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Song H, Sun X, Wang X, Xie T, Zheng Z, Ji Y, Cui Y. β-elemene Ameliorates Cisplatin Resistance of Gastric Cancer via Regulating Exosomal METTL3-m6A-ARF6 Axis. Cell Biochem Biophys 2025; 83:2047-2058. [PMID: 39602058 DOI: 10.1007/s12013-024-01615-z] [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] [Accepted: 11/07/2024] [Indexed: 11/29/2024]
Abstract
The medial overall survival is low in patients with gastric cancer (GC) at advanced stage, in which drug resistance plays an important role. β-elemene has been established as the suppressed role on GC cell proliferation, however, the concrete mechanism of it remains unclear in cisplatin (DDP)-resistance GC. Cell counting kit-8 (CCK8) assay was used to measure the half maximal inhibitory concentration (IC50) values of DDP in DDP-resistance GC cell lines. Cell apoptotic rates and invasive ability were tested by flow cytometry and transwell assay. Western blot and reverse-transcription quantitative polymerase chain reaction (RT-qPCR) were utilized to detect the protein and mRNA levels of methyltransferase like-3 (METTL3) and ADP ribosylation factor 6 (ARF6). SRAMP websites and methylated RNA immunoprecipitation (MeRIP) assay were applied to predicted m6A sites and verified m6A levels of ARF6 respectively. RNA immunoprecipitation (RIP) was used to explore the interaction between these two molecules. Xenograft tumor models were constructed to demonstrate the effects of β-elemene in vivo. β-elemene improved drug sensitivity and curbed malignant cell activities of DDP-resistance GC cells in vitro. ARF6 was upregulated in DDP-resistance GC cells and tissues, and its overexpression could abrogate the effects on DDP-resistant GC cells mediated by β-elemene treatment. Intracellular and exosomal METLL3 expression were elevated in and from DDP-resistance GC cell lines. Exosomal METTL3 released from DDP-resistance GC cells could counteract the effects of β-elemene on DDP-resistance GC cells partly via regulating ARF6 expression in the m6A-dependent manner. β-elemene could suppress DDP-resistance tumor growth in vivo. In conclusion, β-elemene could repress tumor growth and drug resistance via exosomal METTL3-m6A-ARF6 axis.
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Affiliation(s)
- Huicong Song
- Department of Oncology, Affiliated Hospital of Chifeng University, Chifeng, Inner Mongolia, China
| | - Xuefeng Sun
- Department of Oncology, Affiliated Hospital of Chifeng University, Chifeng, Inner Mongolia, China
| | - Xiaohua Wang
- Department of Oncology, Affiliated Hospital of Chifeng University, Chifeng, Inner Mongolia, China
| | - Tianhai Xie
- Department of Oncology, Affiliated Hospital of Chifeng University, Chifeng, Inner Mongolia, China
| | - Zhihui Zheng
- Department of Oncology, Affiliated Hospital of Chifeng University, Chifeng, Inner Mongolia, China
| | - Ying Ji
- Department of Oncology, Affiliated Hospital of Chifeng University, Chifeng, Inner Mongolia, China
| | - Yanyan Cui
- Department of Oncology, Affiliated Hospital of Chifeng University, Chifeng, Inner Mongolia, China.
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Lu X, Chen J, Lu Z, Zang H. Knockdown of PAK1IP1 can Induce Pyroptosis to Inhibit the Progression of Hepatocellular Carcinoma. FRONT BIOSCI-LANDMRK 2025; 30:26654. [PMID: 40302327 DOI: 10.31083/fbl26654] [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: 09/20/2024] [Revised: 12/26/2024] [Accepted: 01/06/2025] [Indexed: 05/02/2025]
Abstract
AIM To identify potential prognostic biomarkers and uncover new mechanisms underlying hepatocellular carcinoma (HCC). BACKGROUND HCC is a prevalent and fatal malignancy originating from hepatic cells, with a consistently rising incidence in recent decades. OBJECTIVE To identify potential prognostic biomarkers, specifically focusing on the role of PAK1-interacting protein 1 (PAK1IP1), and to uncover novel mechanistic insights in HCC. METHODS HCC-related datasets (GSE45267 and GSE49515) and data from The Cancer Genome Atlas (TCGA) were retrieved for the analysis of differentially expressed genes (DEGs). The common DEGs were subsequently subjected to weighted gene co-expression network analysis (WGCNA), protein-protein interaction network (PPI), risk model, expression, survival, and prognostic nomogram to determine key genes associated with HCC. Further, the key gene was analyzed using clinical feature analysis, immunoassay, and cell experiments to investigate its exact role in HCC. RESULTS Based on the above comprehensive analysis, we targeted the key gene PAK1IP1 with a good prognostic value in HCC. PAK1IP1 showed a remarkably higher increase in tumor samples than in normal samples, which might be related to immune cell infiltration in liver cancer. It was up-regulated in HCC cells, and its knockdown could suppress HCC proliferation and migration. Besides, enzyme-linked immunosorbent assay (ELISA) showed that PAK1IP1 could regulate lipopolysaccharide (LPS)-induced pyroptosis of HCC cells. Knocking down PAK1IP1 could lead to increased expression of caspase 3 (CASP-3), gasdermin E (GSDME)-N, cleaved caspase-1, and gasdermin-D (GSDMD)-N in HCC cells, inducing pyroptosis, thereby inhibiting the development of HCC. CONCLUSION To summarize, PAK1IP1 was identified as a promising prognostic biomarker, and the knockdown of PAK1IP1 can induce pyroptosis to suppress HCC development, which sheds new light on HCC tumorigenesis.
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Affiliation(s)
- Xiaoliang Lu
- Hepatobiliary Surgery Department, Nantong First People's Hospital, 226000 Nantong, Jiangsu, China
| | - Jie Chen
- Hepatobiliary Surgery Department, Nantong First People's Hospital, 226000 Nantong, Jiangsu, China
| | - Zefa Lu
- Hepatobiliary Surgery Department, Nantong First People's Hospital, 226000 Nantong, Jiangsu, China
| | - Hong Zang
- Hepatobiliary Surgery Department, Nantong First People's Hospital, 226000 Nantong, Jiangsu, China
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Zhou Y, Takano T, Li X, Wang Y, Wang R, Zhu Z, Tanokura M, Miyakawa T, Hachimura S. β-elemene regulates M1-M2 macrophage balance through the ERK/JNK/P38 MAPK signaling pathway. Commun Biol 2022; 5:519. [PMID: 35641589 PMCID: PMC9156783 DOI: 10.1038/s42003-022-03369-x] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 04/14/2022] [Indexed: 02/06/2023] Open
Abstract
Macrophages are classified into classically activated M1 macrophages and alternatively activated M2 macrophages, and the two phenotypes of macrophages are present during the development of various chronic diseases, including obesity-induced inflammation. In the present study, β-elemene, which is contained in various plant substances, is predicted to treat high-fat diet (HFD)-induced macrophage dysfunction based on the Gene Expression Omnibus (GEO) database and experimental validation. β-elemene impacts the imbalance of M1-M2 macrophages by regulating pro-inflammatory cytokines in mouse white adipose tissue both in vitro and in vivo. In addition, the RAW 264 cell line, which are macrophages from mouse ascites, is used to identify the effects of β-elemene on inhibiting bacterial endotoxin lipopolysaccharide (LPS)-induced phosphorylation of mitogen-activated protein kinase (MAPK) pathways. These pathways both induce and are activated by pro-inflammatory cytokines, and they also participate in the process of obesity-induced inflammation. The results highlight that β-elemene may represent a possible macrophage-mediated therapeutic medicine.
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Affiliation(s)
- Yingyu Zhou
- Research Center for Food Safety, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8657, Japan
- Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8657, Japan
| | - Tomohiro Takano
- Research Center for Food Safety, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8657, Japan
- Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8657, Japan
| | - Xuyang Li
- Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8657, Japan
| | - Yimei Wang
- Research Center for Food Safety, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8657, Japan
- Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8657, Japan
| | - Rong Wang
- Research Center for Food Safety, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8657, Japan
- Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8657, Japan
| | - Zhangliang Zhu
- Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8657, Japan
- Key Laboratory of Industrial Fermentation Microbiology of the Ministry of Education, Tianjin Key Laboratory of Industrial Microbiology, College of Biotechnology, Tianjin University of Science and Technology, National Engineering Laboratory for Industrial Enzymes, Tianjin, 300457, P. R. China
| | - Masaru Tanokura
- Research Center for Food Safety, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8657, Japan.
- Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8657, Japan.
| | - Takuya Miyakawa
- Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8657, Japan.
| | - Satoshi Hachimura
- Research Center for Food Safety, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8657, Japan.
- Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8657, Japan.
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Dai R, Liu M, Xiang X, Li Y, Xi Z, Xu H. OMICS Applications for Medicinal Plants in Gastrointestinal Cancers: Current Advancements and Future Perspectives. Front Pharmacol 2022; 13:842203. [PMID: 35185591 PMCID: PMC8855055 DOI: 10.3389/fphar.2022.842203] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 01/20/2022] [Indexed: 12/24/2022] Open
Abstract
Gastrointestinal cancers refer to a group of deadly malignancies of the gastrointestinal tract and organs of the digestive system. Over the past decades, considerable amounts of medicinal plants have exhibited potent anticancer effects on different types of gastrointestinal cancers. OMICS, systems biology approaches covering genomics, transcriptomics, proteomics and metabolomics, are broadly applied to comprehensively reflect the molecular profiles in mechanistic studies of medicinal plants. Single- and multi-OMICS approaches facilitate the unravelling of signalling interaction networks and key molecular targets of medicinal plants with anti-gastrointestinal cancer potential. Hence, this review summarizes the applications of various OMICS and advanced bioinformatics approaches in examining therapeutic targets, signalling pathways, and the tumour microenvironment in response to anticancer medicinal plants. Advances and prospects in this field are also discussed.
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Affiliation(s)
- Rongchen Dai
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai, China
| | - Mengfan Liu
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai, China
| | - Xincheng Xiang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai, China
| | - Yang Li
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai, China
| | - Zhichao Xi
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai, China
- *Correspondence: Zhichao Xi, ; Hongxi Xu,
| | - Hongxi Xu
- Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- *Correspondence: Zhichao Xi, ; Hongxi Xu,
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Hu D, Gao J, Yang X, Liang Y. A Comprehensive Mini-Review of Curcumae Radix: Ethnopharmacology, Phytochemistry, and Pharmacology. Nat Prod Commun 2021. [DOI: 10.1177/1934578x211020628] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Curcumae Radix is an efficacious ingredient with various medicinal properties empirically used in traditional Chinese medicine (TCM) formula for the treatment of cancer, depression, chest pain, dysmenorrhea, epilepsy, and jaundice. However, either phytochemical or pharmacological information of Curcumae Radix underlying its traditionally medicinal uses is rarely summarized and systematically analyzed. To provide evidence for clinical trials, a comprehensive literature review has been prepared of the phytochemicals, and ethnopharmacological and pharmacological mechanisms of this herb. The review approach consisted of searching several web-based scientific databases, including PubMed, Web of Science, and Elsevier. The keywords included “Curcumae Radix,” “ Curcuma wenyujin,” “ Curcuma longa,” “ Curcuma kwangsiensis,” and “ Curcuma phaeocaulis.” Based on the proposed criteria, 57 articles were evaluated in detail. The accumulated data indicate that Curcumae Radix contains a number of bioactive phytochemicals, mainly sesquiterpenes, diarylheptanoids, and diarylpentanoids, which account for a variety of medicinal values, such as anticancer, anti-inflammation, anti-hepatic fibrosis, and antioxidant. A wide range of apoptotic proteins, cell adhesion molecules, inflammatory cytokines, and enzymic and nonenzymic antioxidants could be modulated by either Curcumae Radix or its bioactive compounds, thus underpinning a fundamental understanding for the pharmacological effects of this herb. This review highlights the therapeutic potential of Curcumae Radix to progress the development of versatile adjuvants or therapeutic agents in the future.
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Affiliation(s)
- Dongyi Hu
- School of Chemical Engineering and Pharmaceutics, Henan University of Science and Technology, Henan, China
| | - Jiayu Gao
- School of Chemical Engineering and Pharmaceutics, Henan University of Science and Technology, Henan, China
| | - Xiao Yang
- School of Clinical Medicine, Henan University of Science and Technology, Henan, China
| | - Ying Liang
- National Clinical Research Center for Mental Disorders, Peking University Sixth Hospital, Institute of Mental Health, Key Laboratory of Mental Health, Ministry of Health, Peking University, Beijing, China
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Anti-Tumor Drug Discovery Based on Natural Product β-Elemene: Anti-Tumor Mechanisms and Structural Modification. Molecules 2021; 26:molecules26061499. [PMID: 33801899 PMCID: PMC7998186 DOI: 10.3390/molecules26061499] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 03/08/2021] [Accepted: 03/08/2021] [Indexed: 12/26/2022] Open
Abstract
Natural products are important sources for drug discovery, especially anti-tumor drugs. β-Elemene, the prominent active ingredient extract from the rhizome of Curcuma wenyujin, is a representative natural product with broad anti-tumor activities. The main molecular mechanism of β-elemene is to inhibit tumor growth and proliferation, induce apoptosis, inhibit tumor cell invasion and metastasis, enhance the sensitivity of chemoradiotherapy, regulate the immune system, and reverse multidrug resistance (MDR). Elemene oral emulsion and elemene injection were approved by the China Food and Drug Administration (CFDA) for the treatment of various cancers and bone metastasis in 1994. However, the lipophilicity and low bioavailability limit its application. To discover better β-elemene-derived anti-tumor drugs with satisfying drug-like properties, researchers have modified its structure under the premise of not damaging the basic scaffold structure. In this review, we comprehensively discuss and summarize the potential anti-tumor mechanisms and the progress of structural modifications of β-elemene.
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Abu-Izneid T, Rauf A, Shariati MA, Khalil AA, Imran M, Rebezov M, Uddin MS, Mahomoodally MF, Rengasamy KRR. Sesquiterpenes and their derivatives-natural anticancer compounds: An update. Pharmacol Res 2020; 161:105165. [PMID: 32835868 DOI: 10.1016/j.phrs.2020.105165] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Revised: 08/07/2020] [Accepted: 08/14/2020] [Indexed: 01/07/2023]
Abstract
Sesquiterpenes belong to the largest group of plant secondary metabolites, which consist of three isoprene building units. These compounds are widely distributed in various angiosperms, a few gymnosperms and bryophytes. Sesquiterpenes and their allied derivatives are bio-synthesized in various plant parts including leaves, fruits and roots. These plant-based metabolites are predominantly identified in the Asteraceae family, wherein up to 5000 complexes have been documented to date. Sesquiterpenes and their derivatives are characteristically associated with plant defence mechanisms owing to their antifungal, antibacterial and antiviral activities. Over the last two decades, these compounds have been reportedly demonstrated health promoting perspectives against a wide range of metabolic syndromes i.e. hyperglycemia, hyperlipidemia, cardiovascular complications, neural disorders, diabetes, and cancer. The high potential of sesquiterpenes and their derivatives against various cancers like breast, colon, bladder, pancreatic, prostate, cervical, brain, liver, blood, ovarium, bone, endometrial, oral, lung, eye, stomach and kidney are the object of this review. Predominantly, it recapitulates the literature elucidating sesquiterpenes and their derivatives while highlighting the mechanistic approaches associated with their potent anticancer activities such as modulating nuclear factor kappa (NF-kB) activity, inhibitory action against lipid peroxidation and retarding the production of reactive oxygen & nitrogen species (ROS&RNS).
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Affiliation(s)
- Tareq Abu-Izneid
- Pharmaceutical Sciences Department, College of Pharmacy, Al Ain University, Al Ain, United Arab Emirates
| | - Abdur Rauf
- Department of Chemistry, University of Swabi, Khyber Pakhtunkhwa, Pakistan
| | - Mohammad Ali Shariati
- K.G. Razumovsky Moscow State University of Technologies and Management (the First Cossack University), Moscow, Russian Federation
| | - Anees Ahmed Khalil
- University Institute of Diet and Nutritional Sciences, Faculty of Allied Health Sciences, The University of Lahore, Pakistan
| | - Muhammad Imran
- University Institute of Diet and Nutritional Sciences, Faculty of Allied Health Sciences, The University of Lahore, Pakistan
| | - Maksim Rebezov
- V. M. Gorbatov Federal Research Center for Food Systems of Russian Academy of Sciences, Moscow, Russian Federation
| | - Md Sahab Uddin
- Pharmakon Neuroscience Research Network, Dhaka, Bangladesh
| | - Mohamad Fawzi Mahomoodally
- Institute of Research and Development, Duy Tan University, Da Nang 550000, Viet Nam; Department of Health Sciences, Faculty of Science, University of Mauritius, Réduit, Mauritius
| | - Kannan R R Rengasamy
- Bionanotechnology Research Group, Ton Duc Thang University, Ho Chi Minh City, Viet Nam; Faculty of Pharmacy, Ton Duc Thang University, Ho Chi Minh City, Viet Nam.
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Hanuš LO, Hod Y. Terpenes/Terpenoids in Cannabis: Are They Important? Med Cannabis Cannabinoids 2020; 3:25-60. [PMID: 34676339 PMCID: PMC8489319 DOI: 10.1159/000509733] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Accepted: 06/26/2020] [Indexed: 11/19/2022] Open
Abstract
Cannabis sativa plant has not only cannabinoids as crucial compounds but also the other compounds that play important role as synergistic and/or entourage compound. Cannabis/hemp plant materials and essential oils were analyzed with the help of gas chromatography/mass spectrometry detector for the content of terpenes and terpenoids. The main terpenes/terpenoids and their abundance in the samples were evaluated. Results of this study will be helpful in the next evaluation of these compound in mixture with cannabinoids and their importance in medical treatment.
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Affiliation(s)
- Lumír Ondřej Hanuš
- Lumir Lab, Asana Bio Group Ltd., The Hadassah Medical Center, Hebrew University Biotechnology Park, Ein Kerem, Jerusalem, Israel
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Gonçalves ECD, Baldasso GM, Bicca MA, Paes RS, Capasso R, Dutra RC. Terpenoids, Cannabimimetic Ligands, beyond the Cannabis Plant. Molecules 2020; 25:E1567. [PMID: 32235333 PMCID: PMC7181184 DOI: 10.3390/molecules25071567] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Revised: 03/26/2020] [Accepted: 03/27/2020] [Indexed: 02/06/2023] Open
Abstract
Medicinal use of Cannabis sativa L. has an extensive history and it was essential in the discovery of phytocannabinoids, including the Cannabis major psychoactive compound-Δ9-tetrahydrocannabinol (Δ9-THC)-as well as the G-protein-coupled cannabinoid receptors (CBR), named cannabinoid receptor type-1 (CB1R) and cannabinoid receptor type-2 (CB2R), both part of the now known endocannabinoid system (ECS). Cannabinoids is a vast term that defines several compounds that have been characterized in three categories: (i) endogenous, (ii) synthetic, and (iii) phytocannabinoids, and are able to modulate the CBR and ECS. Particularly, phytocannabinoids are natural terpenoids or phenolic compounds derived from Cannabis sativa. However, these terpenoids and phenolic compounds can also be derived from other plants (non-cannabinoids) and still induce cannabinoid-like properties. Cannabimimetic ligands, beyond the Cannabis plant, can act as CBR agonists or antagonists, or ECS enzyme inhibitors, besides being able of playing a role in immune-mediated inflammatory and infectious diseases, neuroinflammatory, neurological, and neurodegenerative diseases, as well as in cancer, and autoimmunity by itself. In this review, we summarize and critically highlight past, present, and future progress on the understanding of the role of cannabinoid-like molecules, mainly terpenes, as prospective therapeutics for different pathological conditions.
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Affiliation(s)
- Elaine C. D. Gonçalves
- Laboratory of Autoimmunity and Immunopharmacology (LAIF), Department of Health Sciences, Campus Araranguá, Universidade Federal de Santa Catarina, Araranguá 88906-072, Brazil; (E.C.D.G.); (G.M.B.); (R.S.P.)
- Graduate Program of Neuroscience, Center of Biological Sciences, Campus Florianópolis, Universidade Federal de Santa Catarina, Florianópolis 88040-900, Brazil
| | - Gabriela M. Baldasso
- Laboratory of Autoimmunity and Immunopharmacology (LAIF), Department of Health Sciences, Campus Araranguá, Universidade Federal de Santa Catarina, Araranguá 88906-072, Brazil; (E.C.D.G.); (G.M.B.); (R.S.P.)
| | - Maíra A. Bicca
- Neurosurgery Department, Neurosurgery Pain Research institute, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA;
| | - Rodrigo S. Paes
- Laboratory of Autoimmunity and Immunopharmacology (LAIF), Department of Health Sciences, Campus Araranguá, Universidade Federal de Santa Catarina, Araranguá 88906-072, Brazil; (E.C.D.G.); (G.M.B.); (R.S.P.)
| | - Raffaele Capasso
- Department of Agricultural Sciences, University of Naples Federico II, 80,055 Portici, Italy
| | - Rafael C. Dutra
- Laboratory of Autoimmunity and Immunopharmacology (LAIF), Department of Health Sciences, Campus Araranguá, Universidade Federal de Santa Catarina, Araranguá 88906-072, Brazil; (E.C.D.G.); (G.M.B.); (R.S.P.)
- Graduate Program of Neuroscience, Center of Biological Sciences, Campus Florianópolis, Universidade Federal de Santa Catarina, Florianópolis 88040-900, Brazil
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Luo H, Vong CT, Chen H, Gao Y, Lyu P, Qiu L, Zhao M, Liu Q, Cheng Z, Zou J, Yao P, Gao C, Wei J, Ung COL, Wang S, Zhong Z, Wang Y. Naturally occurring anti-cancer compounds: shining from Chinese herbal medicine. Chin Med 2019; 14:48. [PMID: 31719837 PMCID: PMC6836491 DOI: 10.1186/s13020-019-0270-9] [Citation(s) in RCA: 331] [Impact Index Per Article: 55.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Accepted: 10/23/2019] [Indexed: 12/24/2022] Open
Abstract
Numerous natural products originated from Chinese herbal medicine exhibit anti-cancer activities, including anti-proliferative, pro-apoptotic, anti-metastatic, anti-angiogenic effects, as well as regulate autophagy, reverse multidrug resistance, balance immunity, and enhance chemotherapy in vitro and in vivo. To provide new insights into the critical path ahead, we systemically reviewed the most recent advances (reported since 2011) on the key compounds with anti-cancer effects derived from Chinese herbal medicine (curcumin, epigallocatechin gallate, berberine, artemisinin, ginsenoside Rg3, ursolic acid, silibinin, emodin, triptolide, cucurbitacin B, tanshinone I, oridonin, shikonin, gambogic acid, artesunate, wogonin, β-elemene, and cepharanthine) in scientific databases (PubMed, Web of Science, Medline, Scopus, and Clinical Trials). With a broader perspective, we focused on their recently discovered and/or investigated pharmacological effects, novel mechanism of action, relevant clinical studies, and their innovative applications in combined therapy and immunomodulation. In addition, the present review has extended to describe other promising compounds including dihydroartemisinin, ginsenoside Rh2, compound K, cucurbitacins D, E, I, tanshinone IIA and cryptotanshinone in view of their potentials in cancer therapy. Up to now, the evidence about the immunomodulatory effects and clinical trials of natural anti-cancer compounds from Chinese herbal medicine is very limited, and further research is needed to monitor their immunoregulatory effects and explore their mechanisms of action as modulators of immune checkpoints.
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Affiliation(s)
- Hua Luo
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao, China
| | - Chi Teng Vong
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao, China
| | - Hanbin Chen
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao, China
| | - Yan Gao
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao, China
| | - Peng Lyu
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao, China
| | - Ling Qiu
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao, China
| | - Mingming Zhao
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao, China
| | - Qiao Liu
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao, China
| | - Zehua Cheng
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao, China
| | - Jian Zou
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao, China
| | - Peifen Yao
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao, China
| | - Caifang Gao
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao, China
| | - Jinchao Wei
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao, China
| | - Carolina Oi Lam Ung
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao, China
| | - Shengpeng Wang
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao, China
| | - Zhangfeng Zhong
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao, China
| | - Yitao Wang
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao, China
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Long J, Liu Z, Hui L. Anti-tumor effect and mechanistic study of elemene on pancreatic carcinoma. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2019; 19:133. [PMID: 31215421 PMCID: PMC6582541 DOI: 10.1186/s12906-019-2544-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Accepted: 06/03/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND Elemene is an effective anticancer component extracted from Zingiberaceae plants. This work was aimed to evaluate the anti-tumor effect and mechanism actions of elemene on pancreatic carcinoma in vitro and in vivo. METHODS The anti-proliferation experiment was measured by Methylthiazolyldiphenyl-tetrazolium bromide (MTT) method in the time of 24, 48 and 72 h in three different dosages. The cell cycle was detected by flow cytometer after 12 h treatment. Forty-eight nude mice were subcutaneously xenograft with BxPC-3 pancreatic cancer cells and divided into four groups: Control group and high, medium, low dosage of elemene (20, 40 and 60 mg/kg) treatment groups. Immunoblot and immunohistochemical methods were applied to detect the protein expression of P53 and Bcl-2 in the tumor of pancreatic cancer xenografts. H & E staining was used to detect the histopathological changes in each group. RESULTS A significant inhibition effect was observed in the anti-proliferation of BxPC-3 and Panc-1 cells in vitro in the time course of 24, 48 and 72 h with a dose dependent manner. The cell cycle results showed that elemene could arrest pancreatic cancer cells in the S phase after 12 h treatment in BxPC-3 and Panc-1 cell line. The in vivo BxPC-3 xenografts study exhibited that elemene was significantly decreased the tumor size in the high dosage group, compared to control group. And there is no any significant change in body weight of all animals. H&E pathology section result showed that treatment with elemene significantly decreased the inflammation cells and reduced the histopathological changes with a dose-dependent manner. Meanwhile, treatment with elemene significantly up-regulates the protein expression of P53, while down-regulate the protein expression of Bcl-2 in the tumor tissues, respectively. Furthermore, the western blot result showed that treatment with elemene increased the expression of P53 and decreased the expression of Bcl-2, compared with the control group, which is similar to the results of immunohistochemical staining. CONCLUSIONS This study suggests that elemene has a potential anti pancreatic cancer effect, down-regulation the protein expression of Bcl-2 and up-regulation the protein expression of P53 in a dose dependent manner may be is the anti-tumor mechanism.
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Affiliation(s)
- Jin Long
- Department of General Surgery, The First Hospital of China Medical University, Shenyang, 110001 People’s Republic of China
| | - Zhe Liu
- Department of General Surgery, The First Hospital of China Medical University, Shenyang, 110001 People’s Republic of China
| | - Lian Hui
- Department of Otolaryngology, The First Hospital of China Medical University, Shenyang, 110001 People’s Republic of China
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12
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Wu D, Lv D, Zhang T, Guo L, Ma F, Zhang C, Lv G, Huang L. Antitumor effects of β-elemene via targeting the phosphorylation of insulin receptor. Endocr Relat Cancer 2019; 26:187-199. [PMID: 30422809 PMCID: PMC6347285 DOI: 10.1530/erc-18-0370] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Accepted: 11/12/2018] [Indexed: 12/20/2022]
Abstract
Ewing sarcoma family tumors (ESFTs) are a group of aggressive and highly metastatic tumors lacking efficient therapies. Insulin-like growth factor 1 receptor (IGF1R) blockade is one of the most efficient targeting therapy for ESFTs. However, the appliance is obstructed by drug resistance and disease recurrence due to the activation of insulin receptor (IR) signaling induced by IGF1R blockade. Herein β-elemene, a compound derived from natural plants, exhibited a remarkable proliferation repression on ESFT cells, which was weakened by a caspase inhibitor Z-VAD. β-elemene in combination with IGF1R inhibitors enhanced markedly the repression on cellular proliferation and mTOR activation by IGF1R inhibitors and suppressed the PI3K phosphorylation induced by IGF1R inhibitors. To investigate the mechanisms, we focused on the effects of β-elemene on IR signaling pathway. β-elemene significantly suppressed the insulin-driven cell growth and the activation of mTOR and PI3K in tumor cells, while the toxicity to normal hepatocytes was much lower. Further, the phosphorylation of IR was found to be suppressed notably by β-elemene specifically in tumor cells other than normal hepatocytes. In addition, β-elemene inhibited the growth of ESFT xenografts in vivo, and the phosphorylation of IR and S6 ribosomal protein was significantly repressed in the β-elemene-treated xenografts. These data suggest that β-elemene targets IR phosphorylation to inhibit the proliferation of tumor cells specifically and enhance the effects of IGF1R inhibitors. Thus, this study provides evidence for novel approaches by β-elemene alone or in combination with IGF1R blockades in ESFTs and IR signaling hyperactivated tumors.
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Affiliation(s)
- Dawei Wu
- Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China
| | - Dongwei Lv
- Department of Sports Medicine, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China
| | - Ting Zhang
- Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China
| | - Lianying Guo
- Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China
| | - Fangli Ma
- Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China
| | - Caihua Zhang
- Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China
| | - Guofeng Lv
- Department of Sports Medicine, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China
- Correspondence should be addressed to L Huang or G Lv: or
| | - Lin Huang
- Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China
- Correspondence should be addressed to L Huang or G Lv: or
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Yang YY, Yang FQ, Gao JL. Differential proteomics for studying action mechanisms of traditional Chinese medicines. Chin Med 2019; 14:1. [PMID: 30636970 PMCID: PMC6325846 DOI: 10.1186/s13020-018-0223-8] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Accepted: 12/31/2018] [Indexed: 12/13/2022] Open
Abstract
Differential proteomics, which has been widely used in studying of traditional Chinese medicines (TCMs) during the past 10 years, is a powerful tool to visualize differentially expressed proteins and analyzes their functions. In this paper, the applications of differential proteomics in exploring the action mechanisms of TCMs on various diseases including cancers, cardiovascular diseases, diabetes, liver diseases, kidney disorders and obesity, etc. were reviewed. Furthermore, differential proteomics in studying of TCMs identification, toxicity, processing and compatibility mechanisms were also included. This review will provide information for the further applications of differential proteomics in TCMs studies.
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Affiliation(s)
- Yi-Yao Yang
- School of Chemistry and Chemical Engineering, Chongqing University, Chongqing, 401331 People’s Republic of China
| | - Feng-Qing Yang
- School of Chemistry and Chemical Engineering, Chongqing University, Chongqing, 401331 People’s Republic of China
| | - Jian-Li Gao
- Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053 Zhejiang People’s Republic of China
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Nair A, Amalraj A, Jacob J, Kunnumakkara AB, Gopi S. Non-Curcuminoids from Turmeric and Their Potential in Cancer Therapy and Anticancer Drug Delivery Formulations. Biomolecules 2019; 9:biom9010013. [PMID: 30609771 PMCID: PMC6358877 DOI: 10.3390/biom9010013] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Revised: 12/14/2018] [Accepted: 12/17/2018] [Indexed: 12/13/2022] Open
Abstract
Over the past decades curcuminoids have been extensively studied for their biological activities such as antiulcer, antifibrotic, antiviral, antibacterial, antiprotozoal, antimutagenic, antifertility, antidiabetic, anticoagulant, antivenom, antioxidant, antihypotensive, antihypocholesteremic, and anticancer activities. With the perception of limited toxicity and cost, these compounds forms an integral part of cancer research and is well established as a potential anticancer agent. However, only few studies have focused on the other bioactive molecules of turmeric, known as non-curcuminoids, which are also equally potent as curcuminoids. This review aims to explore the comprehensive potency including the identification, physicochemical properties, and anticancer mechanism inclusive of molecular docking studies of non-curcuminoids such as turmerones, elemene, furanodiene (FN), bisacurone, germacrone, calebin A (CA), curdione, and cyclocurcumin. An insight into the clinical studies of these curcumin-free compounds are also discussed which provides ample evidence that favors the therapeutic potential of these compounds. Like curcuminoids, limited solubility and bioavailability are the most fragile domain, which circumscribe further applications of these compounds. Thus, this review credits the encapsulation of non-curcuminoid components in diverse drug delivery systems such as co-crystals, solid lipid nanoparticles, liposomes, microspheres, polar-non-polar sandwich (PNS) technology, which help abolish their shortcomings and flaunt their ostentatious benefits as anticancer activities.
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Affiliation(s)
- Akhila Nair
- R&D Centre, Aurea Biolabs (P) Ltd., Kolenchery, Cochin, Kerala 682311, India.
| | - Augustine Amalraj
- R&D Centre, Aurea Biolabs (P) Ltd., Kolenchery, Cochin, Kerala 682311, India.
| | - Joby Jacob
- R&D Centre, Aurea Biolabs (P) Ltd., Kolenchery, Cochin, Kerala 682311, India.
| | - Ajaikumar B Kunnumakkara
- Department of Biosciences and Bioengineering, Indian Institute of Technology, Guwahati 781 039, India.
| | - Sreeraj Gopi
- R&D Centre, Aurea Biolabs (P) Ltd., Kolenchery, Cochin, Kerala 682311, India.
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Xu L, Guo T, Qu X, Hu X, Zhang Y, Che X, Song H, Gong J, Ma R, Li C, Fan Y, Ma Y, Hou K, Wu P, Dong H, Liu Y. β-elemene increases the sensitivity of gastric cancer cells to TRAIL by promoting the formation of DISC in lipid rafts. Cell Biol Int 2018; 42:1377-1385. [PMID: 29957841 DOI: 10.1002/cbin.11023] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2018] [Accepted: 06/23/2018] [Indexed: 12/21/2022]
Abstract
β-Elemene, an anti-cancer drug extracted from traditional Chinese medicinal herb, showed anti-tumor effects on gastric cancer cells. Our previous studies reported gastric cancer cells are insensitive to TRAIL. However, whether β-elemene could enhance anti-cancer effects of TRAIL on gastric cancer cells is unknown. In our present study, β-elemene prevented gastric cancer cell viability in dose-dependent manner, and when combined with TRAIL, obviously inhibited proliferation and promoted apoptosis in gastric cancer cells. Compared to β-elemene or TRAIL alone, treatment with β-elemene and TRAIL obviously promoted DR5 clustering as well as translocation of Caspase-8, DR5 and FADD into lipid rafts. This led to cleavage of Caspase-8 and the formation of death-inducing signaling complex (DISC) in lipid rafts. The cholesterol-sequestering agent nystatin partially reversed DR5 clustering and DISC formation, preventing apoptosis triggered by the combination of β-elemene and TRAIL. Our results suggest that β-elemene increases the sensitivity of gastric cancer cells to TRAIL partially by promoting the formation of DISC in lipid rafts.
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Affiliation(s)
- Ling Xu
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, 110001, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, 110001, China
| | - Tianshu Guo
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, 110001, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, 110001, China
| | - Xiujuan Qu
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, 110001, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, 110001, China
| | - Xuejun Hu
- Department of Respiratory and Infectious Disease of Geriatrics, the First Hospital of China Medical University, Shenyang, 110001, China
| | - Ye Zhang
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, 110001, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, 110001, China
| | - Xiaofang Che
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, 110001, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, 110001, China
| | - Huicong Song
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, 110001, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, 110001, China
| | - Jing Gong
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, 110001, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, 110001, China
| | - Rui Ma
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, 110001, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, 110001, China
| | - Ce Li
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, 110001, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, 110001, China
| | - Yibo Fan
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, 110001, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, 110001, China
| | - Yanju Ma
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, 110001, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, 110001, China
| | - Kezuo Hou
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, 110001, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, 110001, China
| | - Peihong Wu
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, 110001, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, 110001, China
| | - Hang Dong
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, 110001, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, 110001, China
| | - Yunpeng Liu
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, 110001, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, 110001, China
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Ciarlini J, Marangoni A, Bolzan A. Selectivity of supercritical CO2 extraction and atmospheric pressure techniques for the major volatile compounds of Eugenia involucrata leaves from Southern Brazil. FOOD AND BIOPRODUCTS PROCESSING 2017. [DOI: 10.1016/j.fbp.2017.08.008] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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17
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Liu Y, Jiang ZY, Zhou YL, Qiu HH, Wang G, Luo Y, Liu JB, Liu XW, Bu WQ, Song J, Cui L, Jia XB, Feng L. β-elemene regulates endoplasmic reticulum stress to induce the apoptosis of NSCLC cells through PERK/IRE1α/ATF6 pathway. Biomed Pharmacother 2017; 93:490-497. [PMID: 28672279 DOI: 10.1016/j.biopha.2017.06.073] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2017] [Revised: 05/28/2017] [Accepted: 06/20/2017] [Indexed: 12/16/2022] Open
Abstract
Endoplasmic reticulum stress (ERs) has been regarded as an important cause for the pathogenesis of non-small-cell lung cancer (NSCLC). β-elemene is an active component in the essential oil extracted from a medicinal herb, Curcuma wenyujin, and has been reported to be effective against non-small-cell lung cancer (NSCLC). However, the potential effect and underlying mechanisms of β-elemene on regulating ERs to inhibit NSCLC are still unclear. In the present study, A549 cells and Lewis tumor-bearing C57BL/6J mice were established to evaluate this effect. Visualsonics Vevo 2100 Small Animal Dedicated High-frequency Color Ultrasound was performed to observe tumor volume in vivo. 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) was used to evaluate cell vitality of A549 cells. Furthermore, western blotting (WB), immunohistochemistry (IHC) and quantitative reverse transcription polymerase chain reaction (q-PCR) were applied to detect the ERs-related proteins. Flow cytometry was also applied to detect cell apoptosis and assay kit for reactive oxygen species (ROS) generation. Our results showed that β-elemene inhibited lung cancer tumor growth and cell vitality in a dose- and time-dependent manner. Not only that, β-elemene could up-regulate ERs-related proteins like PERK, IRE1α, ATF6, ATF4, CHOP and down-regulate the Bcl-2 expression. More importantly, ERs inhibitor 4-PBA, IRE1α inhibitor STF-083010, ATF6 inhibitor Anti-ATF6 and PERK inhibitor GSK2656157 can all reduce the amplitude of protein expression changes and apoptosis rates, then weaken the anti-tumor effect of β-elemene. Therefore, the present in vivo and in vitro study revealed that the anti-NSCLC effect of β-elemene is closely related to the activation of ERs through PERK/IRE1α/ATF6 pathway, and this might be beneficial for clinical therapy of NSCLC.
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Affiliation(s)
- Ying Liu
- Key Laboratory of New Drug Delivery Systems of Chinese Materia Medica, Jiangsu Provincial Academy of Chinese Medicine, Jiangsu Nanjing, 210028, PR China; School of Pharmacy, Anhui University of Chinese Medicine, Anhui Hefei 230038, PR China
| | - Zi-Yu Jiang
- Key Laboratory of New Drug Delivery Systems of Chinese Materia Medica, Jiangsu Provincial Academy of Chinese Medicine, Jiangsu Nanjing, 210028, PR China; Third School of Clinical Medical of Nanjing University of Chinese Medicine, Jiangsu Nanjing 210028, PR China
| | - Yuan-Li Zhou
- Key Laboratory of New Drug Delivery Systems of Chinese Materia Medica, Jiangsu Provincial Academy of Chinese Medicine, Jiangsu Nanjing, 210028, PR China
| | - Hui-Hui Qiu
- Key Laboratory of New Drug Delivery Systems of Chinese Materia Medica, Jiangsu Provincial Academy of Chinese Medicine, Jiangsu Nanjing, 210028, PR China; Third School of Clinical Medical of Nanjing University of Chinese Medicine, Jiangsu Nanjing 210028, PR China
| | - Gang Wang
- Key Laboratory of New Drug Delivery Systems of Chinese Materia Medica, Jiangsu Provincial Academy of Chinese Medicine, Jiangsu Nanjing, 210028, PR China; School of Pharmacy, Anhui University of Chinese Medicine, Anhui Hefei 230038, PR China
| | - Yi Luo
- Key Laboratory of New Drug Delivery Systems of Chinese Materia Medica, Jiangsu Provincial Academy of Chinese Medicine, Jiangsu Nanjing, 210028, PR China; Third School of Clinical Medical of Nanjing University of Chinese Medicine, Jiangsu Nanjing 210028, PR China
| | - Jing-Bing Liu
- Key Laboratory of New Drug Delivery Systems of Chinese Materia Medica, Jiangsu Provincial Academy of Chinese Medicine, Jiangsu Nanjing, 210028, PR China; Third School of Clinical Medical of Nanjing University of Chinese Medicine, Jiangsu Nanjing 210028, PR China
| | - Xiong-Wei Liu
- The Affiliated Jiangyin Hospital of Southeast University Medical Collage, Jiangyin 214400, Jiangsu, PR China
| | - Wei-Quan Bu
- Key Laboratory of New Drug Delivery Systems of Chinese Materia Medica, Jiangsu Provincial Academy of Chinese Medicine, Jiangsu Nanjing, 210028, PR China; Third School of Clinical Medical of Nanjing University of Chinese Medicine, Jiangsu Nanjing 210028, PR China
| | - Jie Song
- Key Laboratory of New Drug Delivery Systems of Chinese Materia Medica, Jiangsu Provincial Academy of Chinese Medicine, Jiangsu Nanjing, 210028, PR China; Third School of Clinical Medical of Nanjing University of Chinese Medicine, Jiangsu Nanjing 210028, PR China
| | - Li Cui
- Key Laboratory of New Drug Delivery Systems of Chinese Materia Medica, Jiangsu Provincial Academy of Chinese Medicine, Jiangsu Nanjing, 210028, PR China; Third School of Clinical Medical of Nanjing University of Chinese Medicine, Jiangsu Nanjing 210028, PR China
| | - Xiao-Bin Jia
- Key Laboratory of New Drug Delivery Systems of Chinese Materia Medica, Jiangsu Provincial Academy of Chinese Medicine, Jiangsu Nanjing, 210028, PR China; Third School of Clinical Medical of Nanjing University of Chinese Medicine, Jiangsu Nanjing 210028, PR China.
| | - Liang Feng
- Key Laboratory of New Drug Delivery Systems of Chinese Materia Medica, Jiangsu Provincial Academy of Chinese Medicine, Jiangsu Nanjing, 210028, PR China; Third School of Clinical Medical of Nanjing University of Chinese Medicine, Jiangsu Nanjing 210028, PR China.
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Harada K, Mizrak Kaya D, Shimodaira Y, Song S, Baba H, Ajani JA. Proteomics approach to identify biomarkers for upper gastrointestinal cancer. Expert Rev Proteomics 2016; 13:1041-1053. [PMID: 27718753 DOI: 10.1080/14789450.2016.1246189] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION The prognosis for patients with upper gastrointestinal cancers remains dismal despite the development of multimodality therapies that incorporate surgery, chemotherapy, and radiotherapy. Early diagnosis and personalized treatment should lead to better prognosis. Given the advances in proteomic technologies over the past decades, proteomics promises to be the most effective technique to identify novel diagnostics and therapeutic targets. Areas covered: For this review, keywords were searched in combination with 'proteomics' and 'gastric cancer' or 'esophageal cancer' in PubMed. Studies that evaluated proteomics associated with upper gastrointestinal cancer were identified through reading, with several studies quoted at second hand. We summarize the proteomics involved in upper gastrointestinal cancer and discuss potential biomarkers and therapeutic targets. Expert commentary: In particular, the development of mass spectrometry has enabled detection of multiple proteins and peptides in more biological samples over a shorter time period and at lower cost than was previously possible. In addition, more sophisticated protein databases have allowed a wider variety of proteins in samples to be quantified. Novel biomarkers that have been identified by new proteomic technologies should be applied in a clinical setting.
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Affiliation(s)
- Kazuto Harada
- a Department of Gastrointestinal Medical Oncology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.,b Department of Gastroenterological Surgery, Graduate School of Medical Science , Kumamoto University , Kumamoto , Japan
| | - Dilsa Mizrak Kaya
- a Department of Gastrointestinal Medical Oncology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA
| | - Yusuke Shimodaira
- a Department of Gastrointestinal Medical Oncology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA
| | - Shumei Song
- a Department of Gastrointestinal Medical Oncology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA
| | - Hideo Baba
- b Department of Gastroenterological Surgery, Graduate School of Medical Science , Kumamoto University , Kumamoto , Japan
| | - Jaffer A Ajani
- a Department of Gastrointestinal Medical Oncology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA
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Feng H, Wang J, Jiang H, Mei X, Zhao Y, Chen F, Qu Y, Sai K, Guo C, Yang Q, Zhang Z, Chen Z. β-Elemene Selectively Inhibits the Proliferation of Glioma Stem-Like Cells Through the Downregulation of Notch1. Stem Cells Transl Med 2016; 6:830-839. [PMID: 28297578 PMCID: PMC5442766 DOI: 10.5966/sctm.2016-0009] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2016] [Accepted: 09/01/2016] [Indexed: 12/21/2022] Open
Abstract
Glioma is the most frequent primary central nervous system tumor. Although the current first-line medicine, temozolomide (TMZ), promotes patient survival, drug resistance develops easily. Thus, it is important to investigate novel therapeutic reagents to solidify the treatment effect. β-Elemene (bELE) is a compound from a Chinese herb whose anticancer effect has been shown in various types of cancer. However, its role in the inhibition of glioma stem-like cells (GSLCs) has not yet been reported. We studied both the in vitro and the in vivo inhibitory effect of bELE and TMZ in GSLCs and parental cells and their combined effects. The molecular mechanisms were also investigated. We also optimized the delivery methods of bELE. We found that bELE selectively inhibits the proliferation and sphere formation of GSLCs, other than parental glioma cells, and TMZ exerts its effects on parental cells instead of GSLCs. The in vivo data confirmed that the combination of bELE and TMZ worked better in the xenografts of GSLCs, mimicking the situation of tumorigenesis of human cancer. Notch1 was downregulated with bELE treatment. Our data also demonstrated that the continuous administration of bELE produces an ideal effect to control tumor progression. Our findings have demonstrated, for the first time, that bELE could compensate for TMZ to kill both GSLCs and nonstem-like cancer cells, probably improving the prognosis of glioma patients tremendously. Notch1 might be a downstream target of bELE. Therefore, our data shed light on improving the outcomes of glioma patients by combining bELE and TMZ. Stem Cells Translational Medicine 2017;6:830-839.
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Affiliation(s)
- Hai‐bin Feng
- Department of Neurosurgery/Neuro‐Oncology, Sun Yat‐sen University Cancer Center, State Key Laboratory of Oncology in South China, and Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, People’s Republic of China
- Department of Neurosurgery, Nongken Central Hospital of Guangdong, Zhanjiang, Guangdong, People’s Republic of China
| | - Jing Wang
- Department of Neurosurgery/Neuro‐Oncology, Sun Yat‐sen University Cancer Center, State Key Laboratory of Oncology in South China, and Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, People’s Republic of China
| | - Hao‐ran Jiang
- Department of Neurosurgery/Neuro‐Oncology, Sun Yat‐sen University Cancer Center, State Key Laboratory of Oncology in South China, and Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, People’s Republic of China
- Department of Neurosurgery, Huizhou First People's Hospital, Huizhou, Guangdong, People’s Republic of China
| | - Xin Mei
- Department of Neurosurgery/Neuro‐Oncology, Sun Yat‐sen University Cancer Center, State Key Laboratory of Oncology in South China, and Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, People’s Republic of China
| | - Yi‐ying Zhao
- Department of Neurosurgery/Neuro‐Oncology, Sun Yat‐sen University Cancer Center, State Key Laboratory of Oncology in South China, and Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, People’s Republic of China
| | - Fu‐rong Chen
- Department of Neurosurgery/Neuro‐Oncology, Sun Yat‐sen University Cancer Center, State Key Laboratory of Oncology in South China, and Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, People’s Republic of China
| | - Yue Qu
- Department of Neurosurgery/Neuro‐Oncology, Sun Yat‐sen University Cancer Center, State Key Laboratory of Oncology in South China, and Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, People’s Republic of China
- Department of Pharmacology, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, Guangdong, People’s Republic of China
| | - Ke Sai
- Department of Neurosurgery/Neuro‐Oncology, Sun Yat‐sen University Cancer Center, State Key Laboratory of Oncology in South China, and Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, People’s Republic of China
| | - Cheng‐cheng Guo
- Department of Neurosurgery/Neuro‐Oncology, Sun Yat‐sen University Cancer Center, State Key Laboratory of Oncology in South China, and Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, People’s Republic of China
| | - Qun‐ying Yang
- Department of Neurosurgery/Neuro‐Oncology, Sun Yat‐sen University Cancer Center, State Key Laboratory of Oncology in South China, and Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, People’s Republic of China
| | - Zong‐ping Zhang
- Department of Neurosurgery, Nongken Central Hospital of Guangdong, Zhanjiang, Guangdong, People’s Republic of China
| | - Zhong‐ping Chen
- Department of Neurosurgery/Neuro‐Oncology, Sun Yat‐sen University Cancer Center, State Key Laboratory of Oncology in South China, and Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, People’s Republic of China
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Synthesis of 13-β-elemene ester derivatives and evaluation of their antioxidant activity in human umbilical vein endothelial cells. Chin J Nat Med 2016; 13:618-27. [PMID: 26253495 DOI: 10.1016/s1875-5364(15)30058-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2014] [Indexed: 11/21/2022]
Abstract
In the present study, a series of 13-β-elemene ester derivatives were designed and prepared, and their antioxidant activity was investigated in the H2O2-treated human umbilical vein endothelial cells (HUVECs). Among the test compounds, the dimer compounds 5v and 5w exhibited the most potent antioxidant activity with significant ROS suppression being observed. Both compounds markedly inhibited the H2O2-induced changes in various biochemical substances, such as superoxide dismutase (SOD), malonyldialdehyde (MDA), nitric oxide (NO), and lactic dehydrogenase (LDH), which were superior to that of the positive control vitamin E. Further more, they did not produce any obvious cytotoxicity, but increased the viability of HUVECs injured by H2O2 in a dose-dependent manner. Additionally, compound 5w, designed as a prodrug-like compound, showed improved stability relative to compound 4 in vitro.
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Wu B, Jiang Y, Zhu F, Sun D, Huang H. Demethylation effects of elemene on the GSTP1 gene in HCC cell line QGY7703. Oncol Lett 2016; 11:2545-2551. [PMID: 27073515 DOI: 10.3892/ol.2016.4243] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2014] [Accepted: 01/21/2015] [Indexed: 12/13/2022] Open
Abstract
The present study aimed to investigate elemene's effects on cell proliferation, apoptosis, and the cell cycle in the hepatocellular carcinoma (HCC) cell line, QYG7703, and to investigate GSTP1 gene methylation change in QGY7703 cells after being treated with elemene to explore whether elemene reversed the abnormal GSTP1 gene methylation. QGY7703 cells were treated with different elemene concentrations. Cell proliferation was measured with MTT assay, cell apoptosis and cell cycle were analyzed by flow cytometry, and GSTP1 gene methylation was analyzed by methlation-specific polymerase chain reaction. The cells' apoptotic rate increased dose-dependently with elemene concentration, and the difference was statistically significant (P<0.05). Elemene treatment arrested the cells in S phase, and thus the percentage of cells in G1 phase decreased while the cells in S phase increased dose-dependently, and the difference was statistically significant compared to the control group (P<0.05). All QGY7703 cells were identified to contain GSTP1 gene methylation before being treated with elemene and the methylation state decreased after treatment. In the present study, elemene induced cell apoptosis, inhibited the cell cycle, and reversed GSTP1 gene methylation in QGY7703 cells.
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Affiliation(s)
- Baoqiang Wu
- Department of Hepatobiliary Surgery, The First People's Hospital of Changzhou, Changzhou 213003, P.R. China
| | - Yong Jiang
- Department of Hepatobiliary Surgery, The First People's Hospital of Changzhou, Changzhou 213003, P.R. China
| | - Feng Zhu
- Department of Hepatobiliary Surgery, The First People's Hospital of Changzhou, Changzhou 213003, P.R. China
| | - Donglin Sun
- Department of Hepatobiliary Surgery, The First People's Hospital of Changzhou, Changzhou 213003, P.R. China
| | - Hongjun Huang
- Department of Hepatobiliary Surgery, The First People's Hospital of Changzhou, Changzhou 213003, P.R. China
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Proteomic Analysis of Anticancer TCMs Targeted at Mitochondria. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2015; 2015:539260. [PMID: 26568766 PMCID: PMC4629060 DOI: 10.1155/2015/539260] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/26/2015] [Accepted: 07/30/2015] [Indexed: 12/16/2022]
Abstract
Traditional Chinese medicine (TCM) is a rich resource of anticancer drugs. Increasing bioactive natural compounds extracted from TCMs are known to exert significant antitumor effects, but the action mechanisms of TCMs are far from clear. Proteomics, a powerful platform to comprehensively profile drug-regulated proteins, has been widely applied to the mechanistic investigation of TCMs and the identification of drug targets. In this paper, we discuss several bioactive TCM products including terpenoids, flavonoids, and glycosides that were extensively investigated by proteomics to illustrate their antitumor mechanisms in various cancers. Interestingly, many of these natural compounds isolated from TCMs mostly exert their tumor-suppressing functions by specifically targeting mitochondria in cancer cells. These TCM components induce the loss of mitochondrial membrane potential, the release of cytochrome c, and the accumulation of ROS, initiating apoptosis cascade signaling. Proteomics provides systematic views that help to understand the molecular mechanisms of the TCM in tumor cells; it bears the inherent limitations in uncovering the drug-protein interactions, however. Subcellular fractionation may be coupled with proteomics to capture and identify target proteins in mitochondria-enriched lysates. Furthermore, translating mRNA analysis, a new technology profiling the drug-regulated genes in translatome level, may be integrated into the systematic investigation, revealing global information valuable for understanding the action mechanism of TCMs.
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Liu JS, Che XM, Chang S, Qiu GL, He SC, Fan L, Zhao W, Zhang ZL, Wang SF. β-elemene enhances the radiosensitivity of gastric cancer cells by inhibiting Pak1 activation. World J Gastroenterol 2015; 21:9945-9956. [PMID: 26379399 PMCID: PMC4566387 DOI: 10.3748/wjg.v21.i34.9945] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2015] [Revised: 05/12/2015] [Accepted: 07/18/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To explore the potential of β-elemene as a radiosensitizer for gastric cancer cells and the underlying mechanisms.
METHODS: SGC7901, MKN45, MKN28, N87, and AGS human gastric cancer cell lines were used to screen for radioresistant gastric cancer cell lines. A 3-(4,5-dimeth-ylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay was used to determine the effects of β-elemene and IPA-3 on cell viability in MKN45 and SGC7901 gastric cancer cell lines. A clonogenic survival assay and annexin V-FITC/PI apoptosis detection assay were used to evaluate cellular radiosensitivity and radiation-induced cell death, respectively. A proteomic method, isobaric tags for relative and absolute quantitation (iTRAQ), was employed to screen the proteins regulated by β-elemene pretreatment prior to ionizing radiation (IR) in SGC7901 gastric cancer cell line. IPA-3 was used as a specific small molecule inhibitor of p21-activated protein kinase 1 (Pak1) to target Pak1 signaling. Protein levels of PAK1IP1 (p21-activated protein kinase-interacting protein 1), total Pak1 (t-Pak1), phospho-Pak1 (T423), phospho-ERK1/2 (Thr202/Tyr204), and cleaved caspase-3 (17 kDa) were assessed by western blotting.
RESULTS: MKN45 and SGC7901 gastric cancer cell lines were relatively more resistant to IR. β-elemene pretreatment decreased clonogenic survival following IR in MKN45 and SGC7901 gastric cancer cell lines. Additionally, β-elemene pretreatment prior to IR increased radiation-induced cell death compared with IR alone in MKN45 (10.4% ± 0.9% vs 34.8% ± 2.8%, P < 0.05) and SGC7901 (11.6% ± 0.9% vs 46.7% ± 5.2%, P < 0.05) human gastric cancer cell lines, respectively, consistent with the level of cleaved caspase-3 (17 kDa). Through iTRAQ analysis and western blot validation, we found that β-elemene upregulated PAK1IP1 and downregulated phospho-Pak1 (T423) and phospho-ERK1/2 in SGC7901 gastric cancer cells. IR increased the level of phospho-Pak1 (T423). Pretreatment with β-elemene decreased radiation-induced Pak1 and ERK1/2 phosphorylation. Inhibition of Pak1 using IPA-3 decreased clonogenic survival following IR. In addition, IPA-3 increased radiation-induced cell death in MKN45 (13.4% ± 0.3% vs 26.6% ± 1.0%, P < 0.05) and SGC7901 (16.0% ± 0.6% vs 37.3% ± 1.7%, P < 0.05) gastric cancer cell lines, respectively, consistent with the level of cleaved caspase-3 (17 kDa). Western blotting showed that IPA-3 decreased radiation-induced Pak1 and ERK1/2 phosphorylation.
CONCLUSION: This is the first demonstration that β-elemene enhances radiosensitivity of gastric cancer cells, and that the mechanism involves inhibition of Pak1 signaling.
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