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Tang X, Luo X, Wang X, Zhang Y, Xie J, Niu X, Lu X, Deng X, Xu Z, Wu F. Chrysin Inhibits TAMs-Mediated Autophagy Activation via CDK1/ULK1 Pathway and Reverses TAMs-Mediated Growth-Promoting Effects in Non-Small Cell Lung Cancer. Pharmaceuticals (Basel) 2024; 17:515. [PMID: 38675475 PMCID: PMC11055150 DOI: 10.3390/ph17040515] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 04/05/2024] [Accepted: 04/10/2024] [Indexed: 04/28/2024] Open
Abstract
The natural flavonoid compound chrysin has promising anti-tumor effects. In this study, we aimed to investigate the mechanism by which chrysin inhibits the growth of non-small cell lung cancer (NSCLC). Through in vitro cell culture and animal models, we explored the impact of chrysin on the growth of NSCLC cells and the pro-cancer effects of tumor-associated macrophages (TAMs) and their mechanisms. We observed that M2-TAMs significantly promoted the growth and migration of NSCLC cells, while also markedly activating the autophagy level of these cells. Chrysin displayed a significant inhibitory effect on the growth of NSCLC cells, and it could also suppress the pro-cancer effects of M2-TAMs and inhibit their mediated autophagy. Furthermore, combining network pharmacology, we found that chrysin inhibited TAMs-mediated autophagy activation in NSCLC cells through the regulation of the CDK1/ULK1 signaling pathway, rather than the classical mTOR/ULK1 signaling pathway. Our study reveals a novel mechanism by which chrysin inhibits TAMs-mediated autophagy activation in NSCLC cells through the regulation of the CDK1/ULK1 pathway, thereby suppressing NSCLC growth. This discovery not only provides new therapeutic strategies for NSCLC but also opens up new avenues for further research on chrysin.
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Affiliation(s)
- Xinglinzi Tang
- Central Lab, The Seventh Clinical Medicial College of Guangzhou University of Chinese Medicine, Shenzhen 518000, China
| | - Xiaoru Luo
- Central Lab, The Seventh Clinical Medicial College of Guangzhou University of Chinese Medicine, Shenzhen 518000, China
| | - Xiao Wang
- Department of Basic Theory of TCM, Guangzhou University of Chinese Medicine, Guangzhou 510330, China
| | - Yi Zhang
- Department of Psychology, School of Public Health and Management, Guangzhou University of Chinese Medicine, Guangzhou 510330, China
| | - Jiajia Xie
- Department of Classic Traditional Chinese Medicine, The Seventh Clinical Medicial College of Guangzhou University of Chinese Medicine, Shenzhen 518000, China
| | - Xuan Niu
- Department of Classic Traditional Chinese Medicine, The Seventh Clinical Medicial College of Guangzhou University of Chinese Medicine, Shenzhen 518000, China
| | - Xiaopeng Lu
- Department of Classic Traditional Chinese Medicine, The Seventh Clinical Medicial College of Guangzhou University of Chinese Medicine, Shenzhen 518000, China
| | - Xi Deng
- Department of Classic Traditional Chinese Medicine, The Seventh Clinical Medicial College of Guangzhou University of Chinese Medicine, Shenzhen 518000, China
| | - Zheng Xu
- Department of Classic Traditional Chinese Medicine, The Seventh Clinical Medicial College of Guangzhou University of Chinese Medicine, Shenzhen 518000, China
| | - Fanwei Wu
- Department of Classic Traditional Chinese Medicine, The Seventh Clinical Medicial College of Guangzhou University of Chinese Medicine, Shenzhen 518000, China
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2
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Oggero J, Gasser FB, Zacarías SM, Burns P, Baravalle ME, Renna MS, Ortega HH, Vaillard SE, Vaillard VA. PEGylation of Chrysin Improves Its Water Solubility while Preserving the In Vitro Biological Activity. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2023; 71:19817-19831. [PMID: 38048427 DOI: 10.1021/acs.jafc.3c06357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/06/2023]
Abstract
Chrysin is a natural flavonoid that despite having numerous biological properties, its therapeutic value is limited due to its very low solubility in aqueous media. In this work, chrysin was conjugated with methoxypolyethylene glycols (mPEGs) of different molecular weights (350, 500, 750, and 2000 g/mol), affording PEGylated chrysins with high yields and excellent purities. In all cases, an increase in the water solubility of the conjugates was observed, which was highest when 500 g/mol of mPEG was used in the PEGylation reaction. Furthermore, in aqueous solution, PEGylated chrysins formed aggregates of ellipsoid shape. Electrochemical studies showed that the redox properties were conserved after PEGylation. While in vitro antibacterial and antifungal studies probed that the intrinsic activity was conserved, in vitro antitumor activities against HepG2 (liver carcinoma cells) and PC3 (prostate cancer cell) showed that PEGylated chrysins retained the cytotoxic activity and the ability of induction of apoptosis for the evaluated human cancer cells.
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Affiliation(s)
- Julia Oggero
- Instituto de Desarrollo Tecnológico para la Industria Química (INTEC), Universidad Nacional del Litoral and Consejo Nacional de Investigaciones Científicas y Técnicas, Ruta Nacional 168, km 0, Paraje "El Pozo", Santa Fe 3000, Argentina
| | - Fátima B Gasser
- Instituto de Ciencias Veterinarias del Litoral (ICIVET), Universidad Nacional del Litoral and Consejo Nacional de Investigaciones Científicas y Técnicas, R. P. Kreder 2805, Esperanza 3080, Argentina
| | - Silvia M Zacarías
- Instituto de Desarrollo Tecnológico para la Industria Química (INTEC), Universidad Nacional del Litoral and Consejo Nacional de Investigaciones Científicas y Técnicas, Ruta Nacional 168, km 0, Paraje "El Pozo", Santa Fe 3000, Argentina
| | - Patricia Burns
- Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Ruta Nacional No. 168, km 472, Ciudad Universitaria UNL, Santa Fe 3000, Argentina
| | - María E Baravalle
- Instituto de Ciencias Veterinarias del Litoral (ICIVET), Universidad Nacional del Litoral and Consejo Nacional de Investigaciones Científicas y Técnicas, R. P. Kreder 2805, Esperanza 3080, Argentina
- Centro Universitario Gálvez, Universidad Nacional del Litoral, Florentino Ameghino 50 bis, Gálvez, Santa Fe S2252, Argentina
| | - Maria Sol Renna
- Instituto de Ciencias Veterinarias del Litoral (ICIVET), Universidad Nacional del Litoral and Consejo Nacional de Investigaciones Científicas y Técnicas, R. P. Kreder 2805, Esperanza 3080, Argentina
| | - Hugo H Ortega
- Instituto de Ciencias Veterinarias del Litoral (ICIVET), Universidad Nacional del Litoral and Consejo Nacional de Investigaciones Científicas y Técnicas, R. P. Kreder 2805, Esperanza 3080, Argentina
| | - Santiago E Vaillard
- Instituto de Desarrollo Tecnológico para la Industria Química (INTEC), Universidad Nacional del Litoral and Consejo Nacional de Investigaciones Científicas y Técnicas, Ruta Nacional 168, km 0, Paraje "El Pozo", Santa Fe 3000, Argentina
| | - Victoria A Vaillard
- Instituto de Desarrollo Tecnológico para la Industria Química (INTEC), Universidad Nacional del Litoral and Consejo Nacional de Investigaciones Científicas y Técnicas, Ruta Nacional 168, km 0, Paraje "El Pozo", Santa Fe 3000, Argentina
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3
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Raina R, Hussain A, Almutary AG, Haque S, Raza T, D’Souza AC, Subramani S, Sajeevan A. Co-administration of Chrysin and Luteolin with Cisplatin and Topotecan Exhibits a Variable Therapeutic Value in Human Cancer Cells, HeLa. ACS OMEGA 2023; 8:41204-41213. [PMID: 37970041 PMCID: PMC10633856 DOI: 10.1021/acsomega.3c04443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 09/27/2023] [Accepted: 10/04/2023] [Indexed: 11/17/2023]
Abstract
Combinational treatment is a promising strategy for better cancer treatment outcomes. Chrysin and luteolin have demonstrated effective anticancer activity. Cisplatin and topotecan are commonly used for the treatment of human cancers. However, various side effects including drug resistance are an imperative restriction to use them as pharmacological therapy. Therefore, the aim was to use these agents in combination with flavones for better efficacy. In the present study, it was found that the combination of chrysin and cisplatin and luteolin and cisplatin significantly improved the anticancer effect as both the combinations showed synergistic interactions [combinational index (CI < 1)]. Remarkably, the combination of chrysin and luteolin with topotecan depicted the antagonistic interaction (CI > 1). Further, increased expression of the pro-apoptotic proteins Bax and caspase 8 and the inhibition of the antiapoptotic protein Bcl-2 were instituted in the synergistic doses (chrysin + cisplatin and luteolin + cisplatin), hence promoting apoptosis. Also, it was found that the synergistic combination inhibited the migration of HeLa cells by downregulation of metalloproteases and upregulation of TIMPs. However, there are no significant changes depicted in the antagonistic combinations which support their role in their antagonistic effects. Based on these results, it can be inferred that the two or more drug combinations need to be explored well for their interaction to enhance the therapeutic outcomes.
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Affiliation(s)
- Ritu Raina
- School
of Life Sciences, Manipal Academy of Higher
of Education, Academic City 345050, Dubai, United Arab Emirates
| | - Arif Hussain
- School
of Life Sciences, Manipal Academy of Higher
of Education, Academic City 345050, Dubai, United Arab Emirates
| | - Abdulmajeed G. Almutary
- Department
of Biomedical Sciences, College of Health Sciences, Abu Dhabi University, Khalifa
City, Abu Dhabi 51072, United Arab Emirates
- Department
of Medical Biotechnology, College of Applied Medical Sciences, Qassim University, Buraydah 52571, Saudi Arabia
| | - Shafiul Haque
- Research
and Scientific Studies Unit, College of Nursing and Allied Health
Sciences, Jazan University, Jazan 45142, Saudi Arabia
| | - Tasleem Raza
- Department
of Biochemistry, Era’s Lucknow Medical
College and Hospital, Lucknow 226003, India
| | - Ashley Cletus D’Souza
- School
of Life Sciences, Manipal Academy of Higher
of Education, Academic City 345050, Dubai, United Arab Emirates
| | - Sachin Subramani
- School
of Life Sciences, Manipal Academy of Higher
of Education, Academic City 345050, Dubai, United Arab Emirates
| | - Akash Sajeevan
- School
of Life Sciences, Manipal Academy of Higher
of Education, Academic City 345050, Dubai, United Arab Emirates
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Al-Ghamdi MA, Alsulami RR, Bakkar A, Kumosani TA, Barrbour EK, Abulnaja KO, Huwait E, Moselhy SS. Khalas date flavonoids inhibited cell viability, induced apoptosis and expression of the pro-autophagy LC3-B gene in human hepatocellular carcinoma cells (HepG2). Nat Prod Res 2023; 37:3109-3113. [PMID: 36346382 DOI: 10.1080/14786419.2022.2140803] [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: 09/13/2022] [Revised: 10/18/2022] [Accepted: 10/20/2022] [Indexed: 11/09/2022]
Abstract
Autophagy is a protective mechanism important in human diseases as cancer. We evaluated the impact of khalas date extract (KDE) (20-60 mg/mL) on cell viability, morphological changes, DNA fragmentation and gene expression of LC3B-II associated with autophagosome on HepG2 cell line. The GC/MS identification of KDE showed its high content of flavonoids including quercetin, myricetin, kaempferol and catechol. KDE reduced cell viability of HepG2 with IC50 (31.52 mg/mL). Cells treated with KDE showed two band of DNA fragments at (30 and 40 mg) indicating that KDE induced DNA damage and apoptosis in HepG2. The analysis RT-PCR data showed a 0.2-fold increase in the expression of LC3-B in the cells treated with KDE versus control. We concluded that, KDE flavonoids such as quercetin, myricetin kaempferol exhibited anticancer properties manifested by inhibition of HepG2 cell viability and induction of apoptosis and upregulation of the pro-autophagy LC3-B gene.
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Affiliation(s)
- Maryam Abdu Al-Ghamdi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University. Jeddah, Saudi Arabia
| | - Rawyah Radi Alsulami
- Department of Biochemistry, Faculty of Science, King Abdulaziz University. Jeddah, Saudi Arabia
| | - Ashraf Bakkar
- Modern Sciences and Arts University (MSA), Giza, Egypt
| | - Taha Abullah Kumosani
- Department of Biochemistry, Faculty of Science, King Abdulaziz University. Jeddah, Saudi Arabia
- Production of natural products for industrial purposes Research Group, King Abdulaziz University, Saudi Arabia
- Experimental Biochemistry Unit, King Fahd Medical Research Centre, King Abdulaziz University, Saudi Arabia
| | - Elie Kamil Barrbour
- Department of Biochemistry, Faculty of Science, King Abdulaziz University. Jeddah, Saudi Arabia
- Production of natural products for industrial purposes Research Group, King Abdulaziz University, Saudi Arabia
- Experimental Biochemistry Unit, King Fahd Medical Research Centre, King Abdulaziz University, Saudi Arabia
- Director of R and D Department, Opticon Hygiene Consulting, Oechsli, Zurich, Switzerland
| | - Khalid Omar Abulnaja
- Department of Biochemistry, Faculty of Science, King Abdulaziz University. Jeddah, Saudi Arabia
- Experimental Biochemistry Unit, King Fahd Medical Research Centre, King Abdulaziz University, Saudi Arabia
- Bioactive natural products Research Group, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Etimad Huwait
- Department of Biochemistry, Faculty of Science, King Abdulaziz University. Jeddah, Saudi Arabia
- Production of natural products for industrial purposes Research Group, King Abdulaziz University, Saudi Arabia
- Experimental Biochemistry Unit, King Fahd Medical Research Centre, King Abdulaziz University, Saudi Arabia
| | - Said Salama Moselhy
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt
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5
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Sánchez-Martín V, Morales P, Iriondo-DeHond A, Hospital XF, Fernández M, Hierro E, Haza AI. Differential Apoptotic Effects of Bee Product Mixtures on Normal and Cancer Hepatic Cells. Antioxidants (Basel) 2023; 12:615. [PMID: 36978864 PMCID: PMC10045410 DOI: 10.3390/antiox12030615] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 02/24/2023] [Accepted: 02/27/2023] [Indexed: 03/06/2023] Open
Abstract
Most effective anticancer drugs normally generate considerable cytotoxicity in normal cells; therefore, the preferential activation of apoptosis in cancer cells and the reduction of toxicity in normal cells is a great challenge in cancer research. Natural products with selective anticancer properties used as complementary medicine can help to achieve this goal. The aim of the present study was to analyze the effect of the addition of bee products [propolis (PR) or royal jelly (RJ) or propolis and royal jelly (PR+RJ), 2-10%] to thyme (TH) and chestnut honeys (CH) on the differential anticancer properties, mainly the cytotoxic and pro-apoptotic effects, in normal and cancer hepatic cells. The cytotoxic effects of samples were analyzed using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay (0-250 mg/mL) and the effects on apoptosis were analyzed using cell cycle analysis, TdT-dUTP terminal nick-end labeling (TUNEL) assay, DR5 (Death Receptor 5) and BAX (BCL-2-Associated X) activation, and caspases 8, 9, and 3 activities. Both honey samples alone and honey mixtures had no or very little apoptotic effect on normal cells. Antioxidant honey mixtures enhanced the apoptotic capacity of the corresponding honey alone via both extrinsic and intrinsic pathways. Of all the samples, chestnut honey enriched with 10% royal jelly and 10% propolis (sample 14, CH+10RJ+10PR) showed the highest apoptotic effect on tumor liver cells. The enrichment of monofloral honey with bee products could be used together with conventional anticancer treatments as a dietary supplement without side effects. On the other hand, it could be included in the diet as a natural sweetener with high added value.
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Affiliation(s)
- Vanesa Sánchez-Martín
- Departamento de Nutrición y Ciencia de los Alimentos, Sección Departamental de Nutrición y Ciencia de los Alimentos, Facultad de Veterinaria, Universidad Complutense, 28040 Madrid, Spain
| | - Paloma Morales
- Departamento de Nutrición y Ciencia de los Alimentos, Sección Departamental de Nutrición y Ciencia de los Alimentos, Facultad de Veterinaria, Universidad Complutense, 28040 Madrid, Spain
| | - Amaia Iriondo-DeHond
- Departamento de Nutrición y Ciencia de los Alimentos, Sección Departamental de Nutrición y Ciencia de los Alimentos, Facultad de Veterinaria, Universidad Complutense, 28040 Madrid, Spain
| | - Xavier F. Hospital
- Departamento de Farmacia Galénica y Tecnología de los Alimentos, Sección Departamental de Farmacia Galénica y Tecnología de los Alimentos, Facultad de Veterinaria, Universidad Complutense, 28040 Madrid, Spain
| | - Manuela Fernández
- Departamento de Farmacia Galénica y Tecnología de los Alimentos, Sección Departamental de Farmacia Galénica y Tecnología de los Alimentos, Facultad de Veterinaria, Universidad Complutense, 28040 Madrid, Spain
| | - Eva Hierro
- Departamento de Farmacia Galénica y Tecnología de los Alimentos, Sección Departamental de Farmacia Galénica y Tecnología de los Alimentos, Facultad de Veterinaria, Universidad Complutense, 28040 Madrid, Spain
| | - Ana I. Haza
- Departamento de Nutrición y Ciencia de los Alimentos, Sección Departamental de Nutrición y Ciencia de los Alimentos, Facultad de Veterinaria, Universidad Complutense, 28040 Madrid, Spain
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Zhang Q, Yu W, Liu Z, Li H, Liu Y, Liu X, Han Z, He J, Zeng Y, Guo Y, Liu Y. Design, synthesis, antitumor activity and ct-DNA binding study of photosensitive drugs based on porphyrin framework. Int J Biol Macromol 2023; 230:123147. [PMID: 36621729 DOI: 10.1016/j.ijbiomac.2023.123147] [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: 09/26/2022] [Revised: 11/29/2022] [Accepted: 01/01/2023] [Indexed: 01/07/2023]
Abstract
Photodynamic therapy is a promising novel tumor treatment method. In this study, novel porphyrin-chrysin photosensitizer derivatives were synthesized. Most of the compounds showed antitumor activity against human cervical cancer HeLa cells and human lung cancer A549 cells, among which compound 4c had the best photodynamic therapy effect on HeLa cells and A549 cells, with IC50 values of 6.26 μM and 23.37 μM, respectively. Free-base porphyrin-chrysin derivatives bind to DNA through surface self-stacking, and zinc metalloporphyrin-chrysin derivatives bind to ct-DNA through intercalation. Notably, the tightness of compound binding to ct-DNA was positively correlated with its antitumor activity. What's more, three-dimensional quantitative conformation studies have shown that increasing the positive charge of the porphyrin ring and introducing a strong electron-withdrawing group at the meso position of the porphyrin ring at the para-position of the benzene ring or reducing the space volume of the compound can enhance the antitumor activity.
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Affiliation(s)
- Qizhi Zhang
- Institute of Pharmacy & Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang City, Hunan Province 421001, PR China; Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, 28 Western Changshen Road, Hengyang City, Hunan Province 421001, PR China
| | - Wenmei Yu
- Institute of Pharmacy & Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang City, Hunan Province 421001, PR China; Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, 28 Western Changshen Road, Hengyang City, Hunan Province 421001, PR China
| | - Zhenhua Liu
- Institute of Pharmacy & Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang City, Hunan Province 421001, PR China; Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, 28 Western Changshen Road, Hengyang City, Hunan Province 421001, PR China
| | - Hui Li
- Institute of Pharmacy & Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang City, Hunan Province 421001, PR China; Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, 28 Western Changshen Road, Hengyang City, Hunan Province 421001, PR China
| | - Yihui Liu
- The second Hospital, University of South China, PR China
| | - Xin Liu
- Institute of Pharmacy & Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang City, Hunan Province 421001, PR China; Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, 28 Western Changshen Road, Hengyang City, Hunan Province 421001, PR China
| | - Zhaoshun Han
- Institute of Chemistry & Chemical Engineering, University of South China, Hengyang City, Hunan Province 421001, PR China
| | - Jun He
- Institute of Chemistry & Chemical Engineering, University of South China, Hengyang City, Hunan Province 421001, PR China
| | - Yaofu Zeng
- Institute of Pharmacy & Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang City, Hunan Province 421001, PR China; Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, 28 Western Changshen Road, Hengyang City, Hunan Province 421001, PR China
| | - Yu Guo
- Institute of Pharmacy & Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang City, Hunan Province 421001, PR China; Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, 28 Western Changshen Road, Hengyang City, Hunan Province 421001, PR China
| | - Yunmei Liu
- Institute of Pharmacy & Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang City, Hunan Province 421001, PR China; Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, 28 Western Changshen Road, Hengyang City, Hunan Province 421001, PR China.
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7
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Salari N, Faraji F, Jafarpour S, Faraji F, Rasoulpoor S, Dokaneheifard S, Mohammadi M. Anti-cancer Activity of Chrysin in Cancer Therapy: a Systematic Review. Indian J Surg Oncol 2022; 13:681-690. [PMID: 36687219 PMCID: PMC9845454 DOI: 10.1007/s13193-022-01550-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 05/03/2022] [Indexed: 01/25/2023] Open
Abstract
Chrysin is a natural bioactive compound that is extracted from many trees, honey, and propolis. Chrysin has several pharmacological activities such as anti-inflammatory, anti-cancer, and antioxidant properties. This study was performed to evaluate the anti-cancer activities of chrysin in cancer therapy. The present study was conducted by systematic review of studies published up to August 2021. Related studies were identified by searching Web of Science (WoS), PubMed, Science Direct, SID, MagIran, Scopus, and Google Scholar databases. The keywords of chrysin, cancer, anti-cancer, and cancer therapy were used for searching. The quality of the studies was assessed by the CONSORT checklist. A total of 21 studies were identified. The results of studies showed that chrysin has an anticancer effect by stimulating apoptosis in a wide range of human cells and rats. Chrysin is also an important factor in inhibiting tumor growth and neoplasticity. Chrysin inhibits the growth and proliferation of cancer cells by inducing cytotoxic effects. Therefore, due to the antitumor effects of chrysin and its safety and non-toxicity towards normal cells, this compound can be considered as an adjuvant along with chemotherapeutic agents in cancer treatment.
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Affiliation(s)
- Nader Salari
- Department of Biostatistics, School of Health, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Farahnaz Faraji
- Department of Pharmaceutics, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Sima Jafarpour
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Fatemeh Faraji
- Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Shna Rasoulpoor
- Medical Biology Research Centre, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Sadat Dokaneheifard
- Department of Human Genetics, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136 USA
| | - Masoud Mohammadi
- Cellular and Molecular Research Center, Gerash University of Medical Sciences, Gerash, Iran
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8
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Huwait E, Awaji SM, Kumosani TA, Barbour EK, Abulnaja KO, Moselhy SS. Ruthana date extract inhibited proliferation of human hepatocellular carcinoma (HepG2) cells by modulation of BAX gene. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2022; 29:63369-63378. [PMID: 35459999 DOI: 10.1007/s11356-022-20240-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 04/09/2022] [Indexed: 06/14/2023]
Abstract
Cancer response to chemotherapeutic agents and its side effects remain a challenge for the development of new anticancer compounds. Dates are consumed worldwide due to their high nutritional value. We investigated the cytotoxicity and expression of the proapoptotic BAX gene in human hepatocellular carcinoma (HepG2) cells treated with Ruthana date ethanolic extract (RDE). The RDE ingredients analyzed by GC/MS and HepG2 cells were treated with different concentrations of RDE for 24, 48, and 72 h. Cytotoxicity, cell viability, DNA fragmentation, and BAX expression were determined. The GC/MS analysis of RDE showed its high content of quercetin, myricetin kaempferol, thymine, and catechol as the most active ingredients. HepG2 treated with RDE showed a significant change in morphological characteristics related to cell death. The antiproliferative activity determined by WST-1 demonstrated that RDE significantly reduced cell viability. Cells treated with RDE (10-60 mg) showed gradual DNA fragmentation in a dose-dependent manner. Gene expression analysis showed upregulation of BAX at 30 mg/ml of RDE (p < 0.001). However, it showed downregulation at (40-60 mg/ml) as compared to control. Our findings indicated that RDE exert cytotoxicity against HepG2 cells due to its high content of flavonoids. This effect through DNA fragmentation and activation of the proapoptotic BAX gene.
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Affiliation(s)
- Etimad Huwait
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Seham M Awaji
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Taha A Kumosani
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
- Production of Natural Products For Industrial Purposes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia
- Experimental Biochemistry Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Elie K Barbour
- Experimental Biochemistry Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
- R and D Department, Opticon Hygiene Consulting, 78807, Oechsli, Switzerland
| | - Khalid O Abulnaja
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
- Experimental Biochemistry Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
- Bioactive Natural Products Research Group, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Said S Moselhy
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt.
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9
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Xie B, Yang J, Zhang J. Chrysin sensitizes osteosarcoma cells against TRAIL-induced apoptosis. Cell Biol Int 2022; 46:1825-1833. [PMID: 35979647 DOI: 10.1002/cbin.11879] [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: 01/16/2022] [Revised: 05/30/2022] [Accepted: 07/05/2022] [Indexed: 11/10/2022]
Abstract
Identifying novel curative and preventive approaches that can specifically target the osteosarcoma cells (OS) without affecting the normal cells is appreciable. The aim of this study is to investigate the combined effect of chrysin as an apigenin analog with high therapeutic potential and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on the treatment of Saos-2 and MG-63 cells. Cell viability were determined using MTT method. The rate of apoptosis was assessed by enzyme-linked immunosorbent assay (ELISA) cell death assay and caspase 8 activity assays. The messenger RNA (mRNA) and protein evaluation of candidate genes include Bcl-2, XIAP, c-IAP1, c-IAP2, and c-FLIP were accomplished before and after the treatment by quantitative real-time polymerase chain reaction (PCR) and Western blot analysis, respectively. Our results showed that chrysin synergistically increased the cytotoxic effects of TRAIL as follows: Chrysin plus TRAIL > TRAIL > Chrysin. Chrysin could sensitize both cells against the TRAIL-induced apoptosis, amplify the caspase 8 activity and this outcome is achieved by decreasing the expression levels of antiapoptotic genes. Our findings suggest that Chrysin can sensitize the OS cell lines against TRAIL through induction of the death receptor pathway. Moreover, the combinational therapy of these agents might be the promising therapeutic regimen for improving the clinical efficacy of TRAIL-induced apoptosis in patients with OS.
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Affiliation(s)
- Bin Xie
- Department of Orthopedics, Yan'an Peoples's Hospital, Yan'an, China
| | - JunQi Yang
- Department of Orthopaedics, Baoji Central Hospital, Baoji, China
| | - Jun Zhang
- Department of Orthopaedics, Baoji Central Hospital, Baoji, China
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10
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Gao Q, Feng J, Liu W, Wen C, Wu Y, Liao Q, Zou L, Sui X, Xie T, Zhang J, Hu Y. Opportunities and challenges for co-delivery nanomedicines based on combination of phytochemicals with chemotherapeutic drugs in cancer treatment. Adv Drug Deliv Rev 2022; 188:114445. [PMID: 35820601 DOI: 10.1016/j.addr.2022.114445] [Citation(s) in RCA: 91] [Impact Index Per Article: 30.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 06/13/2022] [Accepted: 07/06/2022] [Indexed: 02/08/2023]
Abstract
The therapeutic limitations such as insufficient efficacy, drug resistance, metastasis, and undesirable side effects are frequently caused by the long duration monotherapy based on chemotherapeutic drugs. multiple combinational anticancer strategies such as nucleic acids combined with chemotherapeutic agents, chemotherapeutic combinations, chemotherapy and tumor immunotherapy combinations have been embraced, holding great promise to counter these limitations, while still taking including some potential risks. Nowadays, an increasing number of research has manifested the anticancer effects of phytochemicals mediated by modulating cancer cellular events directly as well as the tumor microenvironment. Specifically, these natural compounds exhibited suppression of cancer cell proliferation, apoptosis, migration and invasion of cancer cells, P-glycoprotein inhibition, decreasing vascularization and activation of tumor immunosuppression. Due to the low toxicity and multiple modulation pathways of these phytochemicals, the combination of chemotherapeutic agents with natural compounds acts as a novel approach to cancer therapy to increase the efficiency of cancer treatments as well as reduce the adverse consequences. In order to achieve the maximized combination advantages of small-molecule chemotherapeutic drugs and natural compounds, a variety of functional nano-scaled drug delivery systems, such as liposomes, host-guest supramolecules, supramolecules, dendrimers, micelles and inorganic systems have been developed for dual/multiple drug co-delivery. These co-delivery nanomedicines can improve pharmacokinetic behavior, tumor accumulation capacity, and achieve tumor site-targeting delivery. In that way, the improved antitumor effects through multiple-target therapy and reduced side effects by decreasing dose can be implemented. Here, we present the synergistic anticancer outcomes and the related mechanisms of the combination of phytochemicals with small-molecule anticancer drugs. We also focus on illustrating the design concept, and action mechanisms of nanosystems with co-delivery of drugs to synergistically improve anticancer efficacy. In addition, the challenges and prospects of how these insights can be translated into clinical benefits are discussed.
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Affiliation(s)
- Quan Gao
- School of Pharmacy and Department of Medical Oncology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
| | - Jiao Feng
- School of Pharmacy and Department of Medical Oncology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
| | - Wencheng Liu
- School of Pharmacy and Department of Medical Oncology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
| | - Chengyong Wen
- School of Pharmacy and Department of Medical Oncology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
| | - Yihan Wu
- State Key Laboratory of Southwestern Chinese Medicine Resources, College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Qian Liao
- State Key Laboratory of Southwestern Chinese Medicine Resources, College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Liang Zou
- Key Laboratory of Coarse Cereal Processing, Ministry of Agriculture and Rural Affairs, Chengdu University, No. 2025, Cheng Luo Road, Chengdu 610106, Sichuan, China
| | - Xinbing Sui
- School of Pharmacy and Department of Medical Oncology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
| | - Tian Xie
- School of Pharmacy and Department of Medical Oncology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
| | - Jinming Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
| | - Yichen Hu
- Key Laboratory of Coarse Cereal Processing, Ministry of Agriculture and Rural Affairs, Chengdu University, No. 2025, Cheng Luo Road, Chengdu 610106, Sichuan, China.
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11
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Fakhri S, Moradi SZ, Yarmohammadi A, Narimani F, Wallace CE, Bishayee A. Modulation of TLR/NF-κB/NLRP Signaling by Bioactive Phytocompounds: A Promising Strategy to Augment Cancer Chemotherapy and Immunotherapy. Front Oncol 2022; 12:834072. [PMID: 35299751 PMCID: PMC8921560 DOI: 10.3389/fonc.2022.834072] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Accepted: 01/26/2022] [Indexed: 12/12/2022] Open
Abstract
Background Tumors often progress to a more aggressive phenotype to resist drugs. Multiple dysregulated pathways are behind this tumor behavior which is known as cancer chemoresistance. Thus, there is an emerging need to discover pivotal signaling pathways involved in the resistance to chemotherapeutic agents and cancer immunotherapy. Reports indicate the critical role of the toll-like receptor (TLR)/nuclear factor-κB (NF-κB)/Nod-like receptor pyrin domain-containing (NLRP) pathway in cancer initiation, progression, and development. Therefore, targeting TLR/NF-κB/NLRP signaling is a promising strategy to augment cancer chemotherapy and immunotherapy and to combat chemoresistance. Considering the potential of phytochemicals in the regulation of multiple dysregulated pathways during cancer initiation, promotion, and progression, such compounds could be suitable candidates against cancer chemoresistance. Objectives This is the first comprehensive and systematic review regarding the role of phytochemicals in the mitigation of chemoresistance by regulating the TLR/NF-κB/NLRP signaling pathway in chemotherapy and immunotherapy. Methods A comprehensive and systematic review was designed based on Web of Science, PubMed, Scopus, and Cochrane electronic databases. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed to include papers on TLR/NF-κB/NLRP and chemotherapy/immunotherapy/chemoresistance by phytochemicals. Results Phytochemicals are promising multi-targeting candidates against the TLR/NF-κB/NLRP signaling pathway and interconnected mediators. Employing phenolic compounds, alkaloids, terpenoids, and sulfur compounds could be a promising strategy for managing cancer chemoresistance through the modulation of the TLR/NF-κB/NLRP signaling pathway. Novel delivery systems of phytochemicals in cancer chemotherapy/immunotherapy are also highlighted. Conclusion Targeting TLR/NF-κB/NLRP signaling with bioactive phytocompounds reverses chemoresistance and improves the outcome for chemotherapy and immunotherapy in both preclinical and clinical stages.
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Affiliation(s)
- Sajad Fakhri
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Seyed Zachariah Moradi
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Akram Yarmohammadi
- Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Fatemeh Narimani
- Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Carly E. Wallace
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL, United States
| | - Anupam Bishayee
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL, United States
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12
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Geng A, Xu S, Yao Y, Qian Z, Wang X, Sun J, Zhang J, Shi F, Chen Z, Zhang W, Mao Z, Lu W, Jiang Y. Chrysin impairs genomic stability by suppressing DNA double-strand break repair in breast cancer cells. Cell Cycle 2022; 21:379-391. [PMID: 34985375 PMCID: PMC8855858 DOI: 10.1080/15384101.2021.2020434] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Chrysin, a natural compound isolated from various plants, such as the blue passion flower (Passiflora caerulea L.), exhibits multiple pharmacological activities, such as antitumor, anti-inflammatory and antioxidant activities. Accumulating evidence shows that chrysin inhibits cancer cell growth by inducing apoptosis and regulating cell cycle arrest. However, whether chrysin is involved in regulating genomic stability and its underlying mechanisms in breast cancer cells have not been determined. Here, we demonstrated that chrysin impairs genomic stability in MCF-7 and BT474 cells, inhibits cell survival and enhances the sensitivity of MCF-7 cells to chemotherapeutic drugs. Further experiments revealed that chrysin impairs DNA double-strand break (DSB) repair, resulting in accumulation of DNA damage. Mechanistic studies showed that chrysin inhibits the recruitment of the key NHEJ factor 53BP1 and delays the recruitment of the HR factor RAD51. Thus, we elucidated novel regulatory mechanisms of chrysin in DSB repair and proposed that a combination of chrysin and chemotherapy has curative potential in breast cancers.
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Affiliation(s)
- Anke Geng
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China,Department of Gynecology of Shanghai First Maternity & Infant Hospital, School of Medicine, Tongji University, Shanghai, China,CONTACT Anke Geng Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai200092, China
| | - Shiya Xu
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Yunxia Yao
- College of Pharmacy, Yanbian University, Yanji, Jilin, China
| | - Zhen Qian
- Department of Gynecology of Shanghai First Maternity & Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Xiyue Wang
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China,Department of Gynecology of Shanghai First Maternity & Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Jiahui Sun
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Jingyuan Zhang
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Fangfang Shi
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Zhixi Chen
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Weina Zhang
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Zhiyong Mao
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China,Department of Gynecology of Shanghai First Maternity & Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Wen Lu
- Department of Gynecology of Shanghai First Maternity & Infant Hospital, School of Medicine, Tongji University, Shanghai, China,Wen Lu Department of Gynecology of Shanghai First Maternity & Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Ying Jiang
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China,Ying Jiang Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
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13
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Yosefi S, Pakdel A, Sameni HR, Semnani V, Bandegi AR. Chrysin-Enhanced Cytotoxicity of 5-Fluorouracil-Based Chemotherapy for Colorectal Cancer in Mice: Investigating its Effects on Cyclooxygenase-2 Expression. BRAZ J PHARM SCI 2022. [DOI: 10.1590/s2175-979020202e19381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Affiliation(s)
- Sedighe Yosefi
- Semnan University of Medical Sciences, Iran; Semnan University of Medical Sciences, Iran
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14
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Design concepts of half-sandwich organoruthenium anticancer agents based on bidentate bioactive ligands. Coord Chem Rev 2021. [DOI: 10.1016/j.ccr.2021.213950] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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15
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Chemoprevention and therapeutic role of essential oils and phenolic compounds: Modeling tumor microenvironment in glioblastoma. Pharmacol Res 2021; 169:105638. [PMID: 33933637 DOI: 10.1016/j.phrs.2021.105638] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 03/28/2021] [Accepted: 04/20/2021] [Indexed: 12/18/2022]
Abstract
Glioblastoma (GBM) is the most common primary tumor of the central nervous system. Current treatments available for GBM entails surgical resection followed by temozolomide chemotherapy and/or radiotherapy, which are associated with multidrug resistance and severe side effects. While this treatment could yield good results, in almost all cases, patients suffer from relapse, which leads to reduced survival rates. Thus, therapeutic approaches with improved efficiency and reduced off-target risks are needed to overcome these problems. Regarding this, natural products appear as a safe and attractive strategy as chemotherapeutic agents or adjuvants in the treatment of GBM. Besides the increasing role of natural compounds for chemoprevention of GBM, it has been proposed to prevent carcinogenesis and metastasis of GBM. Numerous investigations showed that natural products are able to inhibit proliferation and angiogenesis, to induce apoptosis, and to target GBM stem cells, which are associated with tumor development and recurrence. This review gives a timely and comprehensive overview of the current literature regarding chemoprevention and therapy of GBM by natural products with a focus on essential oils and phenolic compounds and their molecular mechanisms.
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16
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Talebi M, Talebi M, Farkhondeh T, Simal-Gandara J, Kopustinskiene DM, Bernatoniene J, Samarghandian S. Emerging cellular and molecular mechanisms underlying anticancer indications of chrysin. Cancer Cell Int 2021; 21:214. [PMID: 33858433 PMCID: PMC8050922 DOI: 10.1186/s12935-021-01906-y] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Accepted: 04/07/2021] [Indexed: 02/07/2023] Open
Abstract
Chrysin has been shown to exert several beneficial pharmacological activities. Chrysin has anti-cancer, anti-viral, anti-diabetic, neuroprotective, cardioprotective, hepatoprotective, and renoprotective as well as gastrointestinal, respiratory, reproductive, ocular, and skin protective effects through modulating signaling pathway involved in apoptosis, oxidative stress, and inflammation. In the current review, we discussed the emerging cellular and molecular mechanisms underlying therapeutic indications of chrysin in various cancers. Online databases comprising Scopus, PubMed, Embase, ProQuest, Science Direct, Web of Science, and the search engine Google Scholar were searched for available and eligible research articles. The search was conducted by using MeSH terms and keywords in title, abstract, and keywords. In conclusion, experimental studies indicated that chrysin could ameliorate cancers of the breast, gastrointestinal tract, liver and hepatocytes, bladder, male and female reproductive systems, choroid, respiratory tract, thyroid, skin, eye, brain, blood cells, leukemia, osteoblast, and lymph. However, more studies are needed to enhance the bioavailability of chrysin and evaluate this agent in clinical trial studies.
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Affiliation(s)
- Marjan Talebi
- Department of Pharmacognosy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, 1991953381, Tehran, Iran
| | - Mohsen Talebi
- Department of Chemistry and Biochemistry, University of Texas at Arlington, Arlington, TX, 76019, USA
- Food Safety Net Services (FSNS), San Antonio, TX, 78216, USA
| | - Tahereh Farkhondeh
- Cardiovscular Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran
- Faculty of Pharmacy, Birjand University of Medical Sciences, Birjand, Iran
| | - Jesus Simal-Gandara
- Nutrition and Bromatology Group, Department of Analytical and Food Chemistry, Faculty of Science, University of Vigo, Ourense Campus, 32004, Ourense, Spain
| | - Dalia M Kopustinskiene
- Institute of Pharmaceutical Technologies, Faculty of Pharmacy, Medical Academy, Lithuanian University of Health Sciences, Sukileliu pr. 13, 50161, Kaunas, Lithuania
| | - Jurga Bernatoniene
- Institute of Pharmaceutical Technologies, Faculty of Pharmacy, Medical Academy, Lithuanian University of Health Sciences, Sukileliu pr. 13, 50161, Kaunas, Lithuania
| | - Saeed Samarghandian
- Noncommunicable Diseases Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran.
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17
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Naeem A, Ming Y, Pengyi H, Jie KY, Yali L, Haiyan Z, Shuai X, Wenjing L, Ling W, Xia ZM, Shan LS, Qin Z. The fate of flavonoids after oral administration: a comprehensive overview of its bioavailability. Crit Rev Food Sci Nutr 2021; 62:6169-6186. [PMID: 33847202 DOI: 10.1080/10408398.2021.1898333] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Despite advancements in synthetic chemistry, nature remains the primary source of drug discovery, and this never-ending task of finding novel and active drug molecules will continue. Flavonoids have been shown to possess highly significant therapeutic activities such as anti-inflammatory, anti-oxidant, anti-viral, anti-diabetic, anti-cancer, anti-aging, neuroprotective, and cardioprotective, etc., However, it has been found that orally administered flavonoids have a critical absorption disorder and, therefore, have low bioavailability and show fluctuating pharmacokinetic and pharmacodynamic responses. A detailed investigation is required to assess and analyze the variation in the bioavailability of flavonoids due to interactions with the intestinal barrier. This review will emphasize on the bioavailability and the pharmacological applications of flavonoids, key factors affecting their bioavailability, and strategies for enhancing bioavailability, which may lead to deeper understanding of the extent of flavonoids as a treatment and/or prevention for different diseases in clinics.
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Affiliation(s)
- Abid Naeem
- Jiangxi University of Traditional Chinese Medicine, Nanchang, PR China.,Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, State Key Lab of Innovation Drug and Efficient Energy-Saving Pharmaceutical Equipment, Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi, China
| | - Yang Ming
- Jiangxi University of Traditional Chinese Medicine, Nanchang, PR China.,Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, State Key Lab of Innovation Drug and Efficient Energy-Saving Pharmaceutical Equipment, Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi, China
| | - Hu Pengyi
- Jiangxi University of Traditional Chinese Medicine, Nanchang, PR China.,Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, State Key Lab of Innovation Drug and Efficient Energy-Saving Pharmaceutical Equipment, Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi, China
| | - Kang Yong Jie
- Jiangxi University of Traditional Chinese Medicine, Nanchang, PR China
| | - Liu Yali
- Jiangxi University of Traditional Chinese Medicine, Nanchang, PR China.,Science and Technology College, Jiangxi University of Traditional Chinese Medicine, Nanchang, PR China
| | - Zhang Haiyan
- Jiangxi University of Traditional Chinese Medicine, Nanchang, PR China.,Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, State Key Lab of Innovation Drug and Efficient Energy-Saving Pharmaceutical Equipment, Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi, China
| | - Xiao Shuai
- Jiangxi University of Traditional Chinese Medicine, Nanchang, PR China.,Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, State Key Lab of Innovation Drug and Efficient Energy-Saving Pharmaceutical Equipment, Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi, China
| | - Li Wenjing
- Jiangxi University of Traditional Chinese Medicine, Nanchang, PR China.,Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, State Key Lab of Innovation Drug and Efficient Energy-Saving Pharmaceutical Equipment, Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi, China
| | - Wu Ling
- Jiangxi University of Traditional Chinese Medicine, Nanchang, PR China.,Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, State Key Lab of Innovation Drug and Efficient Energy-Saving Pharmaceutical Equipment, Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi, China
| | - Zhang Ming Xia
- Jiangxi University of Traditional Chinese Medicine, Nanchang, PR China.,Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, State Key Lab of Innovation Drug and Efficient Energy-Saving Pharmaceutical Equipment, Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi, China
| | - Liu Shan Shan
- Jiangxi University of Traditional Chinese Medicine, Nanchang, PR China.,Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, State Key Lab of Innovation Drug and Efficient Energy-Saving Pharmaceutical Equipment, Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi, China
| | - Zheng Qin
- Jiangxi University of Traditional Chinese Medicine, Nanchang, PR China.,Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, State Key Lab of Innovation Drug and Efficient Energy-Saving Pharmaceutical Equipment, Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi, China
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18
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CYP1B1 as a therapeutic target in cardio-oncology. Clin Sci (Lond) 2021; 134:2897-2927. [PMID: 33185690 PMCID: PMC7672255 DOI: 10.1042/cs20200310] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 10/12/2020] [Accepted: 10/28/2020] [Indexed: 02/06/2023]
Abstract
Cardiovascular complications have been frequently reported in cancer patients and survivors, mainly because of various cardiotoxic cancer treatments. Despite the known cardiovascular toxic effects of these treatments, they are still clinically used because of their effectiveness as anti-cancer agents. In this review, we discuss the growing body of evidence suggesting that inhibition of the cytochrome P450 1B1 enzyme (CYP1B1) can be a promising therapeutic strategy that has the potential to prevent cancer treatment-induced cardiovascular complications without reducing their anti-cancer effects. CYP1B1 is an extrahepatic enzyme that is expressed in cardiovascular tissues and overexpressed in different types of cancers. A growing body of evidence is demonstrating a detrimental role of CYP1B1 in both cardiovascular diseases and cancer, via perturbed metabolism of endogenous compounds, production of carcinogenic metabolites, DNA adduct formation, and generation of reactive oxygen species (ROS). Several chemotherapeutic agents have been shown to induce CYP1B1 in cardiovascular and cancer cells, possibly via activating the Aryl hydrocarbon Receptor (AhR), ROS generation, and inflammatory cytokines. Induction of CYP1B1 is detrimental in many ways. First, it can induce or exacerbate cancer treatment-induced cardiovascular complications. Second, it may lead to significant chemo/radio-resistance, undermining both the safety and effectiveness of cancer treatments. Therefore, numerous preclinical studies demonstrate that inhibition of CYP1B1 protects against chemotherapy-induced cardiotoxicity and prevents chemo- and radio-resistance. Most of these studies have utilized phytochemicals to inhibit CYP1B1. Since phytochemicals have multiple targets, future studies are needed to discern the specific contribution of CYP1B1 to the cardioprotective and chemo/radio-sensitizing effects of these phytochemicals.
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19
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Zhou X, Fu L, Wang P, Yang L, Zhu X, Li CG. Drug-herb interactions between Scutellaria baicalensis and pharmaceutical drugs: Insights from experimental studies, mechanistic actions to clinical applications. Biomed Pharmacother 2021; 138:111445. [PMID: 33711551 DOI: 10.1016/j.biopha.2021.111445] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 02/23/2021] [Accepted: 02/25/2021] [Indexed: 02/07/2023] Open
Abstract
Whilst the popular use of herbal medicine globally, it poses challenges in managing potential drug-herb interaction. There are two folds of the drug-herb interaction, a beneficial interaction that may improve therapeutic outcome and minimise the toxicity of drug desirably; by contrast, negative interaction may evoke unwanted clinical consequences, especially with drugs of narrow therapeutic index. Scutellaria baicalensis Georgi is one of the most popular medicinal plants used in Asian countries. It has been widely used for treating various diseases and conditions such as cancer, diabetes, inflammation, and oxidative stress. Studies on its extract and bioactive compounds have shown pharmacodynamic and pharmacokinetic interactions with a wide range of pharmaceutical drugs as evidenced by plenty of in vitro, in vivo and clinical studies. Notably, S. baicalensis and its bioactives including baicalein, baicalin and wogonin exhibited synergistic interactions with many pharmaceutical drugs to enhance their efficacy, reduce toxicity or overcome drug resistance to combat complex diseases such as cancer, diabetes and infectious diseases. On the other hand, S. baicalensis and its bioactives also affected the pharmacokinetic profile of many drugs in absorption, distribution, metabolism and elimination via the regulatory actions of the efflux pumps and cytochrome P450 enzymes. This review provides comprehensive references of the observed pharmacodynamic and pharmacokinetic drug interactions of Scutellaria baicalensis and its bioactives. We have elucidated the interaction with detailed mechanistic actions, identified the knowledge gaps for future research and potential clinical implications. Such knowledge is important for the practice of both conventional and complementary medicines, and it is essential to ensure the safe use of related herbal medicines. The review may be of great interest to practitioners, consumers, clinicians who require comprehensive information on the possible drug interactions with S. baicalensis and its bioactives.
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Affiliation(s)
- Xian Zhou
- NICM Health Research Institute, Western Sydney University, Locked Bag 1797, Penrith, NSW 2751, Australia.
| | - Ling Fu
- Chinese Medicine Centre, School of Health Sciences, Western Sydney University, Penrith, NSW 2751, Australia; The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, People's Republic of China; The Second Affiliated Hospital of Nanjing University of Chinese Medicine (Jiangsu Second Chinese Medicine Hospital), Nanjing, Jiangsu 210017, People's Republic of China
| | - Pengli Wang
- Chinese Medicine Centre, School of Health Sciences, Western Sydney University, Penrith, NSW 2751, Australia; School of Chinese Medicine, School of Integrated Chinese & Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, People's Republic of China
| | - Lan Yang
- Chinese Medicine Centre, School of Health Sciences, Western Sydney University, Penrith, NSW 2751, Australia; School of Chinese Medicine, School of Integrated Chinese & Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, People's Republic of China
| | - Xiaoshu Zhu
- Chinese Medicine Centre, School of Health Sciences, Western Sydney University, Penrith, NSW 2751, Australia
| | - Chun Guang Li
- NICM Health Research Institute, Western Sydney University, Locked Bag 1797, Penrith, NSW 2751, Australia.
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20
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Natural Products Targeting the Mitochondria in Cancers. Molecules 2020; 26:molecules26010092. [PMID: 33379233 PMCID: PMC7795732 DOI: 10.3390/molecules26010092] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 12/23/2020] [Accepted: 12/25/2020] [Indexed: 12/13/2022] Open
Abstract
There are abundant sources of anticancer drugs in nature that have a broad prospect in anticancer drug discovery. Natural compounds, with biological activities extracted from plants and marine and microbial metabolites, have significant antitumor effects, but their mechanisms are various. In addition to providing energy to cells, mitochondria are involved in processes, such as cell differentiation, cell signaling, and cell apoptosis, and they have the ability to regulate cell growth and cell cycle. Summing up recent data on how natural products regulate mitochondria is valuable for the development of anticancer drugs. This review focuses on natural products that have shown antitumor effects via regulating mitochondria. The search was done in PubMed, Web of Science, and Google Scholar databases, over a 5-year period, between 2015 and 2020, with a keyword search that focused on natural products, natural compounds, phytomedicine, Chinese medicine, antitumor, and mitochondria. Many natural products have been studied to have antitumor effects on different cells and can be further processed into useful drugs to treat cancer. In the process of searching for valuable new drugs, natural products such as terpenoids, flavonoids, saponins, alkaloids, coumarins, and quinones cover the broad space.
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21
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Lee S, Lee SK, Jung J. Potentiating activities of chrysin in the therapeutic efficacy of 5-fluorouracil in gastric cancer cells. Oncol Lett 2020; 21:24. [PMID: 33240430 PMCID: PMC7681229 DOI: 10.3892/ol.2020.12285] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Accepted: 09/24/2020] [Indexed: 12/15/2022] Open
Abstract
The incidence and mortality rates of gastric cancer rank among the highest five of all cancer types worldwide. The chemotherapeutic agent 5-fluorouracil (5-FU) is the gold standard for treating gastric cancer, but its efficacy is limited due to high rates of resistance. To improve the therapeutic efficacy of 5-FU and overcome its resistance, the synergistic effect of chrysin with 5-FU was investigated and its mechanism was elucidated. Chrysin was co-administered with 5-FU in AGS cells and 5-FU-resistant AGS cells (AGS/FR). Cytotoxicity was investigated using MTT assay, followed by calculating the combination index (CI). Several biomarkers were detected using western blotting analysis. Apoptosis and cell cycle distribution were measured by flow cytometry. The combination of chrysin and 5-FU significantly increased cytotoxicity more than chrysin or 5-FU alone. 5-FU induced apoptosis through p53-p21 activity, while chrysin arrested the cell cycle in the G2/M phase. The combination of chrysin and 5-FU showed an anticancer effect via S phase arrest. The results indicated that chrysin and 5-FU exhibited anticancer properties via different pathways. Furthermore, the present study found that chrysin enhanced the chemotherapeutic effect of 5-FU in AGS/FR cells. In the resistant cells, the combination of chrysin and 5-FU improved the anticancer effect via G2/M phase arrest. These findings indicated that chrysin potentiated the chemotherapeutic effect of 5-FU in gastric cancer AGS and AGS/FR cells via cell cycle arrest. Therefore, chrysin may be used to treat gastric cancers that have become resistant to 5-FU.
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Affiliation(s)
- Sunyi Lee
- Duksung Innovative Drug Center, Duksung Women's University, Seoul 01369, Republic of Korea.,College of Pharmacy, Duksung Women's University, Seoul 01369, Republic of Korea
| | - Suk Kyeong Lee
- Department of Medical Life Sciences, Department of Biomedicine and Health Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Joohee Jung
- Duksung Innovative Drug Center, Duksung Women's University, Seoul 01369, Republic of Korea.,College of Pharmacy, Duksung Women's University, Seoul 01369, Republic of Korea
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22
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Yang B, Dong Y, Wang F, Zhang Y. Nanoformulations to Enhance the Bioavailability and Physiological Functions of Polyphenols. Molecules 2020; 25:E4613. [PMID: 33050462 PMCID: PMC7587200 DOI: 10.3390/molecules25204613] [Citation(s) in RCA: 99] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 10/04/2020] [Accepted: 10/06/2020] [Indexed: 12/11/2022] Open
Abstract
Polyphenols are micronutrients that are widely present in human daily diets. Numerous studies have demonstrated their potential as antioxidants and anti-inflammatory agents, and for cancer prevention, heart protection and the treatment of neurodegenerative diseases. However, due to their vulnerability to environmental conditions and low bioavailability, their application in the food and medical fields is greatly limited. Nanoformulations, as excellent drug delivery systems, can overcome these limitations and maximize the pharmacological effects of polyphenols. In this review, we summarize the biological activities of polyphenols, together with systems for their delivery, including phospholipid complexes, lipid-based nanoparticles, protein-based nanoparticles, niosomes, polymers, micelles, emulsions and metal nanoparticles. The application of polyphenol nanoparticles in food and medicine is also discussed. Although loading into nanoparticles solves the main limitation to application of polyphenolic compounds, there are some concerns about their toxicological safety after entry into the human body. It is therefore necessary to conduct toxicity studies and residue analysis on the carrier.
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Affiliation(s)
| | | | | | - Yu Zhang
- Jiangsu Provincial Key Lab for the Chemistry and Utilization of Agro-Forest Biomass, Jiangsu Key Lab of Biomass-Based Green Fuels and Chemicals, Jiangsu Co-Innovation Center of Efficient Processing and Utilization of Forest Resources, College of Chemical Engineering, Nanjing Forestry University, Nanjing 210037, China; (B.Y.); (Y.D.); (F.W.)
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Ye M, Xu M, Fan S, Zhang M, Zhou B, Yang S, Wei W, Ji C, Ji J, Ji F. Protective effects of three propolis-abundant flavonoids against ethanol-induced injuries in HepG2 cells involving the inhibition of ERK1/2-AHR-CYP1A1 signaling pathways. J Funct Foods 2020. [DOI: 10.1016/j.jff.2020.104166] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
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Moghadam ER, Ang HL, Asnaf SE, Zabolian A, Saleki H, Yavari M, Esmaeili H, Zarrabi A, Ashrafizadeh M, Kumar AP. Broad-Spectrum Preclinical Antitumor Activity of Chrysin: Current Trends and Future Perspectives. Biomolecules 2020; 10:E1374. [PMID: 32992587 PMCID: PMC7600196 DOI: 10.3390/biom10101374] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Revised: 09/21/2020] [Accepted: 09/23/2020] [Indexed: 02/06/2023] Open
Abstract
Pharmacological profile of phytochemicals has attracted much attention to their use in disease therapy. Since cancer is a major problem for public health with high mortality and morbidity worldwide, experiments have focused on revealing the anti-tumor activity of natural products. Flavonoids comprise a large family of natural products with different categories. Chrysin is a hydroxylated flavonoid belonging to the flavone category. Chrysin has demonstrated great potential in treating different disorders, due to possessing biological and therapeutic activities, such as antioxidant, anti-inflammatory, hepatoprotective, neuroprotective, etc. Over recent years, the anti-tumor activity of chrysin has been investigated, and in the present review, we provide a mechanistic discussion of the inhibitory effect of chrysin on proliferation and invasion of different cancer cells. Molecular pathways, such as Notch1, microRNAs, signal transducer and activator of transcription 3 (STAT3), nuclear factor-kappaB (NF-κB), PI3K/Akt, MAPK, etc., as targets of chrysin are discussed. The efficiency of chrysin in promoting anti-tumor activity of chemotherapeutic agents and suppressing drug resistance is described. Moreover, poor bioavailability, as one of the drawbacks of chrysin, is improved using various nanocarriers, such as micelles, polymeric nanoparticles, etc. This updated review will provide a direction for further studies in evaluating the anti-tumor activity of chrysin.
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Affiliation(s)
- Ebrahim Rahmani Moghadam
- Department of Anatomical Sciences, School of Medicine, Shiraz University of Medical Sciences, Shiraz 7134814336, Iran;
| | - Hui Li Ang
- Cancer Science Institute of Singapore and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore;
| | - Sholeh Etehad Asnaf
- Department of Cell and Molecular Biology, Faculty of Biological Sciences, North Tehran Branch, IslamicAzad University, Tehran 165115331, Iran;
| | - Amirhossein Zabolian
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran 1916893813, Iran; (A.Z.); (H.S.); (H.E.)
| | - Hossein Saleki
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran 1916893813, Iran; (A.Z.); (H.S.); (H.E.)
| | - Mohammad Yavari
- Nursing and Midwifery Department, Islamic Azad University, Tehran Medical Sciences Branch, Tehran 1916893813, Iran;
| | - Hossein Esmaeili
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran 1916893813, Iran; (A.Z.); (H.S.); (H.E.)
| | - Ali Zarrabi
- Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla, Istanbul 34956, Turkey
| | - Milad Ashrafizadeh
- Faculty of Veterinary Medicine, University of Tabriz, Tabriz 5166616471, Iran
| | - Alan Prem Kumar
- Cancer Science Institute of Singapore and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore;
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25
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Lv M, Zhuang X, Zhang Q, Cheng Y, Wu D, Wang X, Qiao T. Acetyl-11-keto-β-boswellic acid enhances the cisplatin sensitivity of non-small cell lung cancer cells through cell cycle arrest, apoptosis induction, and autophagy suppression via p21-dependent signaling pathway. Cell Biol Toxicol 2020; 37:209-228. [PMID: 32562082 PMCID: PMC8012341 DOI: 10.1007/s10565-020-09541-5] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Accepted: 06/09/2020] [Indexed: 02/06/2023]
Abstract
Cisplatin-based therapy is a widely used chemotherapeutic regimen for non-small cell lung cancer (NSCLC); however, drug resistance limits its efficacy. Acetyl-11-keto-β-boswellic acid (AKBA), a bioactive compound from frankincense, has been shown to exert anti-cancer effects. The aim of this study is to explore the potential of AKBA in combination with cisplatin as a new regimen for NSCLC. CCK8 assay and clone formation assay were used to determine the effects of AKBA in combination with cisplatin on cell viability of NSCLC cell lines. A three-dimensional spherification assay was used to simulate in vivo tumor formation. Flow cytometry was performed to examine cell cycle distribution and the percentages of apoptotic cells. The associated proteins and mRNA of cell cycle, apoptosis, and autophagy were measured by western blotting and real-time fluorescence quantitative PCR. Immunofluorescence assay was used to test apoptotic nuclei and autolysosome. Small interfering RNA experiments were used to silence the expression of p21. Combination treatment of AKBA and cisplatin inhibited cell viability, clone formation, and three-dimensional spherification, enhanced G0/G1 phase arrest, increased the percentages of apoptotic cells, and decreased the ratio of positive autolysosomes, compared with cisplatin alone. AKBA in combination with cisplatin suppressed the protein expressions of cyclin A2, cyclin E1, p-cdc2, CDK4, Bcl-xl, Atg5, and LC3A/B, and upregulated p27 and p21 mRNA levels in A549 cells. Downregulation of p21 decreased G0/G1 phase arrest and the percentages of apoptotic cells, and promoted autophagy in NSCLC A549 cells. Our study demonstrates that AKBA enhances the cisplatin sensitivity of NSCLC cells and that the mechanisms involve G0/G1 phase arrest, apoptosis induction, and autophagy suppression via targeting p21-dependent signaling pathway.
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Affiliation(s)
- Minghe Lv
- Center for Tumor Diagnosis and Therapy, Jinshan Hospital, Fudan University, Jinshan District, Shanghai, 201508, China
| | - Xibing Zhuang
- Center for Tumor Diagnosis and Therapy, Jinshan Hospital, Fudan University, Jinshan District, Shanghai, 201508, China
| | - Qi Zhang
- Center for Tumor Diagnosis and Therapy, Jinshan Hospital, Fudan University, Jinshan District, Shanghai, 201508, China
| | - Yunfeng Cheng
- Center for Tumor Diagnosis and Therapy, Jinshan Hospital, Fudan University, Jinshan District, Shanghai, 201508, China
| | - Duojiao Wu
- Center for Tumor Diagnosis and Therapy, Jinshan Hospital, Fudan University, Jinshan District, Shanghai, 201508, China
| | - Xiangdong Wang
- Center for Tumor Diagnosis and Therapy, Jinshan Hospital, Fudan University, Jinshan District, Shanghai, 201508, China
| | - Tiankui Qiao
- Center for Tumor Diagnosis and Therapy, Jinshan Hospital, Fudan University, Jinshan District, Shanghai, 201508, China.
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Gujar K, Wairkar S. Nanocrystal technology for improving therapeutic efficacy of flavonoids. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2020; 71:153240. [PMID: 32450461 DOI: 10.1016/j.phymed.2020.153240] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 04/05/2020] [Accepted: 05/02/2020] [Indexed: 06/11/2023]
Abstract
BACKGROUND Bioflavonoids, secondary metabolites of plants, are beneficial in regulating human physiological mechanisms. Bioflavonoids majorly exist in the dietary intake of fruits, vegetables, legumes, pulses, etc. In addition to their cardio-protective and neuroprotective activities, they also possess prominent pharmacological effects including anti-oxidant, anti-inflammatory, anti-proliferative and anti-thrombogenic actions. However, therapeutic efficacy of the bioflavonoids is hampered by their lipophilic nature, low solubility and variable bioavailability which catch the eyes of formulation scientists. PURPOSE Nanocrystal formulations were studied for many bioflavonoids, although enough attention has not been given to their commercial exploitation, unlike drug nanocrystals. Nanocrystals of bioflavonoid can be prepared by top-down technique, bottom-up technique or combination of both. This review primarily focuses on nanocrystal technology for bioflavonoids, methods of production, critical process parameters, in vitro and in vivo studies conducted to evaluate the efficiency. METHOD The detailed literature survey was systematically carried out using different electronic databases. It includes Scopus, Web of Science, Medline via PubMed, EMBASE, and Google Scholar. Also up-to-date patent search was conducted to understand the prior art and available intellectual properties. RESULT AND CONCLUSION It was observed that several formulation and process parameters have an impact on flavonoids nanocrystals and their therapeutic efficacy. Also, clinical studies of flavonoid nanocrystals are barely done so far and thus, substantial safety and efficacy data is necessary for its commercial applications. Nevertheless, nanocrystals can be explored as a promising technology platform for improving overall therapeutic performance of flavonoids in future.
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Affiliation(s)
- Ketaki Gujar
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKMs NMIMS, V.L. Mehta Road, Vile Parle (W), Mumbai-400056, India
| | - Sarika Wairkar
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKMs NMIMS, V.L. Mehta Road, Vile Parle (W), Mumbai-400056, India.
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27
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Ortiz-Islas E, Manríquez-Ramírez ME, Sosa-Muñoz A, Almaguer P, Arias C, Guevara P, Hernández-Cortez G, Aguirre-Cruz ML. Preparation and characterisation of silica-based nanoparticles for cisplatin release on cancer brain cells. IET Nanobiotechnol 2020; 14:191-197. [PMID: 32338626 PMCID: PMC8676590 DOI: 10.1049/iet-nbt.2019.0239] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 10/09/2019] [Accepted: 12/05/2019] [Indexed: 12/15/2022] Open
Abstract
In the present work, the preparation, characterisation, and efficiency of two different silica nanostructures as release vehicles of Cisplatin are reported. The 1-hexadeciltrimethyl-ammonium bromide templating agent was used to obtain mesoporous silica nanoparticles which were later loaded with Cisplatin. While sol-gel silica was very fast prepared using an excess of acetic acid during the hydrolysis-condensation reactions of tetraethylorthosilicate and at the same time the Cisplatin was added. Several physicochemical techniques including spectroscopies, electronic microscopy, X-ray diffraction, N2 adsorption-desorption were used to characterise the silica nanostructures. An in vitro Cisplatin release test was carried out using artificial cerebrospinal fluid. Finally, the toxicity of all silica nanostructures was tested using the C6 cancer cell line. The spectroscopic results showed the suitable stabilisation of Cisplatin into the two different silica nanostructures. A large surface area was obtained for the mesoporous silica nanoparticles, while low areas were obtained in the silica nanoparticles. Cisplatin was released faster from mesoporous silica channels than from inside of aggregates nanoparticles silica. Cisplatin alone, as well as, cisplatin released from both silica nanostructures exerted a toxic effect on cancer cells. In contrast, both silica structures without the drug did not exert any toxic effect.
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Affiliation(s)
- Emma Ortiz-Islas
- Nanotechnology Laboratory, National Institute of Neurology and Neurosurgery, Insurgentes Sur 3877, La Fama, 14269 México City, Mexico.
| | - María Elena Manríquez-Ramírez
- ESIQIE-National Polytechnic Institute, Instituto Politécnico Nacional s/n, Col. Zacatenco, 07738 México City, Mexico
| | - Amarilis Sosa-Muñoz
- Nanotechnology Laboratory, National Institute of Neurology and Neurosurgery, Insurgentes Sur 3877, La Fama, 14269 México City, Mexico
| | - Paola Almaguer
- ESIQIE-National Polytechnic Institute, Instituto Politécnico Nacional s/n, Col. Zacatenco, 07738 México City, Mexico
| | - Carlos Arias
- ESIQIE-National Polytechnic Institute, Instituto Politécnico Nacional s/n, Col. Zacatenco, 07738 México City, Mexico
| | - Patricia Guevara
- Neuroimmunology Laboratory, National Institute of Neurology and Neurosurgery, Insurgentes Sur 3877, La Fama, 14269 México City, Mexico
| | - Gonzalo Hernández-Cortez
- Gerencia de materiales y productos químicos, Instituto Mexicano del Petróleo, Eje Lázaro Cárdenas 152, 07730 México City, Mexico
| | - Ma Lucinda Aguirre-Cruz
- Laboratory of Neuroimmunoendocrinology, National Institute of Neurology and Neurosurgery, Insurgentes Sur 3877, La Fama, 14269 México City, Mexico
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Zou XG, Li J, Sun PL, Fan YW, Yang JY, Deng ZY. Orbitides isolated from flaxseed induce apoptosis against SGC-7901 adenocarcinoma cells. Int J Food Sci Nutr 2020; 71:929-939. [PMID: 32281434 DOI: 10.1080/09637486.2020.1750573] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Unique plant-derived cyclic peptides family exhibiting various key biological activities has great possibility for anticancer therapy. In this study, we investigated the effects of orbitides isolated from flax (Linum usitatissimum L.) on the growth of SGC-7901 cancer cells and the potential mechanism. Results showed that flaxseed orbitides killed off cancer cells by inducing apoptosis in a dose-dependent manner, which was confirmed by the appearance of nuclear shrinkage and DNA fragmentation, and the inhibitory effect was stronger than that of pure orbitide [1-9-NαC]-linusorb B2 or [1-9-NαC]-linusorb B3. Besides, the mitochondrial apoptosis pathway-related protein cytochrome C (Cyt C) was released from mitochondria to cytosol, associated with the activation of caspases 9 and 3, and the cleavage of PARP. Taken together, these results indicated that flaxseed orbitides induced apoptosis via the mitochondrial pathway, releasing Cyt C, increasing Bax/Bcl-2 ratio and elevating the expression of cleaved caspase 9 and 3 in SGC-7901 cells.
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Affiliation(s)
- Xian-Guo Zou
- College of Food Science and Technology, Zhejiang University of Technology, Hangzhou, Zhejiang, China.,State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, Jiangxi, China
| | - Jing Li
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, Jiangxi, China
| | - Pei-Long Sun
- College of Food Science and Technology, Zhejiang University of Technology, Hangzhou, Zhejiang, China
| | - Ya-Wei Fan
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, Jiangxi, China
| | - Jian-Yuan Yang
- College of Pharmaceutical and Life Sciences, Jiujiang University, Jiujiang, Jiangxi, China
| | - Ze-Yuan Deng
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, Jiangxi, China
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29
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Neuroprotective potential of chrysin in Parkinson's disease: Molecular mechanisms and clinical implications. Neurochem Int 2020; 132:104612. [DOI: 10.1016/j.neuint.2019.104612] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Revised: 11/24/2019] [Accepted: 11/25/2019] [Indexed: 01/09/2023]
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30
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Kashyap D, Tuli HS, Yerer MB, Sharma A, Sak K, Srivastava S, Pandey A, Garg VK, Sethi G, Bishayee A. Natural product-based nanoformulations for cancer therapy: Opportunities and challenges. Semin Cancer Biol 2019; 69:5-23. [PMID: 31421264 DOI: 10.1016/j.semcancer.2019.08.014] [Citation(s) in RCA: 218] [Impact Index Per Article: 36.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2019] [Revised: 08/10/2019] [Accepted: 08/12/2019] [Indexed: 01/09/2023]
Abstract
Application of natural product-based nanoformulations for the treatment of different human diseases, such as cancer, is an emerging field. The conventional cancer therapeutic modalities, including surgery, chemotherapy, immunotherapy, radiotherapy has limited achievements. A larger number of drawbacks are associated with these therapies, including damage to proliferating healthy tissues, structural deformities, systemic toxicity, long-term side effects, resistance to the drug by tumor cells, and psychological problems. The advent of nanotechnology in cancer therapeutics is recent; however, it has progressed and transformed the field of cancer treatment at a rapid rate. Nanotherapeutics have promisingly overcome the limitations of conventional drug delivery system, i.e., low aqueous solubility, low bioavailability, multidrug resistance, and non-specificity. Specifically, natural product-based nanoformulations are being intentionally studied in different model systems. Where it is found that these nanoformulations has more proximity and reduced side effects. The nanoparticles can specifically target tumor cells, enhancing the specificity and efficacy of cancer therapeutic modalities which in turn improves patient response and survival. The integration of phytotherapy and nanotechnology in the clinical setting may improve pharmacological response and better clinical outcome of patients.
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Affiliation(s)
- Dharambir Kashyap
- Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh - 160 012, Punjab, India
| | - Hardeep Singh Tuli
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala - 133 207, Haryana, India.
| | - Mukerrem Betul Yerer
- Department of Pharmacology, Faculty of Pharmacy, University of Erciyes, Kayseri 38039, Turkey
| | - Ajay Sharma
- Department of Chemistry, Career Point University, Tikker-Kharwarian, Hamirpur - 176 041, Himachal Pradesh, India
| | | | - Saumya Srivastava
- Department of Biotechnology, Motilal Nehru National Institute of Technology Allahabad, Allahabad - 211 004, Uttar Pradesh, India
| | - Anjana Pandey
- Department of Biotechnology, Motilal Nehru National Institute of Technology Allahabad, Allahabad - 211 004, Uttar Pradesh, India
| | - Vivek Kumar Garg
- Department of Biochemistry, Government Medical College and Hospital, Sector 32, Chandigarh - 160 031, Punjab, India
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore.
| | - Anupam Bishayee
- Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA.
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31
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Li X, Guo S, Xiong XK, Peng BY, Huang JM, Chen MF, Wang FY, Wang JN. Combination of quercetin and cisplatin enhances apoptosis in OSCC cells by downregulating xIAP through the NF-κB pathway. J Cancer 2019; 10:4509-4521. [PMID: 31528215 PMCID: PMC6746132 DOI: 10.7150/jca.31045] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Accepted: 04/24/2019] [Indexed: 12/28/2022] Open
Abstract
While cisplatin is a first-line chemotherapeutic drug commonly used to treat patients with oral squamous cell carcinoma (OSCC), the cisplatin-resistance poses a major challenge for its clinical application. Recent studies have shown that quercetin, a natural flavonoid found in various plants and foods possesses an anti-cancer effect. The following study examined the combined effect of quercetin and cisplatin on OSCC apoptosis in vitro and in vivo (using a mice tumor model). We found that quercetin promotes cisplatin-induced apoptosis in human OSCC (cell lines Tca-8113 and SCC-15) by down-regulating NF-κB. Pretreatment of cancer cells with quercetin inhibited the phosphorylation Akt and IKKβ, and led to the suppression of NF-κB and anti-apoptotic protein xIAP. In addition, we observed that the pretreatment of cancer cells with quercetin improves extrinsic and intrinsic apoptosis by activating caspase-8 and caspase-9, respectively. Our in vivo data also indicated that the combination of quercetin and cisplatin may inhibit the xenograft growth in mice. To sum up, our results provide a new evidence for the application of quercetin and cisplatin in OSCC therapy.
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Affiliation(s)
- Xin Li
- Guangdong Provincial Center for Disease Control and Prevention, 160 Qunxian Road, Dashi, Panyu District, Guangzhou, Guangdong Province, P.R. China, 511430
| | - Shu Guo
- State Environmental Protection Key Laboratory of Environmental Pollution Health Risk Assessment, South China Institute of Environmental Sciences, Ministry of Environmental Protection, Guangzhou, Guangdong Province, P.R. China, 510655
| | - Xi-Kun Xiong
- Guangdong Provincial Center for Disease Control and Prevention, 160 Qunxian Road, Dashi, Panyu District, Guangzhou, Guangdong Province, P.R. China, 511430
| | - Bao-Ying Peng
- Guangdong Provincial Center for Disease Control and Prevention, 160 Qunxian Road, Dashi, Panyu District, Guangzhou, Guangdong Province, P.R. China, 511430
| | - Jun-Ming Huang
- Guangdong Provincial Center for Disease Control and Prevention, 160 Qunxian Road, Dashi, Panyu District, Guangzhou, Guangdong Province, P.R. China, 511430
| | - Mei-Fen Chen
- Guangdong Provincial Center for Disease Control and Prevention, 160 Qunxian Road, Dashi, Panyu District, Guangzhou, Guangdong Province, P.R. China, 511430
| | - Feng-Yan Wang
- Guangdong Provincial Center for Disease Control and Prevention, 160 Qunxian Road, Dashi, Panyu District, Guangzhou, Guangdong Province, P.R. China, 511430
| | - Jian-Ning Wang
- Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Institute of Stomatological Research, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Stomatology, 56, Ling Yuan Xi Road, Guangzhou, Guangdong Province, P.R. China, 510055
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Ye Q, Liu K, Shen Q, Li Q, Hao J, Han F, Jiang RW. Reversal of Multidrug Resistance in Cancer by Multi-Functional Flavonoids. Front Oncol 2019; 9:487. [PMID: 31245292 PMCID: PMC6581719 DOI: 10.3389/fonc.2019.00487] [Citation(s) in RCA: 94] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Accepted: 05/23/2019] [Indexed: 12/22/2022] Open
Abstract
Multidrug resistance (MDR) resulting from different defensive mechanisms in cancer is one of the major obstacles of clinical treatment. To circumvent MDR many reversal agents have been developed, but most of them fail in clinical trials due to severely adverse effects. Recently, certain natural products have been reported to overcome MDR, including flavonoids which are abundant in plants, foods, and herbs. The structure of flavonoids can be abbreviated as C6-C3-C6 (C for carbon), and further categorized into flavonoids, iso-flavonoids and neo-flavonoids, according to their structural backbones. Flavonoids possess multiple bioactivities, and a growing body of research has indicated that both flavonoids and iso-flavonoids can either kill or re-sensitize conventional chemotherapeutics to resistant cancer cells. Here, we summarize the research and discuss the underlying mechanisms, concluding that these flavonoids do not function as specific regulators of target proteins, but rather as multi-functional agents that negatively regulate the key factors contributing to MDR.
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Affiliation(s)
| | - Kai Liu
- Hainan General Hospital, Haikou, China
| | - Qun Shen
- Hainan General Hospital, Haikou, China
| | | | - Jinghui Hao
- Jiaozuo Second People's Hospital, Jiaozuo, China
| | | | - Ren-Wang Jiang
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education, Jinan University, Guangzhou, China
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Zhang Y, Chen F, Xiao X, Pan W, Yuan Q, Cao J. Chrysin inhibits sphere formation in SMMC-7721 cells via modulation of SHP-1/STAT3 signaling pathway. Cancer Manag Res 2019; 11:2977-2985. [PMID: 31114345 PMCID: PMC6497861 DOI: 10.2147/cmar.s193647] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Accepted: 02/27/2019] [Indexed: 12/17/2022] Open
Abstract
Background: Chrysin is a natural flavonoid which has been identified as a candidate anti-cancer agent due to its inhibitory effect on a variety of cancer cells, including targeted inhibition of sphere formation in hepatocellular carcinoma (HCC) cell lines. However, the mechanism by which chrysin modulates HCC spheres remains unclear. Materials and methods: In this study, we investigate the effect of chrysin on the regulation of SHP-1 and its downstream signal molecule STAT3 to explain the mechanism by which chrysin inhibits sphere formation of HCC cell lines. Results: Here, we found that SHP-1 protein expression was markedly down-regulated in the spheres from both SMMC-7721 and MHCC97H cells. Chrysin significantly inhibited sphere formation and upregulated the expression of SHP-1 protein in both SMMC-7721 and MHCC97H cells, as well as reduced p-STAT3 and Twist1 expressions in SMMC-7721 cells. Furthermore, knockdown of SHP-1 in SMMC-7721 cells resulted in the induction of p-STAT3 and Twist1 protein expression and antagonizing the inhibitory effect of chrysin on sphere formation in SMMC-7721 cells. Conclusion: Overall, the study findings demonstrated that chrysin acts as a candidate for the treatment of HCC through modulating SHP-1/STAT3 signaling pathway.
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Affiliation(s)
- Yanqin Zhang
- Department of Pharmacy, Xiangya Hospital of Central South University, Changsha, 410008, People's Republic of China.,Department of Pharmacy, Hunan Food and Drug Vocational College, Changsha, 410208, People's Republic of China
| | - Feng Chen
- Department of Pharmacy, Xiangya Hospital of Central South University, Changsha, 410008, People's Republic of China
| | - Xinghua Xiao
- Department of Pharmacy, Xiangya Hospital of Central South University, Changsha, 410008, People's Republic of China
| | - Weinan Pan
- Department of Pharmacy, Hunan Food and Drug Vocational College, Changsha, 410208, People's Republic of China
| | - Qing Yuan
- Department of Pharmaceutical Science, Medical College, Hunan Normal University, Changsha 410013, People's Republic of China
| | - Jianguo Cao
- Department of Pharmaceutical Science, Medical College, Hunan Normal University, Changsha 410013, People's Republic of China
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Wen P, Wei X, Liang G, Wang Y, Yang Y, Qin L, Pang W, Qin G, Li H, Jiang Y, Wu Q. Long-term exposure to low level of fluoride induces apoptosis via p53 pathway in lymphocytes of aluminum smelter workers. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2019; 26:2671-2680. [PMID: 30478774 DOI: 10.1007/s11356-018-3726-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/16/2018] [Accepted: 11/09/2018] [Indexed: 06/09/2023]
Abstract
Long-term occupational exposure to low level of fluoride can induce oxidative stress and apoptosis in many cells, including lymphocyte. However, the underlying mechanism remains unclear. Hence, this study was designed to explore the potential oxidative stress and apoptosis of long-term occupational exposure to low level of fluoride in aluminum smelter workers. A total of 120 aluminum smelter workers were recruited in control, low-, middle-, and high-fluoride exposure groups with 30 workers for each group. The peripheral blood samples were collected, centrifuged, and isolated to obtain serum and lymphocyte suspensions. The air and serum fluoride concentrations were detected by fluoride ion-selective electrode method. The lymphocytic apoptosis rate, DNA damage, oxidative stress, and mRNA levels of p53, Bcl-2, and Bax were assessed by Annexin V/PI staining, comet assay, attenuated total reflectance Fourier transform infrared spectroscopy and real-time polymerase chain reaction, respectively. Results showed that the air and serum fluoride concentrations of fluoride-exposed groups were higher than those of the control group (p < 0.05). Fluoride exposure might induce apoptosis, DNA damage and oxidative stress in a dose-dependent manner in lymphocytes (p < 0.05). The expression levels of p53 and Bax were increased with fluoride exposure in lymphocytes (p < 0.05), whereas the Bcl-2 expression was decreased but not significantly. Taken together, these observations indicate that long-term occupational exposure to low level of fluoride may lead to oxidative stress and induce apoptosis through the p53-dependent pathway in peripheral blood lymphocytes of aluminum smelter workers. Serum fluoride level may be the potential biomarker of fluoride exposure.
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Affiliation(s)
- Pingjing Wen
- Department of Toxicology, School of Public Health, Guangxi Medical University, No. 22 Shuangyong, Nanning, Guangxi, 530021, People's Republic of China
- Department of Toxicology, Guangxi Center for Disease Prevention and Control, Nanning, Guangxi, People's Republic of China
| | - Xiaomin Wei
- Department of Toxicology, School of Public Health, Guangxi Medical University, No. 22 Shuangyong, Nanning, Guangxi, 530021, People's Republic of China
| | - Guiqiang Liang
- Department of Preventive Medicine, School of Public Health and Management, Guangxi University of Chinese Medicine, No. 13 Wuhe Avenue, Nanning, Guangxi, 530200, People's Republic of China
| | - Yanfei Wang
- Primary Care Division, Maternal and Child Health Hospital, Chongqing, People's Republic of China
| | - Yiping Yang
- Department of Toxicology, School of Public Health, Guangxi Medical University, No. 22 Shuangyong, Nanning, Guangxi, 530021, People's Republic of China
| | - Lilin Qin
- Department of Toxicology, School of Public Health, Guangxi Medical University, No. 22 Shuangyong, Nanning, Guangxi, 530021, People's Republic of China
| | - Weiyi Pang
- Department of Occupational and Environmental Health, Guilin Medical University, Guilin, Guangxi, People's Republic of China
| | - Guangqiu Qin
- Department of Preventive Medicine, School of Public Health and Management, Guangxi University of Chinese Medicine, No. 13 Wuhe Avenue, Nanning, Guangxi, 530200, People's Republic of China
| | - Hai Li
- Department of Preventive Medicine, School of Public Health and Management, Guangxi University of Chinese Medicine, No. 13 Wuhe Avenue, Nanning, Guangxi, 530200, People's Republic of China
| | - Yueming Jiang
- Department of Toxicology, School of Public Health, Guangxi Medical University, No. 22 Shuangyong, Nanning, Guangxi, 530021, People's Republic of China.
| | - Qijun Wu
- Department of Preventive Medicine, School of Public Health and Management, Guangxi University of Chinese Medicine, No. 13 Wuhe Avenue, Nanning, Guangxi, 530200, People's Republic of China.
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Abotaleb M, Samuel SM, Varghese E, Varghese S, Kubatka P, Liskova A, Büsselberg D. Flavonoids in Cancer and Apoptosis. Cancers (Basel) 2018; 11:cancers11010028. [PMID: 30597838 PMCID: PMC6357032 DOI: 10.3390/cancers11010028] [Citation(s) in RCA: 389] [Impact Index Per Article: 55.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2018] [Revised: 12/12/2018] [Accepted: 12/13/2018] [Indexed: 12/19/2022] Open
Abstract
Cancer is the second leading cause of death globally. Although, there are many different approaches to cancer treatment, they are often painful due to adverse side effects and are sometimes ineffective due to increasing resistance to classical anti-cancer drugs or radiation therapy. Targeting delayed/inhibited apoptosis is a major approach in cancer treatment and a highly active area of research. Plant derived natural compounds are of major interest due to their high bioavailability, safety, minimal side effects and, most importantly, cost effectiveness. Flavonoids have gained importance as anti-cancer agents and have shown great potential as cytotoxic anti-cancer agents promoting apoptosis in cancer cells. In this review, a summary of flavonoids and their effectiveness in cancer treatment targeting apoptosis has been discussed.
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Affiliation(s)
- Mariam Abotaleb
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha, P.O. Box 24144, Qatar.
| | - Samson Mathews Samuel
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha, P.O. Box 24144, Qatar.
| | - Elizabeth Varghese
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha, P.O. Box 24144, Qatar.
| | - Sharon Varghese
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha, P.O. Box 24144, Qatar.
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia.
| | - Alena Liskova
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia.
| | - Dietrich Büsselberg
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha, P.O. Box 24144, Qatar.
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A novel all-trans retinoic acid derivative inhibits proliferation and induces apoptosis of myelodysplastic syndromes cell line SKM-1 cells via up-regulating p53. Int Immunopharmacol 2018; 65:561-570. [DOI: 10.1016/j.intimp.2018.10.041] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Revised: 10/19/2018] [Accepted: 10/30/2018] [Indexed: 12/31/2022]
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Boothapandi M, Ravichandran R. Antiproliferative activity of chrysin (5, 7-dihydroxyflavone) from Indigofera tinctoria on human epidermoid carcinoma (A431) cells. Eur J Integr Med 2018. [DOI: 10.1016/j.eujim.2018.10.015] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
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38
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Favero G, Moretti E, Bonomini F, Reiter RJ, Rodella LF, Rezzani R. Promising Antineoplastic Actions of Melatonin. Front Pharmacol 2018; 9:1086. [PMID: 30386235 PMCID: PMC6198052 DOI: 10.3389/fphar.2018.01086] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Accepted: 09/06/2018] [Indexed: 12/19/2022] Open
Abstract
Melatonin is an endogenous indoleamine with an incredible variety of properties and activities. In recent years, an increasing number of studies have investigated this indoleamine’s interaction with cancerous cells. In particular, it seems that melatonin not only has the ability to improve the efficacy of many drugs used in chemotherapy but also has a direct inhibitory action on neoplastic cells. Many publications underlined the ability of melatonin to suppress the proliferation of various cancer cells or to modulate the expression of membrane receptors on these cells, thereby reducing tumor aggressiveness to metastasize. In addition, while melatonin has antiapoptotic actions in normal cells, in many cancer cells it has proapoptotic effects; these dichotomous actions have gained the interest of researchers. The increasing focus on melatonin in the field of oncology and the growing number of studies on this topic require a deep understanding of what we already know about the antineoplastic actions of melatonin. This information would be of value for potential use of melatonin against neoplastic diseases.
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Affiliation(s)
- Gaia Favero
- Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Enrico Moretti
- Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Francesca Bonomini
- Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.,Interdipartimental University Center of Research "Adaption and Regeneration of Tissues and Organs," University of Brescia, Brescia, Italy
| | - Russel J Reiter
- Department of Cell Systems and Anatomy, UT Health Science Center, San Antonio, TX, United States
| | - Luigi Fabrizio Rodella
- Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.,Interdipartimental University Center of Research "Adaption and Regeneration of Tissues and Organs," University of Brescia, Brescia, Italy
| | - Rita Rezzani
- Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.,Interdipartimental University Center of Research "Adaption and Regeneration of Tissues and Organs," University of Brescia, Brescia, Italy
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39
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Park W, Park S, Lim W, Song G. Chrysin disrupts intracellular homeostasis through mitochondria-mediated cell death in human choriocarcinoma cells. Biochem Biophys Res Commun 2018; 503:3155-3161. [PMID: 30139515 DOI: 10.1016/j.bbrc.2018.08.109] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Accepted: 08/16/2018] [Indexed: 11/30/2022]
Abstract
The trophoblast cells which form the placenta, have a high potential for invading other tissues. Owing to certain mechanisms, trophoblast cells may lose their ability to control cell proliferation, and develop into pregnancy-related tumors, known as choriocarcinomas. Choriocarcinomas mostly develop from the hydatidiform mole, which is frequently found in pregnant women. Owing to their ability to rapidly metastasize through the hematogenous route, choriocarcinomas are very hard to cure if not detected at the proper time. Although numerous studies are attempting to identify the major pathways in choriocarcinoma cells, the critical pathway responsible for the origin of choriocarcinomas is still unclear. In this study, we identified that chrysin has inhibitory effects on human choriocarcinoma cells. The study demonstrated that chrysin disrupts intracellular homeostasis by altering the mitochondrial membrane potential (MMP), cytosolic Ca2+ levels, production of reactive oxygen species (ROS), and lipid peroxidation, leading to the death of choriocarcinoma cells (JAR and JEG3). Additionally, the effects of chrysin on choriocarcinoma cells were found to be mediated via the regulation of the AKT, ERK1/2, and JNK signaling pathways. Altogether, the anti-cancer effects of chrysin can aid the development of a novel therapeutic strategy against the progression of human choriocarcinomas.
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Affiliation(s)
- Wonhyoung Park
- Institute of Animal Molecular Biotechnology and Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea
| | - Sunwoo Park
- Institute of Animal Molecular Biotechnology and Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea
| | - Whasun Lim
- Department of Biomedical Sciences, Catholic Kwandong University, Gangneung, 25601, Republic of Korea.
| | - Gwonhwa Song
- Institute of Animal Molecular Biotechnology and Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea.
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40
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Anti-Tumorigenic Activity of Chrysin from Oroxylum indicum via Non-Genotoxic p53 Activation through the ATM-Chk2 Pathway. Molecules 2018; 23:molecules23061394. [PMID: 29890668 PMCID: PMC6099937 DOI: 10.3390/molecules23061394] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Revised: 06/06/2018] [Accepted: 06/07/2018] [Indexed: 12/16/2022] Open
Abstract
The p53 tumor suppressor plays critical roles in cell cycle regulation and apoptotic cell death in response to various cellular stresses, thereby preventing cancer development. Therefore, the activation of p53 through small molecules is an attractive therapeutic strategy for the treatment of cancers retaining wild-type p53. We used a library of 700 Myanmar wild plant extracts to identify small molecules that induce p53 transcriptional activity. A cell-based screening method with a p53-responsive luciferase-reporter assay system revealed that an ethanol extract of Oroxylum indicum bark increased p53 transcriptional activity. Chrysin was isolated and identified as the active ingredient in the O. indicum bark extract. A treatment with chrysin increased p53 protein expression and the p53-mediated expression of downstream target genes, and decreased cell viability in MCF7 cells, but not in p53-knockdown MCF7 cells. We also found that chrysin activated the ATM-Chk2 pathway in the absence of DNA damage. Hence, the inactivation of the ATM-Chk2 pathway suppressed p53 activation induced by chrysin. These results suggest the potential of chrysin as an anti-cancer drug through the activation of p53 without DNA damage.
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41
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Sun CY, Zhu Y, Li XF, Wang XQ, Tang LP, Su ZQ, Li CY, Zheng GJ, Feng B. Scutellarin Increases Cisplatin-Induced Apoptosis and Autophagy to Overcome Cisplatin Resistance in Non-small Cell Lung Cancer via ERK/p53 and c-met/AKT Signaling Pathways. Front Pharmacol 2018; 9:92. [PMID: 29487530 PMCID: PMC5816782 DOI: 10.3389/fphar.2018.00092] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Accepted: 01/26/2018] [Indexed: 01/16/2023] Open
Abstract
Cisplatin, as the first-line anti-tumor agent, is widely used for treatment of a variety of malignancies including non-small cell lung cancer (NSCLC). However, the acquired resistance has been a major obstacle for the clinical application. Scutellarin is a active flavone extracted from Erigeron breviscapus Hand-Mazz that has been shown to exhibit anticancer activities on various types of tumors. Here, we reported that scutellarin was capable of sensitizing A549/DDP cells to cisplatin by enhancing apoptosis and autophagy. Mechanistic analyses indicated that cisplatin-induced caspase-3-dependent apoptosis was elevated in the presence of scutellarin through activating extracellular signal-regulated kinases (ERK)-mediated p53 pathway. Furthermore, scutellarin also promoted cisplatin-induced cytotoxic autophagy, downregulated expression of p-AKT and c-met. Deficiency of c-met reduced p-AKT level, and inhibition of p-AKT or c-met improved autophagy in A549/DDP cells. Interestingly, loss of autophagy attenuated the synergism of this combination. In vivo, the co-treatment of cisplatin and scutellarin notably reduced the tumor size when compared with cisplatin treatment alone. Notably, scutellarin significantly reduced the toxicity generated by cisplatin in tumor-bearing mice. This study identifies the unique role of scutellarin in reversing cisplatin resistance through apoptosis and autophagy, and suggests that combined cisplatin and scutellarin might be a novel therapeutic strategy for patients with NSCLC.
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Affiliation(s)
- Chao-Yue Sun
- Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ying Zhu
- Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiao-Feng Li
- Guangzhou Higher Education Mega Center, Clinical Medical College of Acupuncture and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xie-Qi Wang
- Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Li-Peng Tang
- Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zu-Qing Su
- Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Cai-Yun Li
- Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Guang-Juan Zheng
- Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Bing Feng
- Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
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42
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Pharmacotherapeutic potential of phytochemicals: Implications in cancer chemoprevention and future perspectives. Biomed Pharmacother 2018; 97:564-586. [DOI: 10.1016/j.biopha.2017.10.124] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Revised: 10/14/2017] [Accepted: 10/23/2017] [Indexed: 12/17/2022] Open
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43
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Mani R, Natesan V. Chrysin: Sources, beneficial pharmacological activities, and molecular mechanism of action. PHYTOCHEMISTRY 2018; 145:187-196. [PMID: 29161583 DOI: 10.1016/j.phytochem.2017.09.016] [Citation(s) in RCA: 230] [Impact Index Per Article: 32.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Revised: 09/19/2017] [Accepted: 09/21/2017] [Indexed: 05/05/2023]
Abstract
In recent years, public and scientific interest in plant flavonoids has tremendously increased because of their postulated health benefits. This review was mainly focuses on the flavone chrysin (5,7-dihydroxyflavone), which occurs naturally in many plants, honey, and propolis. A number of in vitro and in vivo studies have revealed the therapeutic effects of chrysin against various diseases. In general, chrysin exhibits many biological activities and pharmacological effects, including antioxidant, anti-inflammatory, anticancer, and antiviral activities. Moreover, many studies have reported on the bioavailability of chrysin. Because of its compromised bioavailability and enhanced protein stability, chrysin solid lipid nanoparticle (SLN) synthesis avoids proteolytic degradation and sustained release of drug delivery. To clarify the mechanism of action of chrysin, researchers have investigated the structural binding relationship of chrysin through the docking computation method.
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Affiliation(s)
- Renuka Mani
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar, 608002, India
| | - Vijayakumar Natesan
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar, 608002, India.
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44
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Torres MG, Torres CM, Torres AM, Muñoz SV, Talavera RR, Ruíz-Baltazar ÁDJ, Brostow W. Validation of a method to quantify platinum in cisplatin by inductively-coupled plasma. CHEMISTRY & CHEMICAL TECHNOLOGY 2017. [DOI: 10.23939/chcht11.04.437] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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45
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Sabzichi M, Mohammadian J, Bazzaz R, Pirouzpanah MB, Shaaker M, Hamishehkar H, Chavoshi H, Salehi R, Samadi N. Chrysin loaded nanostructured lipid carriers (NLCs) triggers apoptosis in MCF-7 cancer cells by inhibiting the Nrf2 pathway. Process Biochem 2017. [DOI: 10.1016/j.procbio.2017.05.024] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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46
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Davatgaran-Taghipour Y, Masoomzadeh S, Farzaei MH, Bahramsoltani R, Karimi-Soureh Z, Rahimi R, Abdollahi M. Polyphenol nanoformulations for cancer therapy: experimental evidence and clinical perspective. Int J Nanomedicine 2017; 12:2689-2702. [PMID: 28435252 PMCID: PMC5388197 DOI: 10.2147/ijn.s131973] [Citation(s) in RCA: 170] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Cancer is defined as the abnormal cell growth that can cause life-threatening malignancies with high financial costs for patients as well as the health care system. Natural polyphenols have long been used for the prevention and treatment of several disorders due to their antioxidant, anti-inflammatory, cytotoxic, antineoplastic, and immunomodulatory effects discussed in the literature; thus, these phytochemicals are potentially able to act as chemopreventive and chemotherapeutic agents in different types of cancer. One of the problems regarding the use of polyphenolic compounds is their low bioavailability. Different types of formulations have been designed for the improvement of bioavailability of these compounds, nanonization being one of the most notable approaches among them. This study aimed to review current data on the nanoformulations of natural polyphenols as chemopreventive and chemotherapeutic agents and to discuss their molecular anticancer mechanisms of action. Nanoformulations of natural polyphenols as bioactive agents, including resveratrol, curcumin, quercetin, epigallocatechin-3-gallate, chrysin, baicalein, luteolin, honokiol, silibinin, and coumarin derivatives, in a dose-dependent manner, result in better efficacy for the prevention and treatment of cancer. The impact of nanoformulation methods for these natural agents on tumor cells has gained wider attention due to improvement in targeted therapy and bioavailability, as well as enhancement of stability. Today, several nanoformulations are designed for delivery of polyphenolic compounds, including nanosuspensions, solid lipid nanoparticles, liposomes, gold nanoparticles, and polymeric nanoparticles, which have resulted in better antineoplastic activity, higher intracellular concentration of polyphenols, slow and sustained release of the drugs, and improvement of proapoptotic activity against tumor cells. To conclude, natural polyphenols demonstrate remarkable anticancer potential in pharmacotherapy; however, the obstacles in terms of their bioavailability in and toxicity to normal cells, as well as targeted drug delivery to malignant cells, can be overcome using nanoformulation-based technologies, which optimize the bioefficacy of these natural drugs.
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Affiliation(s)
- Yasamin Davatgaran-Taghipour
- Department of Medical Nanotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
- PhytoPharmacology Interest Group (PPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Salar Masoomzadeh
- Zanjan Pharmaceutical Nanotechnology Research Center, School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Mohammad Hosein Farzaei
- Pharmaceutical Sciences Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Roodabeh Bahramsoltani
- Department of Traditional Pharmacy, School of Traditional Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Zahra Karimi-Soureh
- School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Roja Rahimi
- Department of Traditional Pharmacy, School of Traditional Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Evidence-Based Medicine Group, Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Abdollahi
- Toxicology and Diseases Group, Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran
- Department of Toxicology and Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran
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Hou XF, Xu LP, Song HY, Li S, Wu C, Wang JF. ECRG2 enhances the anti-cancer effects of cisplatin in cisplatin-resistant esophageal cancer cells via upregulation of p53 and downregulation of PCNA. World J Gastroenterol 2017; 23:1796-1803. [PMID: 28348485 PMCID: PMC5352920 DOI: 10.3748/wjg.v23.i10.1796] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Revised: 01/06/2017] [Accepted: 01/18/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To explore the anti-tumor effects of esophageal cancer-related gene 2 (ECRG2) in combination with cisplatin (DDP) in DDP-resistant esophageal cancer cells (EC9706/DDP).
METHODS A drug-resistant cell model was established, with EC9706/DDP cells being treated with ECRG2 and/or DDP. Cell viability was examined by MTT assay. The rate of cell apoptosis was determined by flow cytometry. The mRNA expression levels of proliferating cell nuclear antigen (PCNA), metallothionein (MT), and p53 were determined by RT-PCR and PCNA, while MT and p53 protein expression levels were determined by western blotting.
RESULTS The anti-proliferative effect of ECRG2 in combination with DDP was superior when compared to ECRG2 or DDP alone. The inhibition rate for the combination reached its peak (51.33%) at 96 h. The early apoptotic rates of the control, ECRG2 alone, DDP alone, and ECRG2 plus DDP groups were 5.71% ± 0.27%, 12.68% ± 0.61%, 14.15% ± 0.87%, and 27.96% ± 0.36%, respectively. Although all treatment groups were significantly different from the control group (P < 0.05), the combination treatment of ECRG2 plus DDP performed significantly better when compared to either ECRG2 or DDP alone (P < 0.05). The combination of ECRG2 and DDP significantly upregulated p53 mRNA and protein levels and downregulated PCNA mRNA and protein levels compared to ECRG2 or DDP alone (P < 0.05). However, no changes were seen in the expression of MT mRNA or protein.
CONCLUSION ECRG2 in combination with DDP can inhibit viability and induce apoptosis in esophageal cancer DDP-resistant cells, possibly via upregulation of p53 expression and downregulation of PCNA expression. These findings suggest that the combination of ECRG2 and DDP may be a promising strategy for the clinical treatment of esophageal cancers that are resistant to DDP.
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Kim KM, Lim HK, Shim SH, Jung J. Improved chemotherapeutic efficacy of injectable chrysin encapsulated by copolymer nanoparticles. Int J Nanomedicine 2017; 12:1917-1925. [PMID: 28331315 PMCID: PMC5352247 DOI: 10.2147/ijn.s132043] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Chrysin is a flavone that is found in several plants and in honeycomb and possesses various biological activities. However, its low solubility means it has poor bioavailability, which must be resolved to enable its pharmaceutical applications. In the present study, chrysin was incorporated into methoxy poly(ethylene glycol)-β-polycaprolactone nanoparticles (chrysin-NPs) using the oil-in-water technique in order to overcome problems associated with chrysin. The properties of chrysin-NPs were analyzed, and their anticancer effects were investigated in vitro and in vivo. Chrysin-NPs were 77 nm sized (as determined by dynamic laser light scattering) and showed a monodisperse distribution. The zeta potential of chrysin-NPs was -2.22 mV, and they were spherically shaped by cryo-transmission electron microscopy (cryo-TEM). The loading efficiency of chrysin-NPs was 46.96%. Chrysin-NPs retained the cytotoxicity of chrysin in A549 cells. The therapeutic efficacies of chrysin-NPs were compared with those of chrysin in an A549-derived xenograft mouse model. Chrysin-NPs were intravenously injected at a 10 times lower dosage than chrysin 3 times per week (q2d×3/week). However, free chrysin was orally administrated 5 times per week (q1d×5/week). Chrysin-NP-treated group showed significant tumor growth delay, which was similar to that of chrysin-treated group, despite the considerably lower total dosage. These results suggest that the injectable chrysin-NPs enhance therapeutic efficacy in vivo and offer a beneficial formulation for chemotherapy.
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Affiliation(s)
- Kyoung Mee Kim
- College of Pharmacy
- Innovative Drug Center, Duksung Women’s University, Seoul, Republic of Korea
| | - Hyun Kyung Lim
- College of Pharmacy
- Innovative Drug Center, Duksung Women’s University, Seoul, Republic of Korea
| | - Sang Hee Shim
- College of Pharmacy
- Innovative Drug Center, Duksung Women’s University, Seoul, Republic of Korea
| | - Joohee Jung
- College of Pharmacy
- Innovative Drug Center, Duksung Women’s University, Seoul, Republic of Korea
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Liu H, Chen F, Zhang L, Zhou Q, Gui S, Wang Y. A novel all-trans retinoic acid derivative 4-amino‑2‑trifluoromethyl-phenyl retinate inhibits the proliferation of human hepatocellular carcinoma HepG2 cells by inducing G0/G1 cell cycle arrest and apoptosis via upregulation of p53 and ASPP1 and downregulation of iASPP. Oncol Rep 2016; 36:333-41. [PMID: 27177208 DOI: 10.3892/or.2016.4795] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2015] [Accepted: 01/21/2016] [Indexed: 11/06/2022] Open
Abstract
4-Amino-2-trifluoromethyl-phenyl retinate (ATPR), a novel all-trans retinoic acid (ATRA) derivative, was reported to function as a tumor inhibitor in various types of cancer cells in vitro. However, little is known concerning its antitumor effect on human hepatocellular carcinoma (HCC) HepG2 cells. The aims of the present study were to investigate the effects of ATPR on the proliferation of HepG2 cells and to explore the probable mechanisms. A series of experiments were performed following the treatment of HepG2 cells with ATRA and ATPR. MTT and plate colony formation assays were used to measure the cell viability. To confirm the influence on proliferation, flow cytometry was used to detect the distribution of the cell cycle. Apoptosis was observed by Hoechst staining and flow cytometry. In addition, to characterize the underlying molecular mechanisms, immunofluorescence was applied to observe the distribution of p53. The transcription and translation levels of p53 were analyzed by real-time quantitative RT-PCR (qRT-PCR) and western blotting. The expression levels of murine double minute 2 (MDM2), apoptosis stimulating proteins of p53 (ASPP), cell cycle- and apoptosis-associated proteins were detected by western blotting. After HepG2 cells were incubated with ATRA and ATPR, the viability of the HepG2 cells was inhibited in a dose- and time-dependent manner. As well, ATPR significantly suppressed HepG2 cell colony formation and arrested cells at the G0/G1 phase, while ATRA had no obvious effects. Both Hoechst staining and flow cytometry unveiled the apoptosis of HepG2 cells. Moreover, the fluorescent density of p53 was higher in the nuclei after exposure to ATPR than that in the ATRA group. HepG2 cells treated with ATPR showed elevated mRNA and protein levels of p53 when compared with these levels in the ATRA-treated cells. Western blotting showed that ATPR increased ASPP1, p21 and Bax expression and decreased MDM2, iASPP, cyclin D and E, cyclin-dependent kinase 6 (CDK6) and Bcl-2 expression, while CDK4 and ASPP2 expression were scarcely altered. Consequently, ATPR exerted a better inhibitory effect on the proliferation of HepG2 cells than ATRA through increased expression of p53 and ASPP1 and downregulation of iASPP, thereby resulting in G0/G1 cell cycle arrest and apoptosis.
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Affiliation(s)
- Hui Liu
- Laboratory of Molecular Biology and Department of Biochemistry, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Feihu Chen
- College of Pharmacy, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Ling Zhang
- Laboratory of Molecular Biology and Department of Biochemistry, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Qing Zhou
- Laboratory of Molecular Biology and Department of Biochemistry, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Shuyu Gui
- Key Laboratory of Gene Research of Anhui Province, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Yuan Wang
- Laboratory of Molecular Biology and Department of Biochemistry, Anhui Medical University, Hefei, Anhui 230032, P.R. China
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Lim HK, Kim KM, Jeong SY, Choi EK, Jung J. Chrysin Increases the Therapeutic Efficacy of Docetaxel and Mitigates Docetaxel-Induced Edema. Integr Cancer Ther 2016; 16:496-504. [PMID: 27151585 PMCID: PMC5739130 DOI: 10.1177/1534735416645184] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
Docetaxel (DTX) is an effective commercial anticancer agent for chemotherapy in non-small cell lung cancer (NSCLC), breast cancer, gastric cancer, and prostate cancer, but its adverse effects including edema, neurotoxicity, and hair loss limit its application. To improve the chemotherapeutic efficacy of DTX and reduce adverse effects, combination therapy is one of the alternative methods. So chrysin, which has various biological activities including anticancer effects, was considered. In vitro, the combination of chrysin and DTX was investigated in A549 cells. Increased cytotoxicity, suppressed cellular proliferation, and induced apoptosis were observed with posttreatment of chrysin following DTX treatment. In vivo, chrysin enhanced the tumor growth delay of DTX and increased DTX-induced apoptosis in the A549-derived xenograft model. Furthermore, chrysin prevented DTX-induced edema in ICR mouse. These results indicated that chrysin strengthened the therapeutic efficacy of DTX and diminished the adverse effect of DTX, suggesting chrysin could be exploited as an adjuvant therapy for NSCLC.
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Affiliation(s)
- Hyun-Kyung Lim
- 1 Innovative Drug Center, Duksung Women's University, Seoul, Korea
| | - Kyoung Mee Kim
- 1 Innovative Drug Center, Duksung Women's University, Seoul, Korea.,2 Duksung Women's University, Seoul, Korea
| | - Seong-Yun Jeong
- 3 ASAN Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Eun Kyung Choi
- 3 ASAN Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Joohee Jung
- 1 Innovative Drug Center, Duksung Women's University, Seoul, Korea.,2 Duksung Women's University, Seoul, Korea
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