Perspectives on the Pharmacological Effects and Mechanisms of Tanshinone IIA. Front Pharmacol 2021; 12:778847. [PMID: 34819867 PMCID: PMC8606659 DOI: 10.3389/fphar.2021.778847] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Accepted: 10/26/2021] [Indexed: 12/15/2022] Open
Abstract
Tanshinone IIA (Tan IIA) is an important characteristic component and active ingredient in Salvia miltiorrhiza, and its various aspects of research are constantly being updated to explore its potential application. In this paper, we review the recent progress on pharmacological activities and the therapeutic mechanisms of Tan IIA according to literature during the years 2015-2021. Tan IIA shows multiple pharmacological effects, including anticarcinogenic, cardiovascular, nervous, respiratory, urinary, digestive, and motor systems activities. Tan IIA modulates multi-targets referring to Nrf2, AMPK, GSK-3β, EGFR, CD36, HO-1, NOX4, Beclin-1, TLR4, TNF-α, STAT3, Caspase-3, and bcl-2 proteins and multi-pathways including NF-κB, SIRT1/PGC1α, MAPK, SREBP-2/Pcsk9, Wnt, PI3K/Akt/mTOR pathways, TGF-β/Smad and Hippo/YAP pathways, etc., which directly or indirectly influence disease course. Further, with the reported targets, the potential effects and possible mechanisms of Tan IIA against diseases were predicted by bioinformatic analysis. This paper provides new insights into the therapeutic effects and mechanisms of Tan IIA against diseases.
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Affiliation(s)
- Chenhui Zhong
- Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, China
| | - Zuan Lin
- Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, China
| | - Liyuan Ke
- Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, China
| | - Peiying Shi
- Department of Traditional Chinese Medicine Resource and Bee Products, College of Animal Sciences (College of Bee Science), Fujian Agriculture and Forestry University, Fuzhou, China
| | - Shaoguang Li
- Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, China
| | - Liying Huang
- Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, China
| | - Xinhua Lin
- Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, China
- Higher Educational Key Laboratory for Nano Biomedical Technology of Fujian Province, Fujian Medical University, Fuzhou, China
| | - Hong Yao
- Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, China
- Higher Educational Key Laboratory for Nano Biomedical Technology of Fujian Province, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Drug Target Discovery and Structural and Functional Research, Fujian Medical University, Fuzhou, China
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17
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Tanshinone IIA induces ferroptosis in gastric cancer cells through p53-mediated SLC7A11 down-regulation. Biosci Rep 2021; 40:226033. [PMID: 32776119 PMCID: PMC7953492 DOI: 10.1042/bsr20201807] [Citation(s) in RCA: 154] [Impact Index Per Article: 38.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 08/04/2020] [Accepted: 08/06/2020] [Indexed: 12/22/2022] Open
Abstract
Gastric cancer represents a malignant type of cancer worldwide. Tanshinone IIA (Tan IIA), a pharmacologically active component isolated from the rhizome of the Chinese herb Salvia miltiorrhiza Bunge (Danshen), has been reported to possess an anti-cancer effect in gastric cancer. However, its mechanisms are still not fully understood. In the present study, we found that Tan IIA induced ferroptosis in BGC-823 and NCI-H87 gastric cancer cells. Tan IIA increased lipid peroxidation and up-regulated Ptgs2 and Chac1 expression, two markers of ferroptosis. Ferrostatin-1 (Fer-1), an inhibitor of lipid peroxidation, inhibited Tan IIA caused-lipid peroxidation and Ptgs2 and Chac1 expression. In addition, Tan IIA also up-regulated p53 expression and down-regulated xCT expression. Tan IIA caused decreased intracellular glutathione (GSH) level and cysteine level and increased intracellular reactive oxygen species (ROS) level. p53 knockdown attenuated Tan IIA-induced lipid peroxidation and ferroptosis. Tan IIA also induced lipid peroxidation and ferroptosis in BGC-823 xenograft model, and the anti-cancer effect of Tan IIA was attenuated by Fer-1 in vivo. Therefore, Tan IIA could suppress the proliferation of gastric cancer via inducing p53 upregulation-mediated ferroptosis. Our study have identified a novel mechanism of Tan IIA against gastric cancer, and might provide a critical insight into the application of Tan IIA in gastric cancer intervention.
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18
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Fang ZY, Zhang M, Liu JN, Zhao X, Zhang YQ, Fang L. Tanshinone IIA: A Review of its Anticancer Effects. Front Pharmacol 2021; 11:611087. [PMID: 33597880 PMCID: PMC7883641 DOI: 10.3389/fphar.2020.611087] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Accepted: 11/26/2020] [Indexed: 12/13/2022] Open
Abstract
Tanshinone IIA (Tan IIA) is a pharmacologically lipophilic active constituent isolated from the roots and rhizomes of the Chinese medicinal herb Salvia miltiorrhiza Bunge (Danshen). Tan IIA is currently used in China and other neighboring countries to treat patients with cardiovascular system, diabetes, apoplexy, arthritis, sepsis, and other diseases. Recently, it was reported that tan IIA could have a wide range of antitumor effects on several human tumor cell lines, but the research of the mechanism of tan IIA is relatively scattered in cancer. This review aimed to summarize the recent advances in the anticancer effects of tan IIA and to provide a novel perspective on clinical use of tan IIA.
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Affiliation(s)
- Zhong-Ying Fang
- School of Biological Sciences and Technology, University of Jinan, Jinan, China.,School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Miao Zhang
- School of Biological Sciences and Technology, University of Jinan, Jinan, China
| | - Jia-Ning Liu
- School of Biological Sciences and Technology, University of Jinan, Jinan, China
| | - Xue Zhao
- School of Biological Sciences and Technology, University of Jinan, Jinan, China
| | - Yong-Qing Zhang
- School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Lei Fang
- School of Biological Sciences and Technology, University of Jinan, Jinan, China.,School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
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19
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Pharmacological basis of tanshinone and new insights into tanshinone as a multitarget natural product for multifaceted diseases. Biomed Pharmacother 2020; 130:110599. [PMID: 33236719 DOI: 10.1016/j.biopha.2020.110599] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2020] [Revised: 07/18/2020] [Accepted: 07/31/2020] [Indexed: 12/14/2022] Open
Abstract
Drug development has long included the systematic exploration of various resources. Among these, natural products are one of the most important resources from which novel agents are developed due to the multiple pharmacologic effects of these natural products on diseases. Tanshinone, a representative natural product, is the main compound extracted from the dried root and rhizome of Salvia miltiorrhiza Bge. Research on tanshinone began in the early 1930s. With the in-depth investigation of an increasing number of identified analogs, tanshinone has demonstrated a wide variety of bioactivities and contradicted the saying, 'You can't teach an old dog new tricks'. This review is focused on the pharmacological action of tanshinone and status of research on tanshinone in recent years. The mechanism of tanshinone has also drawn much attention, with the findings of representative targets and pathways of tanshinone. The most recent studies have comprehensively shown that tanshinone can be used to treat leukemia and solid carcinoma, protect against cardiovascular and cerebrovascular diseases, and alleviate liver- and kidney-related diseases, among its other effects. Multiple signaling pathways, including antiproliferative, antiapoptotic, anti-inflammatory, and antioxidative stress pathways, are involved in its actions.
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20
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Nie ZY, Zhao MH, Cheng BQ, Pan RF, Wang TR, Qin Y, Zhang XJ. Tanshinone IIA regulates human AML cell proliferation, cell cycle, and apoptosis through miR-497-5p/AKT3 axis. Cancer Cell Int 2020; 20:379. [PMID: 32782437 PMCID: PMC7412841 DOI: 10.1186/s12935-020-01468-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Accepted: 07/31/2020] [Indexed: 12/11/2022] Open
Abstract
Background The roots of Salvia miltiorrhiza are used in traditional Chinese medicine (TCM) and have high medicinal value. Tanshinone IIA (Tan IIA) is the active ingredient of Salvia miltiorrhiza which can inhibit the growth of acute leukemia cell lines in vitro, although the mechanism remains unclear. Methods CCK-8 assays and BrdU stain were used to evaluate cell proliferation ability. Western blot analysis was used to detect protein expression. miR-497-5p expression level was detected by using qRT-PCR, and Annexin V-FITC/propidium iodide (PI) was used to detect cell apoptosis. Results Here we reported that Tan IIA could inhibit cell proliferation, induce cell cycle arrest, and promote cell apoptosis in acute myeloid leukemia (AML) cells. Thus, Tan IIA had the anti-cancer activity in AML cell lines, which was likely mediated by up-regulation of miR-497-5p expression. Our data further showed that in AML cells, the same effects were observed with overexpression of miR-497-5p by a miR-497-5p mimic. We demonstrated that Tan IIA could inhibit the expression of AKT3 by up-regulating the expression of miR-497-5p. We subsequently identified that AKT3 was the direct target of miR-497-5p, and that treatment with Tan IIA obviously reversed the effect of treatment with an miR-497-5p inhibitor under harsh conditions. In turn, PCNA expression was increased and cleaved Caspase-3 was suppressed, which contributed to the growth of AML cells. Conclusions Our results showed that Tan IIA could inhibit cell proliferation in AML cells through miR-497-5p-mediated AKT3 downregulation pathway.
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Affiliation(s)
- Zi-Yuan Nie
- Department of Hematology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000 China
| | - Ming-Hui Zhao
- Department of Radiology, Affiliated Hospital of Hebei University, Baoding, 071000 China
| | - Bao-Qian Cheng
- Department of Clinical Medicine, Hebei Medical University, Shijiazhuang, 050000 China
| | - Rong-Fang Pan
- Department of Nutrition, The Affiliated Hospital of Qingdao University, Qingdao, 266003 China
| | - Tian-Rui Wang
- Department of Orthopaedic Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, 050051 China
| | - Yan Qin
- Central Laboratory, Affiliated Hospital of Hebei University, 212 Yuhua East Road, Baoding, 071000 China.,Department of Life Science and Green Development, Hebei University, Baoding, 071000 China
| | - Xue-Jun Zhang
- Department of Hematology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000 China
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21
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Wang L, Lu YF, Wang CS, Xie YX, Zhao YQ, Qian YC, Liu WT, Wang M, Jiang BH. HB-EGF Activates the EGFR/HIF-1α Pathway to Induce Proliferation of Arsenic-Transformed Cells and Tumor Growth. Front Oncol 2020; 10:1019. [PMID: 32695675 PMCID: PMC7338480 DOI: 10.3389/fonc.2020.01019] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Accepted: 05/22/2020] [Indexed: 12/27/2022] Open
Abstract
Arsenic was recently identified as a pollutant that is a major cause of lung cancer. Since heparin-binding EGF-like growth factor (HB-EGF) was reported to be a promising therapeutic target for lung cancer, we investigated the role and mechanism of HB-EGF during arsenic-induced carcinogenesis and development of lung cancer. HB-EGF expression were upregulated in As-T cells, lung cancer cell lines, and in most lung cancer tissue samples; and HB-EGF activated the EGFR/p-ERK/HIF-1α pathway and induced VEGF by regulating HIF-1α transcription. HIF-1α transcriptional stimulation by HB-EGF was facilitated by PKM2 and played an important role in HB-EGF's effect on cells. An HB-EGF inhibitor(CRM197, cross-reacting material 197) slowed cell proliferation and inhibited migration of As-T and A549 cells, and inhibited tumor growth. PKM2 also played an important role in the proliferation and migration in As-T cells. The positive staining ratios of EGFR phosphorylation (Y1068) and PKM2 were significantly higher in most cases of lung cancer than in paired normal tumor-adjacent lung tissues; and HB-EGF expression levels strongly correlated with p-EGFR expression levels. Thus, HB-EGF drives arsenic-induced carcinogenesis, tumor growth, and lung cancer development via the EGFR/PKM2/HIF-1α pathway.
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Affiliation(s)
- Lin Wang
- Department of Pathology, Nanjing Medical University, Nanjing, China.,The Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Yi-Fan Lu
- Department of Pathology, Nanjing Medical University, Nanjing, China
| | - Chao-Shan Wang
- Department of Pathology, Nanjing Medical University, Nanjing, China
| | - Yun-Xia Xie
- The Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Yan-Qiu Zhao
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
| | - Ying-Chen Qian
- Department of Pathology, Nanjing Medical University, Nanjing, China
| | - Wei-Tao Liu
- Department of Pathology, Nanjing Medical University, Nanjing, China
| | - Min Wang
- Department of Pathology, Nanjing Medical University, Nanjing, China
| | - Bing-Hua Jiang
- Department of Pathology, The University of Iowa, Iowa City, IA, United States
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22
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Naz I, Merarchi M, Ramchandani S, Khan MR, Malik MN, Sarwar S, Narula AS, Ahn KS. An overview of the anti-cancer actions of Tanshinones, derived from Salvia miltiorrhiza (Danshen). EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2020; 1:153-170. [PMID: 36046197 PMCID: PMC9400791 DOI: 10.37349/etat.2020.00010] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 05/17/2020] [Indexed: 11/19/2022] Open
Abstract
Tanshinone is a herbal medicinal compound described in Chinese medicine, extracted from the roots of Salvia miltiorrhiza (Danshen). This family of compounds, including Tanshinone IIA and Tanshinone I, have shown remarkable potential as anti-cancer molecules, especially against breast, cervical, colorectal, gastric, lung, and prostate cancer cell lines, as well as leukaemia, melanoma, and hepatocellular carcinoma among others. Recent data has indicated that Tanshinones can modulate multiple molecular pathways such as PI3K/Akt, MAPK and JAK/STAT3, and exert their pharmacological effects against different malignancies. In addition, preclinical and clinical data, together with the safety profile of Tanshinones, encourage further applications of these compounds in cancer therapeutics. In this review article, the effect of Tanshinones on different cancers, challenges in their pharmacological development, and opportunities to harness their clinical potential have been documented.
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Affiliation(s)
- Irum Naz
- Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan
| | - Myriam Merarchi
- Faculty of Pharmacy, University of Paris Descartes, 75006 Paris, France
| | - Shanaya Ramchandani
- Department of Pharmacology-Biomedicine, The University of Melbourne, Parkville, VIC 3010, Australia
| | | | - Muhammad Nouman Malik
- Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan
| | - Sumaira Sarwar
- Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan
| | | | - Kwang Seok Ahn
- Department of Science in Korean Medicine, College of Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, South Korea
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23
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Fu L, Han B, Zhou Y, Ren J, Cao W, Patel G, Kai G, Zhang J. The Anticancer Properties of Tanshinones and the Pharmacological Effects of Their Active Ingredients. Front Pharmacol 2020; 11:193. [PMID: 32265690 PMCID: PMC7098175 DOI: 10.3389/fphar.2020.00193] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Accepted: 02/11/2020] [Indexed: 12/31/2022] Open
Abstract
Cancer is a common malignant disease worldwide with an increasing mortality in recent years. Salvia miltiorrhiza, a well-known traditional Chinese medicine, has been used for the treatment of cardiovascular and cerebrovascular diseases for thousands of years. The liposoluble tanshinones in S. miltiorrhiza are important bioactive components and mainly include tanshinone IIA, dihydrodanshinone, tanshinone I, and cryptotanshinone. Previous studies showed that these four tanshinones exhibited distinct inhibitory effects on tumor cells through different molecular mechanisms in vitro and in vivo. The mechanisms mainly include the inhibition of tumor cell growth, metastasis, invasion, and angiogenesis, apoptosis induction, cell autophagy, and antitumor immunity, and so on. In this review, we describe the latest progress on the antitumor functions and mechanisms of these four tanshinones to provide a deeper understanding of the efficacy. In addition, the important role of tumor immunology is also reviewed.
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Affiliation(s)
- Li Fu
- School of Life Sciences, Institute of Plant Biotechnology, Shanghai Normal University, Shanghai, China
| | - Bing Han
- Laboratory of Medicinal Plant Biotechnology, College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yang Zhou
- School of Life Sciences, Institute of Plant Biotechnology, Shanghai Normal University, Shanghai, China
| | - Jie Ren
- School of Life Sciences, Institute of Plant Biotechnology, Shanghai Normal University, Shanghai, China
| | - Wenzhi Cao
- School of Life Sciences, Institute of Plant Biotechnology, Shanghai Normal University, Shanghai, China
| | - Gopal Patel
- Laboratory of Medicinal Plant Biotechnology, College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, China
| | - Guoyin Kai
- School of Life Sciences, Institute of Plant Biotechnology, Shanghai Normal University, Shanghai, China.,Laboratory of Medicinal Plant Biotechnology, College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, China
| | - Jun Zhang
- School of Life Sciences, Institute of Plant Biotechnology, Shanghai Normal University, Shanghai, China
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24
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Yin CF, Kao SC, Hsu CL, Chang YW, Cheung CHY, Huang HC, Juan HF. Phosphoproteome Analysis Reveals Dynamic Heat Shock Protein 27 Phosphorylation in Tanshinone IIA-Induced Cell Death. J Proteome Res 2020; 19:1620-1634. [DOI: 10.1021/acs.jproteome.9b00836] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Affiliation(s)
- Chieh-Fan Yin
- Department of Life Science and Institute of Molecular and Cellular Biology, National Taiwan University, No. 1, Section 4, Roosevelt Road, Taipei 10617, Taiwan
| | - Shih-Chieh Kao
- Department of Life Science and Institute of Molecular and Cellular Biology, National Taiwan University, No. 1, Section 4, Roosevelt Road, Taipei 10617, Taiwan
| | - Chia-Lang Hsu
- Department of Life Science and Institute of Molecular and Cellular Biology, National Taiwan University, No. 1, Section 4, Roosevelt Road, Taipei 10617, Taiwan
- Department of Medical Research, National Taiwan University Hospital, Taipei 10002, Taiwan
| | - Yi-Wen Chang
- Department of Life Science and Institute of Molecular and Cellular Biology, National Taiwan University, No. 1, Section 4, Roosevelt Road, Taipei 10617, Taiwan
| | - Chantal Hoi Yin Cheung
- Department of Life Science and Institute of Molecular and Cellular Biology, National Taiwan University, No. 1, Section 4, Roosevelt Road, Taipei 10617, Taiwan
| | - Hsuan-Cheng Huang
- Institute of Biomedical Informatics, National Yang-Ming University, No. 155, Section 2, Linong Street, Taipei 11221, Taiwan
| | - Hsueh-Fen Juan
- Department of Life Science and Institute of Molecular and Cellular Biology, National Taiwan University, No. 1, Section 4, Roosevelt Road, Taipei 10617, Taiwan
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25
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Zhou J, Jiang Y, Chen H, Wu Y, Zhang L. Tanshinone I attenuates the malignant biological properties of ovarian cancer by inducing apoptosis and autophagy via the inactivation of PI3K/AKT/mTOR pathway. Cell Prolif 2020; 53:e12739. [PMID: 31820522 PMCID: PMC7046305 DOI: 10.1111/cpr.12739] [Citation(s) in RCA: 216] [Impact Index Per Article: 43.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 10/29/2019] [Accepted: 11/06/2019] [Indexed: 12/23/2022] Open
Abstract
OBJECTIVES Tanshinone I (Tan-I) is one of the vital fatsoluble monomer components, which extracted from Chinese medicinal herb Salvia miltiorrhiza Bunge. It has been shown that Tan-I exhibited anti-tumour activities on different types of cancers. However, the underlying mechanisms by which Tan-Ⅰ regulates apoptosis and autophagy in ovarian cancer remain unclear. Thus, this study aimed to access the therapy effect of Tan-Ⅰ and the underlying mechanisms. METHODS Ovarian cancer cells A2780 and ID-8 were treated with different concentrations of Tan-Ⅰ (0, 1.2, 2.4, 4.8 and 9.6 μg/mL) for 24 hours. The cell proliferation was analysed by CCK8 assay, EdU staining and clone formation assay. Apoptosis was assessed by the TUNEL assay and flow cytometry. The protein levels of apoptosis protein (Caspase-3), autophagy protein (Beclin1, ATG7, p62 and LC3II/LC3I) and PI3K/AKT/mTOR pathway were determined by Western blot. Autophagic vacuoles in cells were observed with LC3 dyeing using confocal fluorescent microscopy. Anti-tumour activity of Tan-Ⅰ was accessed by subcutaneous xeno-transplanted tumour model of human ovarian cancer in nude mice. The Ki67, Caspase-3 level and apoptosis level were analysed by immunohistochemistry and TUNEL staining. RESULTS Tan-Ⅰ inhibited the proliferation of ovarian cancer cells A2780 and ID-8 in a dose-dependent manner, based on CCK8 assay, EdU staining and clone formation assay. In additional, Tan-Ⅰ induced cancer cell apoptosis and autophagy in a dose-dependent manner in ovarian cancer cells by TUNEL assay, flow cytometry and Western blot. Tan-Ⅰ significantly inhibited tumour growth by inducing cell apoptosis and autophagy. Mechanistically, Tan-Ⅰ activated apoptosis-associated protein Caspase-3 cleavage to promote cell apoptosis and inhibited PI3K/AKT/mTOR pathway to induce autophagy. CONCLUSIONS This is the first evidence that Tan-Ⅰ induced apoptosis and promoted autophagy via the inactivation of PI3K/AKT/mTOR pathway on ovarian cancer and further inhibited tumour growth, which might be considered as effective strategy.
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Affiliation(s)
- Jin Zhou
- College of ScienceSichuan Agricultural UniversityYa'anChina
| | | | - Huan Chen
- College of ScienceSichuan Agricultural UniversityYa'anChina
| | - Yi‐chao Wu
- College of Life ScienceChina West Normal UniversityNanchongChina
| | - Li Zhang
- College of ScienceSichuan Agricultural UniversityYa'anChina
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26
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Teng Z, Xu S, Lei Q. Tanshinone IIA enhances the inhibitory effect of imatinib on proliferation and motility of acute leukemia cell line TIB‑152 in vivo and in vitro by inhibiting the PI3K/AKT/mTOR signaling pathway. Oncol Rep 2020; 43:503-515. [PMID: 31894340 PMCID: PMC6967082 DOI: 10.3892/or.2019.7453] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Accepted: 09/06/2019] [Indexed: 02/07/2023] Open
Abstract
Acute lymphoblastic leukemia (ALL) is a malignant hematological disease. Tanshinone IIA (Tan IIA) has antitumor activity in vitro and in vivo. The aim of the present study was to investigate the effects of Tan IIA in combination with imatinib (IM) on the proliferation, apoptosis, migration and invasion of acute T lymphocytic leukemia TIB‑152 cells in vivo and in vitro, and analyze the potential underlying mechanism. Tan IIA and IM, alone and in combination, significantly inhibited proliferation, migration and invasion of TIB‑152 cells, and promoted apoptosis; the effect of co‑treatment with Tan IIA plus IM was enhanced. IGF‑1 promoted the proliferation, migration and invasion of TIB‑152 cells and inhibited apoptosis, while Tan IIA treatment significantly reversed these effects. In vivo experiments demonstrated that treatment with Tan IIA and IM, alone or in combination, significantly inhibited tumor growth in TIB‑152 xenograft mice; the growth inhibition of Tan IIA plus IM was the strongest observed. Western blot analysis revealed that the combination of Tan IIA and IM resulted in significantly lower levels of p‑PI3K, p‑AKT and p‑mTOR in cells and tissues compared with the IM and Tan alone treatment groups. In addition, the combination of Tan IIA and IM significantly decreased the levels of Ki67, cleaved caspase‑3, VEGF and MMP‑9 in cells and tissues, and the level of caspase‑3 was significantly increased. Taken together, the results revealed that Tan IIA enhanced the inhibitory effect of imatinib on TIB‑152 cell proliferation, migration and invasion, and induced apoptosis, which may be associated with inhibition of the PI3K/AKT/mTOR signaling pathway.
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Affiliation(s)
- Zhi Teng
- Department of Hematology, 215 Hospital of Shanxi Nuclear Industry, Xianyang, Shanxi 712000, P.R. China
| | - Shijuan Xu
- Department of Hematology, 215 Hospital of Shanxi Nuclear Industry, Xianyang, Shanxi 712000, P.R. China
| | - Qin Lei
- Department of Hematology, 215 Hospital of Shanxi Nuclear Industry, Xianyang, Shanxi 712000, P.R. China
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27
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Ma L, Jiang H, Xu X, Zhang C, Niu Y, Wang Z, Tao Y, Li Y, Cai F, Zhang X, Wang X, Yu Y. Tanshinone IIA mediates SMAD7-YAP interaction to inhibit liver cancer growth by inactivating the transforming growth factor beta signaling pathway. Aging (Albany NY) 2019; 11:9719-9737. [PMID: 31711043 PMCID: PMC6874425 DOI: 10.18632/aging.102420] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2019] [Accepted: 10/28/2019] [Indexed: 02/07/2023]
Abstract
Tanshinone IIA (TanIIA)-an active constituent of Salvia miltiorrhiza, a traditional Chinese medicinal plant-is known to have blood circulation promotion and anti-tumor properties. Tan IIA can induce tumor cell death and inhibit tumor growth. However, the functions and underling molecular mechanisms of Tan IIA action on human liver cancer cells remain poorly understand. In this study, we found that Tanshinone IIA mediates SMAD7-YAP interaction to induce liver cancer cell apoptosis and inhibit cell growth and migration by inactivating the transforming growth factor beta (TGF-β) signaling pathway. Our findings showed that the Tan IIA-SMAD7-YAP regulatory network might be an effective strategy for liver cancer treatment.
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Affiliation(s)
- Lifang Ma
- Department of Clinical Laboratory Medicine, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P.R. China.,Institute for Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China
| | - Hongyuan Jiang
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P.R. China
| | - Xin Xu
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P.R. China
| | - Congcong Zhang
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P.R. China
| | - Yongjie Niu
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P.R. China
| | - Zhixian Wang
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P.R. China
| | - Yuquan Tao
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P.R. China
| | - Yan Li
- Department of Oncology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P.R. China
| | - Feng Cai
- Department of Clinical Laboratory Medicine, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P.R. China
| | - Xiao Zhang
- Institute for Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China
| | - Xinghe Wang
- Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, P.R. China
| | - Yongchun Yu
- Institute for Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.,Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P.R. China
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28
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Guo Y, Li Y, Wang FF, Xiang B, Huang XO, Ma HB, Gong YP. The combination of Nutlin-3 and Tanshinone IIA promotes synergistic cytotoxicity in acute leukemic cells expressing wild-type p53 by co-regulating MDM2-P53 and the AKT/mTOR pathway. Int J Biochem Cell Biol 2018; 106:8-20. [PMID: 30389549 DOI: 10.1016/j.biocel.2018.10.008] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 10/17/2018] [Accepted: 10/23/2018] [Indexed: 02/05/2023]
Abstract
P53 dysfunction has been associated with various malignant tumors, including acute leukemia. The overexpression of mouse double minute 2 (MDM2) causes the inactivation of p53 in acute leukemia. MDM2 inhibitors that activate p53 and induce apoptosis are currently being developed for potential treatment of acute leukemia. However, MDM2 inhibitors alone have limited efficacy in acute leukemia therapeutics. Combining other drugs to enhance the efficacy of MDM2 inhibitors is the thus considered as a potential treatment scheme. Here, we report that the combination of Nutlin-3 and Tanshinone IIA synergistically induces cytotoxicity, cell cycle arrest, apoptosis, and autophagic cell death, thereby imparting anti-leukemia effect in an acute leukemia cell line with wild-type p53 by effectively activating p53, inhibiting the AKT/mTOR pathway, and activating the RAF/MEK pathway. Using primary samples from acute leukemia patients, we show that the combination of Nutlin-3 plus Tanshinone IIA synergistically induces cytotoxicity by activating p53 and inhibiting the AKT/mTOR pathway. This specific combination of Nutlin-3 and Tanshinone IIA is also effective in preventing the recurrence of refractory leukemia, such as Ph+ ALL with the ABL kinase T315I mutation and AML with the FLT3-ITD mutation. Taken together, the results of this study demonstrate that the Nutlin-3 plus Tanshinone IIA combination exerts synergistic anti-leukemia effects by regulating the p53 and AKT/mTOR pathways, although further investigation is warranted. Small-molecule MDM2 antagonists plus Tanshinone IIA may thus be a promising strategy for the treatment of acute leukemia.
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Affiliation(s)
- Yong Guo
- Department of Hematology, West China Hospital of Sichuan University, China
| | - Yi Li
- Department of Human Sciences, Texas A&M University-Kingsville, Kingsville, TX 78363, USA
| | - Fang-Fang Wang
- School of Medicine, University of Electronic Science and Technology of China, China
| | - Bing Xiang
- Department of Hematology, West China Hospital of Sichuan University, China
| | - Xiao-Ou Huang
- Department of Hematology, West China Hospital of Sichuan University, China
| | - Hong-Bing Ma
- Department of Hematology, West China Hospital of Sichuan University, China
| | - Yu-Ping Gong
- Department of Hematology, West China Hospital of Sichuan University, China.
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Cao YF, Wang SF, Li X, Zhang YL, Qiao YJ. The anticancer mechanism investigation of Tanshinone II A by pharmacological clustering in protein network. BMC SYSTEMS BIOLOGY 2018; 12:90. [PMID: 30373594 PMCID: PMC6206912 DOI: 10.1186/s12918-018-0606-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Accepted: 09/11/2018] [Indexed: 12/22/2022]
Abstract
BACKGROUND Cancer is the second most common cause of death globally. The anticancer effects of Tanshinone IIA (Tan IIA) has been confirmed by numerous researches. However, the underlying mechanism remained to be integrated in systematic format. Systems biology embraced the complexity of cancer; therefore, a system study approach was proposed in the present study to explore the anticancer mechanism of Tan IIA based on network pharmacology. METHOD Agilent Literature Search (ALS), a text-mining tool, was used to pull protein targets of Tan IIA. Then, pharmacological clustering was applied to classify obtained hits, the anticancer module was analysed further. The top ten essential nodes in the anticancer module were obtained by ClusterONE. Functional units in the anticancer module were catalogued and validated by Gene Ontology (GO) analysis. Meanwhile, KEGG and Cell Signalling Technology Pathway were employed to provide pathway data for potential anticancer pathways construction. Finally, the pathways were plotted using Cytoscape 3.5.1. Furthermore, in vitro experiments with five carcinoma cell lines were conducted. RESULTS A total of 258 proteins regulated by Tan IIA were identified through ALS and were visualized by protein network. Pharmacological clustering further sorted 68 proteins that intimately involved in cancer pathogenesis based on Gene Ontology. Subsequently, pathways on anticancer effect of Tan IIA were delineated. Five functional units were clarified according to literature: including regulation on apoptosis, proliferation, sustained angiogenesis, autophagic cell death, and cell cycle. The GO analysis confirmed the classification was statistically significant. The inhibiting influence of Tan IIA on p70 S6K/mTOR pathway was revealed for the first time. The in vitro experiments displayed the selectivity of Tan IIA on HeLa, MDA-MB-231, HepG2, A549, and ACHN cell lines, the IC50 values were 0.54 μM, 4.63 μM, 1.42 μM, 17.30 μM and 204.00 μM, respectively. This result further reinforced the anticancer effect of Tan IIA treatment. CONCLUSIONS The current study provides a systematic methodology for discovering the coordination of the anticancer pathways regulated by Tan IIA via protein network. And it also offers a valuable guidance for systematic study on the therapeutic values of other herbs and their active compounds.
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Affiliation(s)
- Yan-Feng Cao
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100102, China.,Beijing University of Chinese Medicine, No. 11, Bei San Huan Dong Lu, Chaoyang District, Beijing, 100029, China
| | - Shi-Feng Wang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100102, China
| | - Xi Li
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100102, China
| | - Yan-Ling Zhang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100102, China.
| | - Yan-Jiang Qiao
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100102, China.
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30
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Lu Z, Xu A, Yuan X, Chen K, Wang L, Guo T. Anticancer effect of resibufogenin on gastric carcinoma cells through the phosphoinositide 3-kinase/protein kinase B/glycogen synthase kinase 3β signaling pathway. Oncol Lett 2018; 16:3297-3302. [PMID: 30127928 DOI: 10.3892/ol.2018.8979] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Accepted: 10/24/2017] [Indexed: 01/20/2023] Open
Abstract
The aim of the present study was to investigate the anticancer effect of resibufogenin in gastric carcinoma cells through the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/glycogen synthase kinase 3β (GSK3β) signaling pathway. MGC-803 cells were treated with 0, 1, 2, 4 and 8 µM resibufogenin for 12, 24 and 48 h. Cell viability and apoptosis were measured using an MTT assay and annexin V staining. Caspase-3 and caspase-8 activity were identified using caspase-3 and caspase-8 activity kits and a variety of protein expression [B cell lymphoma (Bcl)-2, Bcl-2-associated X protein (Bax), cyclin D1, cyclin E, PI3K, phosphorylated AKT, phosphorylated GSK3β and β-catenin] were quantified using western blot analysis. It was revealed that resibufogenin effectively inhibited cell proliferation, and induced apoptosis and caspase-3 and caspase-8 activity in MGC-803 cells. Furthermore, treatment with resibufogenin effectively increased Bax/Bcl-2 expression, and suppressed cyclin D1, cyclin E, PI3K, phosphorylated AKT, phosphorylated GSK3β and β-catenin protein expression in MGC-803 cells. These results suggest that the anticancer effect of resibufogenin induces gastric carcinoma cell death through the PI3K/AKT/GSK3β signaling pathway, offering a novel view of the mechanism by which resibufogenin functions as an agent to treat gastric carcinoma.
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Affiliation(s)
- Zhen Lu
- Department of General Surgery, The Fourth Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Aman Xu
- Department of General Surgery, The Fourth Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Xiao Yuan
- Department of General Surgery, The Fourth Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Kaiwei Chen
- Department of General Surgery, The Fourth Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Likun Wang
- Department of General Surgery, The Fourth Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Tao Guo
- Department of General Surgery, The Fourth Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
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Zhang J, Zhang J, Qiu W, Zhang J, Li Y, Kong E, Lu A, Xu J, Lu X. MicroRNA-1231 exerts a tumor suppressor role through regulating the EGFR/PI3K/AKT axis in glioma. J Neurooncol 2018; 139:547-562. [PMID: 29774498 PMCID: PMC6132976 DOI: 10.1007/s11060-018-2903-8] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Accepted: 05/09/2018] [Indexed: 11/26/2022]
Abstract
PURPOSE MicroRNAs (miRNAs) have been shown to be involved in the initiation and progression of glioma. However, the underlying molecular mechanisms are still unclear. METHODS We performed microarray analysis to evaluate miRNA expression levels in 158 glioma tissue samples, and examined miR-1231 levels in glioma samples and healthy brain tissues using qRT-PCR. In vitro analyses were performed using miR-1231 mimics, inhibitors, and siRNA targeting EGFR. We used flow cytometry, CCK-8 assays, and colony formation assays to examine glioma proliferation and cell cycle analysis. A dual luciferase reporter assay was performed to examine miR-1231 regulation of EGFR, and the effect of upregulated miR-1231 was investigated in a subcutaneous GBM model. RESULTS We found that miR-1231 expression was decreased in human glioma tissues and negatively correlated with EGFR levels. Moreover, the downregulation of miR-1231 negatively correlated with the clinical stage of human glioma patients. miR-1231 overexpression dramatically downregulated glioma cell proliferation, and suppressed tumor growth in a nude mouse model. Bioinformatics prediction and a luciferase assay confirmed EGFR as a direct target of miR-1231. EGFR overexpression abrogated the suppressive effect of miR-1231 on the PI3K/AKT pathway and G1 arrest. CONCLUSIONS Taken together, these results demonstrated that EGFR is a direct target of miR-1231. Our findings suggest that the miR-1231/EGFR axis may be a helpful future diagnostic target for malignant glioma.
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Affiliation(s)
- Jiale Zhang
- Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, People's Republic of China
| | - Jie Zhang
- Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, People's Republic of China
| | - Wenjin Qiu
- Department of Neurosurgery, The Affiliated Hospital of Guizhou Medical University, 28 Guiyi Street Road, Guiyang, 550004, Guizhou Province, People's Republic of China
| | - Jian Zhang
- Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, People's Republic of China
| | - Yangyang Li
- Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, People's Republic of China
| | - Enjun Kong
- Department of Emergency, Danyang People's Hospital of Jiangsu Province, 2 Xinmin West Road, Danyang, 212300, Jiangsu Province, People's Republic of China
| | - Ailin Lu
- Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, People's Republic of China
| | - Jia Xu
- Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, People's Republic of China
| | - Xiaoming Lu
- Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, People's Republic of China.
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32
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Zhu S, Wei W, Liu Z, Yang Y, Jia H. Tanshinone‑IIA attenuates the deleterious effects of oxidative stress in osteoporosis through the NF‑κB signaling pathway. Mol Med Rep 2018; 17:6969-6976. [PMID: 29568934 PMCID: PMC5928650 DOI: 10.3892/mmr.2018.8741] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Accepted: 05/16/2017] [Indexed: 02/04/2023] Open
Abstract
Osteoclasts are responsible for bone resorption caused by bone microstructural damage and bone-related disorders. Evidence shows that tanshinone IIA (Tan‑IIA), a traditional Chinese medicine, is used clinically as a drug for the treatment of cardiovascular and cerebrovascular diseases. However, the efficacy and mechanism underlying the effect of Tan‑IIA on the viability of osteoclasts remain to be fully elucidated. The present study investigated the therapeutic effects of Tan‑IIA on osteoblast differentiation and oxidative stress in vitro and in vivo. Cell viability was analyzed and oxidative stress was examined in the osteoblasts. Wnt1sw/sw mice were used to investigate the therapeutic effects of Tan‑IIA on spontaneous tibia fractures and severe osteopenia. The bone strength, collagen and mineral were examined in the tibia. Osteoblast activity was also analyzed in the experimental mice. The Tan‑IIA‑induced differentiation of osteoclasts and the mechanism of action were investigated in osteocytes. The data showed that Tan‑IIA treatment improved cell viability. The data also demonstrated that Tan‑IIA decreased the levels of H2O2, accumulation of reactive oxygen species and apoptosis of osteoblasts. Tan‑IIA inhibited the deleterious outcomes triggered by oxidative stress. In addition, Tan‑IIA inhibited the activation of nuclear factor (NF)‑κB and its target genes, tumor necrosis factor (TNF)‑α, inducible nitric oxide synthase and cyclooxygenase 2, and increased the levels of TNF receptor‑associated factor 1 and inhibitor of apoptosis protein‑1/2 in the osteocytes. Furthermore, it was shown that Tan‑IIA reduced the propensity to fractures and severe osteopenia in mice with osteoporosis. Tan‑IIA also exhibited improved bone strength, mineral and collagen in the bone matrix of the experimental mice. It was found that the Tan‑IIA‑mediated benefits on osteoblast activity and function were through the NF‑κB signaling pathway. Taken together, the data obtained in the present study suggested that Tan‑IIA had protective effects against oxidative stress in osteoblastic differentiation in mice with osteoporosis by regulating the NF‑κB signaling pathway.
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Affiliation(s)
- Shaowen Zhu
- Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Wanfu Wei
- Department of Orthopedics, Tianjin Hospital, Tianjin 300211, P.R. China
| | - Zhiwei Liu
- Basic Medicine Institution, Public Health Center, Peking University, Beijing 100871, P.R. China
| | - Yang Yang
- Department of Orthopedics, Tianjin Hospital, Tianjin 300211, P.R. China
| | - Haobo Jia
- Department of Orthopedics, Tianjin Hospital, Tianjin 300211, P.R. China
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Chiu CM, Huang SY, Chang SF, Liao KF, Chiu SC. Synergistic antitumor effects of tanshinone IIA and sorafenib or its derivative SC-1 in hepatocellular carcinoma cells. Onco Targets Ther 2018; 11:1777-1785. [PMID: 29636623 PMCID: PMC5881525 DOI: 10.2147/ott.s161534] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Introduction Hepatocellular carcinoma (HCC) is the most common form of hepatic malignancy in the world. We aimed to determine the effect of tanshinone IIA (Tan-IIA) in combination with sorafenib or its derivative SC-1 on cytotoxicity, apoptosis, and metastasis in human HCC cells. Materials and methods Cytotoxicity was detected by MTT assay. Apoptosis and sub-G1 populations were analyzed by flow cytometry. Cell migration and invasion were evaluated by Transwell assay. Protein expression was detected by Western blot. Results Tan-IIA combined with sorafenib or SC-1 exerted synergistic cytotoxicity in HCC cells. Elevated proportions of sub-G1 and caspase activation were observed in the combinative treatments; in addition, marked inhibition of cell migration and invasion, which could be mediated by the modulation of epithelial–mesenchymal transition was observed. pSTAT3 levels were significantly reduced as well. Conclusion A combination therapy using Tan-IIA and sorafenib or SC-1 could be a promising approach to target HCC, and further preclinical investigations are warranted to establish their synergetic advantage.
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Affiliation(s)
- Chien-Ming Chiu
- Division of Colorectal Surgery, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, Taiwan
| | - Sung-Ying Huang
- Department of Ophthalmology, Hsinchu Mackay Memorial Hospital, Hsinchu, Taiwan
| | - Shu-Fang Chang
- Department of Research, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, Taiwan
| | - Kuan-Fu Liao
- Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan.,Department of Internal Medicine, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, Taiwan
| | - Sheng-Chun Chiu
- Department of Research, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, Taiwan.,Department of Laboratory Medicine, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, Taiwan.,General Education Center, Tzu Chi University of Science and Technology, Hualien, Taiwan
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Zhu Y, Tang Q, Wang G, Han R. Tanshinone IIA Protects Hippocampal Neuronal Cells from Reactive Oxygen Species Through Changes in Autophagy and Activation of Phosphatidylinositol 3-Kinase, Protein Kinas B, and Mechanistic Target of Rapamycin Pathways. Curr Neurovasc Res 2018; 14:132-140. [PMID: 28260507 PMCID: PMC5543574 DOI: 10.2174/1567202614666170306105315] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2017] [Revised: 02/18/2017] [Accepted: 02/20/2017] [Indexed: 12/29/2022]
Abstract
Background: Tanshinone IIA is a key active ingredient of danshen, which is derived from the dried root or rhizome of Salviae miltiorrhizae Bge. The tanshinone IIA has protective effects against the focal cerebral ischemic injury. However, the underlying mechanisms remain unclear. Methods: An in vitro model of cerebral ischemia was established by subjecting cultures of hippocampal neuronal cells to oxygen-glucose deprivation followed by reperfusion (OGD/R). The probes of 5-(and-6)-chloromethyl-2’,7’-dichlorodihydrofluorescein diacetate, acetyl ester (CM-H2DCFDA) and 5’,6,6’-tetrachloro-1,1’,3,3’-tetraethylbenzimidazolylcarbocyanine,iodide (JC-1) were used to determine the mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) production. Western-blot was used to detect the expression of proteins in HT-22 cells. Results: The results of cell proliferative assays showed that the tanshinone IIA attenuated OGD/R-mediated neuronal cell death, with the evidence of increased cell viability. In addition, OGD/R exposure led to increase the levels of intracellular reactive oxygen species (ROS), which were significantly suppressed by tanshinone IIA treatment. Furthermore, tanshinone IIA treatment inhibited elevations in MMP and autophagy following exposure to OGD/R. Additionally, OGD/R promoted cell death with concomitant inhibiting phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/ mammalian target of Rapamycin (mTOR) pathway, which was reversed by tanshinone IIA. Conclusion: These results suggest that the tanshinone IIA protects against OGD/R-mediated cell death in HT-22 cells, in part, due to activating PI3K/Akt/mTOR pathway.
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Affiliation(s)
- Yingchun Zhu
- Department of Neurology Disease, the Affiliated Anhui Provincial Hospital of Anhui Medical University, Hefei 230022, Anhui, China
| | - Qiqiang Tang
- Department of Neurology Disease, the Affiliated Anhui Provincial Hospital of Anhui Medical University, Hefei 230022, Anhui, China
| | - Guopin Wang
- Department of Neurology Disease, the Affiliated Anhui Provincial Hospital of Anhui Medical University, Hefei 230022, Anhui, China
| | - Ruodong Han
- Department of Intensive Care Division, The People's Hospital of Bozhou, Bozhou 236800, Anhui, China
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Lv C, Zeng HW, Wang JX, Yuan X, Zhang C, Fang T, Yang PM, Wu T, Zhou YD, Nagle DG, Zhang WD. The antitumor natural product tanshinone IIA inhibits protein kinase C and acts synergistically with 17-AAG. Cell Death Dis 2018; 9:165. [PMID: 29416003 PMCID: PMC5833361 DOI: 10.1038/s41419-017-0247-5] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2017] [Revised: 12/16/2017] [Accepted: 12/18/2017] [Indexed: 12/16/2022]
Abstract
Tanshinone IIA (Tan IIA), the primary bioactive compound derived from the traditional Chinese medicine (TCM) Salvia miltiorrhiza Bunge, has been reported to possess antitumor activity. However, its antitumor mechanisms are not fully understood. To resolve the potential antitumor mechanism(s) of Tan IIA, its gene expression profiles from our database was analyzed by connectivity map (CMAP) and the CMAP-based mechanistic predictions were confirmed/validated in further studies. Specifically, Tan IIA inhibited total protein kinase C (PKC) activity and selectively suppressed the expression of cytosolic and plasma membrane PKC isoforms ζ and ε. The Ras/MAPK pathway that is closely regulated by the PKC signaling is also inhibited by Tan IIA. While Tan IIA did not inhibit heat shock protein 90 (Hsp90), it synergistically enhanced the antitumor efficacy of the Hsp90 inhibitors 17-AAG and ganetespib in human breast cancer MCF-7 cells. In addition, Tan IIA significantly inhibited PI3K/Akt/mTOR signaling, and induced both cell cycle arrest and autophagy. Collectively, these studies provide new insights into the molecular mechanisms responsible for antitumor activity of Tan IIA.
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Affiliation(s)
- Chao Lv
- Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, 201203, P.R. China
| | - Hua-Wu Zeng
- School of Pharmacy, Second Military Medical University, Shanghai, 200433, P.R. China
| | - Jin-Xin Wang
- School of Pharmacy, Second Military Medical University, Shanghai, 200433, P.R. China
| | - Xing Yuan
- School of Pharmacy, Second Military Medical University, Shanghai, 200433, P.R. China
| | - Chuang Zhang
- School of Pharmaceutical Sciences, Zhengzhou University, Henan, 450001, P.R. China
| | - Ting Fang
- School of Pharmacy, Fujian University of Traditional Chinese Medicine, Fujian, 350108, P.R. China
| | - Pei-Ming Yang
- Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, 201203, P.R. China
| | - Tong Wu
- Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, 201203, P.R. China
| | - Yu-Dong Zhou
- Institute of Interdisciplinary Integrative Biomedical Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.,Department of Chemistry and Biochemistry, College of Liberal Arts, University of Mississippi, University, Mississippi, MS, 38677-1848, USA
| | - Dale G Nagle
- Institute of Interdisciplinary Integrative Biomedical Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.,Department of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, Mississippi, MS, 38677-1848, USA
| | - Wei-Dong Zhang
- Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, 201203, P.R. China. .,School of Pharmacy, Second Military Medical University, Shanghai, 200433, P.R. China.
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Lu J, Chen M, Gao S, Yuan J, Zhu Z, Zou X. LY294002 inhibits the Warburg effect in gastric cancer cells by downregulating pyruvate kinase M2. Oncol Lett 2018. [PMID: 29541204 PMCID: PMC5835956 DOI: 10.3892/ol.2018.7843] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
The ‘Warburg effect’ is considered a vital hallmark of cancer cells, characterized by an altered metabolism, in which cells rely on aerobic glycolysis. As a key enzyme of aerobic glycolysis, pyruvate kinase M2 (PKM2) serves a crucial role in tumorigenesis. Accumulating studies have indicated that PKM2 is a potential target for cancer therapy. The aim of the present study was to assess the anticancer effects of LY294002, a specific phosphatidylinositol-3-kinase inhibitor, on gastric cancer (GC) cells and further explore its possible mechanism in vitro. The present study revealed that LY294002 inhibited GC cell proliferation, induced early apoptosis and significantly decreased lactate dehydrogenase activity and lactate production, in part through inhibiting PKM2 expression. In summary, LY294002 exhibits anticancer effects on GC, partly via the downregulation of PKM2.
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Affiliation(s)
- Jian Lu
- Department of Gastroenterology, The Affiliated Drum Tower Clinical Medical School of Nanjing Medical University, Nanjing, Jiangsu 210008, P.R. China.,Department of Gastroenterology, The Affiliated Wuxi Second Hospital of Nanjing Medical University, Wuxi, Jiangsu 214002, P.R. China.,Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu 210008, P.R. China
| | - Min Chen
- Department of Gastroenterology, The Affiliated Drum Tower Clinical Medical School of Nanjing Medical University, Nanjing, Jiangsu 210008, P.R. China.,Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu 210008, P.R. China
| | - Sumeng Gao
- Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu 210008, P.R. China
| | - Jigang Yuan
- Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu 210008, P.R. China
| | - Zhu Zhu
- Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu 210008, P.R. China
| | - Xiaoping Zou
- Department of Gastroenterology, The Affiliated Drum Tower Clinical Medical School of Nanjing Medical University, Nanjing, Jiangsu 210008, P.R. China.,Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu 210008, P.R. China
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Nutlin-3 plus tanshinone IIA exhibits synergetic anti-leukemia effect with imatinib by reactivating p53 and inhibiting the AKT/mTOR pathway in Ph+ ALL. Biochem J 2017; 474:4153-4170. [PMID: 29046392 DOI: 10.1042/bcj20170386] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2017] [Revised: 10/09/2017] [Accepted: 10/16/2017] [Indexed: 02/05/2023]
Abstract
Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is triggered by BCR/ABL kinase. Recent efforts focused on the development of more potent tyrosine kinase inhibitors (TKIs) that also inhibit mutant tyrosine kinases such as nilotinib and dasatinib. Although major advances in the treatment of this aggressive disease with potent inhibitors of the BCR/ABL kinases, patients in remission frequently relapse due to drug resistance possibly mediated, at least in part, by compensatory activation of growth-signaling pathways and protective feedback signaling of leukemia cells in response to TKI treatment. Continuous activation of AKT/mTOR signaling and inactivation of p53 pathway were two mechanisms of TKI resistance. Here, we reported that nutlin-3 plus tanshinone IIA significantly potentiated the cytotoxic and apoptotic induction effects of imatinib by down-regulation of the AKT/mTOR pathway and reactivating the p53 pathway deeply in Ph+ ALL cell line. In primary samples from Ph+ ALL patients, nutlin-3 plus tanshinone IIA also exhibited synergetic cytotoxic effects with imatinib. Of note, three samples from Ph+ ALL patients harboring T315I mutation also showed sensitivity to the combined treatment of imatinib, nutlin-3 plus tanshinone IIA. In Ph+ ALL mouse models, imatinib combined with nutlin-3 plus tanshinone IIA also exhibited synergetic effects on reduction in leukemia burden. These results demonstrated that nutlin-3 plus tanshinone IIA combined TKI might be a promising treatment strategy for Ph+ ALL patients.
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Zhang J, Liu Y, Yu CJ, Dai F, Xiong J, Li HJ, Wu ZS, Ding R, Wang H. Role of ARPC2 in Human Gastric Cancer. Mediators Inflamm 2017; 2017:5432818. [PMID: 28694563 PMCID: PMC5485321 DOI: 10.1155/2017/5432818] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2016] [Accepted: 03/06/2017] [Indexed: 01/01/2023] Open
Abstract
Gastric cancer continues to be the second most frequent cause of cancer deaths worldwide. However, the exact molecular mechanisms are still unclear. Further research to find potential targets for therapy is critical and urgent. In this study, we found that ARPC2 promoted cell proliferation and invasion in the human cancer cell line MKN-28 using a cell total number assay, MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide) assay, cell colony formation assay, migration assay, invasion assay, and wound healing assay. For downstream pathways, CTNND1, EZH2, BCL2L2, CDH2, VIM, and EGFR were upregulated by ARPC2, whereas PTEN, BAK, and CDH1 were downregulated by ARPC2. In a clinical study, we examined the expression of ARPC2 in 110 cases of normal human gastric tissues and 110 cases of human gastric cancer tissues. ARPC2 showed higher expression in gastric cancer tissues than in normal gastric tissues. In the association analysis of 110 gastric cancer tissues, ARPC2 showed significant associations with large tumor size, lymph node invasion, and high tumor stage. In addition, ARPC2-positive patients exhibited lower RFS and OS rates compared with ARPC2-negative patients. We thus identify that ARPC2 plays an aneretic role in human gastric cancer and provided a new target for gastric cancer therapy.
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Affiliation(s)
- Jun Zhang
- Department of General Surgery, Third Affiliated Hospital (Hefei First People's Hospital) of Anhui Medical University, Hefei, China
| | - Yi Liu
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Chang-Jun Yu
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Fu Dai
- Department of General Surgery, Third Affiliated Hospital (Hefei First People's Hospital) of Anhui Medical University, Hefei, China
| | - Jie Xiong
- Department of General Surgery, Third Affiliated Hospital (Hefei First People's Hospital) of Anhui Medical University, Hefei, China
| | - Hong-Jun Li
- Department of General Surgery, Third Affiliated Hospital (Hefei First People's Hospital) of Anhui Medical University, Hefei, China
| | - Zheng-Sheng Wu
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Rui Ding
- Department of General Surgery, Third Affiliated Hospital (Hefei First People's Hospital) of Anhui Medical University, Hefei, China
| | - Hong Wang
- Department of General Surgery, Third Affiliated Hospital (Hefei First People's Hospital) of Anhui Medical University, Hefei, China
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