|
1
|
Gao Z, Yang Y, Huang N, Zhao W. Updated progression of honokiol in lung cancer treatment. J Pharm Pharmacol 2025:rgaf007. [PMID: 40184222 DOI: 10.1093/jpp/rgaf007] [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: 03/20/2024] [Accepted: 02/10/2025] [Indexed: 04/06/2025]
Abstract
OBJECTIVES Despite significant advancements in innovative therapy, lung cancer continues to have an unexpectedly low 5-year survival rate. This necessitates the urgent development of novel and effective therapies. One such potential therapy is Honokiol (HNK, C18H18O2), a biphenolic natural compound isolated from the leaves and bark of Magnolia plant species. The objective of this review is to examine the various studies supporting the anti-lung cancer effects of HNK and its potential use in the treatment of lung cancer. KEY FINDINGS Emerging research has shown that HNK possesses a range of pharmacological characteristics that make it a promising agent in the fight against lung cancer. Specifically, HNK has been found to regulate various molecular targets, including the activation of pro-apoptotic factors and the suppression of anti-apoptotic proteins and different transcription factors. It also downregulates various enzymes, chemokines, cell surface adhesion molecules, and cell cycle proteins. Additionally, HNK inhibits the activity of protein tyrosine kinases and serine/threonine kinases. These effects contribute to its ability to efficiently prevent the progression of lung cancer, either solely or in combination with other therapeutic strategies. Furthermore, several nanotechnologies have been employed to modify HNK for the treatment of lung cancer, enhancing its potential efficacy. SUMMARY In summary, Honokiol (HNK) is a biphenolic natural compound with significant anti-lung cancer properties. Its pharmacological characteristics, including the regulation of various molecular targets and the inhibition of key enzymes and kinases, make it a promising agent for the treatment of lung cancer. Emerging research supports its ability to prevent the progression of lung cancer, either alone or in combination with other therapies. Additionally, nanotechnologies have been used to modify HNK, potentially enhancing its efficacy in the treatment of lung cancer. This review highlights the various studies documenting the anti-lung cancer effects of HNK, underscoring its potential as a novel and effective therapy for this deadly disease.
Collapse
Affiliation(s)
- Ziwei Gao
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan 610500, China
- Key Laboratory of Geriatic Respiratory Diseases of Sichuan Higher Education Institutes, Chengdu, Sichuan 610500, China
| | - Yuping Yang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan 610500, China
- Key Laboratory of Geriatic Respiratory Diseases of Sichuan Higher Education Institutes, Chengdu, Sichuan 610500, China
| | - Na Huang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan 610500, China
- Key Laboratory of Geriatic Respiratory Diseases of Sichuan Higher Education Institutes, Chengdu, Sichuan 610500, China
| | - Wei Zhao
- School of Clinical Medicine, The First Affiliated Hospital, Chengdu Medical College, Chengdu, Sichuan 610500, China
- School of Laboratory Medicine, Chengdu Medical College, Chengdu, Sichuan 610500, China
| |
Collapse
|
|
2
|
Cheng Y, Han X, Lai X, Wei X. Liposomal honokiol inhibits non-small cell lung cancer progression and enhances PD-1 blockade via suppressing M2 macrophages polarization. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 135:156093. [PMID: 39531934 DOI: 10.1016/j.phymed.2024.156093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 08/31/2024] [Accepted: 09/23/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND Honokiol (HNK), a natural phenolic compound derived from Magnolia plants, exhibits therapeutic effects on various diseases, including cancer. The advent of immune checkpoint inhibitors (ICIs) has marked a breakthrough in non-small cell lung cancer (NSCLC) treatment. However, a significant subset of patients exhibits primary or acquired resistance to anti-PD-1/PD-L1 therapies, necessitating the development of novel combination strategies to enhance therapeutic efficacy and overcome resistance. PURPOSE This study aimed to explore the anti-tumor efficacy of liposomal honokiol (Lipo-HNK) and elucidate the synergistic effects of Lipo-HNK and ICIs on NSCLC. METHODS The effects of Lipo-HNK on cell proliferation and apoptosis were assessed in human lung cancer cell lines H460 and A549, and mouse Lewis lung cancer cell line (LL2). A murine lung cancer model was established by injecting LL2 cells via the tail vein to evaluate the therapeutic effects of Lipo-HNK and ICIs. Tumor microenvironment features were characterized using immunofluorescence and flow cytometry. Primary macrophages were extracted from mouse bone marrow for mechanistic studies. High-throughput sequencing and bioinformatics analyses of Lipo-HNK-treated macrophages were conducted to identify key signaling pathways, which were subsequently confirmed by Western blotting and inhibitor blockade. RESULTS Lipo-HNK, with enhanced solubility and bioavailability, demonstrated potent cytotoxicity against NSCLC cell lines. In the murine lung cancer model, Lipo-HNK exhibited synergistic anti-cancer effects when combined with anti-PD-1 therapy. Immunofluorescence and flow cytometry analyses revealed that Lipo-HNK significantly reduced the infiltration of myeloid-derived suppressor cells (MDSCs) and M2 macrophages (CD206+). Macrophage depletion experiment showed the anti-tumor effects of Lipo-HNK was macrophage-dependent. M2 macrophages induced by tumor-conditioned medium (TCM) or interleukin-4 (IL-4) released immunosuppressive cytokines such as IL-10, Arg-1, and TGF-β. RNA sequencing analyses showed that Lipo-HNK effectively inhibited the PI3K/Akt signaling pathway, blocking macrophage polarization to the M2 type. Furthermore, the combination of Lipo-HNK and anti-PD-1 therapy led to increased CD8+ T-cell infiltration and activation, enhancing the overall anti-tumor immune response. CONCLUSION This study validated the anti-tumor efficacy of Lipo-HNK against NSCLC. Lipo-HNK reduced the infiltration of MDSCs and M2 macrophages by inhibiting the PI3K/Akt pathway and enhanced the therapeutic effects of ICIs. These findings provide evidence and new insights into Lipo-HNK as a promising anti-cancer drug for NSCLC treatment, highlighting its potential to overcome resistance to current ICI therapies.
Collapse
Affiliation(s)
- Yuan Cheng
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, Department of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, People's Republic of China
| | - Xuejiao Han
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, Department of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, People's Republic of China
| | - Xintian Lai
- Chengdu Jinrui Foundation Biotech Co., Ltd, Yizhou Avenue, High Tech Zone, Chengdu 610041, Sichuan, People's Republic of China
| | - Xiawei Wei
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, Department of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, People's Republic of China.
| |
Collapse
|
|
3
|
Dominiak K, Gostyńska A, Szulc M, Stawny M. The Anticancer Application of Delivery Systems for Honokiol and Magnolol. Cancers (Basel) 2024; 16:2257. [PMID: 38927963 PMCID: PMC11201421 DOI: 10.3390/cancers16122257] [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: 05/14/2024] [Revised: 06/13/2024] [Accepted: 06/14/2024] [Indexed: 06/28/2024] Open
Abstract
Cancer is a leading cause of death worldwide, and the effectiveness of treatment is consistently not at a satisfactory level. This review thoroughly examines the present knowledge and perspectives of honokiol (HON) in cancer therapeutics. The paper synthesizes critical insights into the molecular mechanisms underlying the observed anticancer effects, emphasizing both in vitro and in vivo studies. The effects of HON application, primarily in the common types of cancers, are presented. Because the therapeutic potential of HON may be limited by its physicochemical properties, appropriate delivery systems are sought to overcome this problem. This review discusses the effect of different nanotechnology-based delivery systems on the efficiency of HON. The data presented show that HON exhibits anticancer effects and can be successfully administered to the site of action. Honokiol exerts its anticancer activity through several mechanisms. Moreover, some authors used the combinations of classical anticancer drugs with HON. Such an approach is very interesting and worth further investigation. Understanding HON's multiple molecular mechanisms would provide valuable insights into how HON might be developed as an effective therapeutic. Therefore, further research is needed to explore its specific applications and optimize its efficacy in diverse cancer types.
Collapse
Affiliation(s)
- Katarzyna Dominiak
- Department of Pharmaceutical Chemistry, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznań, Poland;
| | - Aleksandra Gostyńska
- Department of Pharmaceutical Chemistry, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznań, Poland;
| | - Michał Szulc
- Department of Pharmacology, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznań, Poland;
| | - Maciej Stawny
- Department of Pharmaceutical Chemistry, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznań, Poland;
| |
Collapse
|
|
4
|
Pan C, Li Q, Xiong S, Yang Y, Yang Y, Huang C, Wang ZP. Delivery Strategies, Structural Modification, and Pharmacological Mechanisms of Honokiol: A Comprehensive Review. Chem Biodivers 2024; 21:e202302032. [PMID: 38308434 DOI: 10.1002/cbdv.202302032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 02/01/2024] [Accepted: 02/02/2024] [Indexed: 02/04/2024]
Abstract
Honokiol (HK) is a traditional Chinese herbal bioactive compound that originates mainly from the Magnolia species, traditionally used to treat anxiety and stroke, as well as alleviation of flu symptoms. This natural product and its derivatives displayed diverse biological activities, including anticancer, antioxidant, anti-inflammatory, neuroprotective, and antimicrobial activities. However, its poor bioavailability and pharmacological activity require primary consideration in the development of HK-based drugs. Recent innovative HK formulations based on the nanotechnology approach allowed for improvement in both bioavailability and therapeutic efficacy. Chemical derivation and drug combination are also effective strategies to ameliorate the drawbacks of HK. In recent years, studies on HK derivatives and compositions have made great progress in the treatment of cancer, inflammation, bacterial infection, cardiovascular, and cerebrovascular diseases, demonstrating better activity than HK. The objective of this review is an examination of the recent developments in the field of pharmacological activity of HK and its drug-related issues, and approaches to improve its physicochemical and biological properties, including solubility, stability, and bioavailability. Recent patents and the ongoing clinical trials in HK are also summarized.
Collapse
Affiliation(s)
- Congying Pan
- Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, No. 55 Daxuecheng South Road, Shapingba, Chongqing, 401331, P. R. China
| | - Qing Li
- Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, No. 55 Daxuecheng South Road, Shapingba, Chongqing, 401331, P. R. China
| | - Shuxin Xiong
- Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, No. 55 Daxuecheng South Road, Shapingba, Chongqing, 401331, P. R. China
| | - Yan Yang
- Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, No. 55 Daxuecheng South Road, Shapingba, Chongqing, 401331, P. R. China
| | - Yi Yang
- Chongqing Energy College, No. 2 Fuxing Avenue, Shuangfu New District, Jiangjin District, Chongqing, 402260, P. R. China
| | - Chao Huang
- Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, No. 55 Daxuecheng South Road, Shapingba, Chongqing, 401331, P. R. China
| | - Zhi-Peng Wang
- College of Pharmacy, Chongqing Medical University, Yixueyuan Road, Yuzhong District, Chongqing, 400016, P. R. China
| |
Collapse
|
|
5
|
Fei Y, Zhang X, Wang X, Sun Y, He J, Liu X, Song Z, Li L, Qiu L, Qian Z, Zhou S, Liu X, Zhang H, Wang X. Upregulation of tumor suppressor PIAS3 by Honokiol promotes tumor cell apoptosis via selective inhibition of STAT3 tyrosine 705 phosphorylation. J Nat Med 2024; 78:285-295. [PMID: 38082192 DOI: 10.1007/s11418-023-01757-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 10/15/2023] [Indexed: 02/29/2024]
Abstract
The natural product Honokiol exhibits robust antitumor activity against a range of cancers, and it has also received approval to undergo phase I clinical trial testing. We confrmed that honokiol can promote the apoptotic death of tumor cells through cell experiments. Then siRNA constructs specific for PIAS3, PIAS3 overexpression plasmid and the mutation of the STAT3 Tyr705 residue were used to confirm the mechanism of Honokiol-induced apoptosis. Finally, we confrmed that honokiol can promote PIAS3 upregulation, in turn suppressing STAT3 Tyr705 phosphorylation through the in vivo and in vitro experiments. Honokiol was ultimately found to reduce tumor cell viability by promoting apoptosis through a mechanism dependent on the ability of Honokiol to promote PIAS3 upregulation and the selective inhibition of p-STAT3 (Tyr705) without affecting p-STAT3 (Ser727) or p-STAT1 (Tyr701) levels. PIAS3 knockdown and overexpression in tumor cells altered STAT3 activation and associated DNA binding activity through the control of Tyr705 phosphorylation via PIAS3-STAT3 complex formation, ultimately shaping Honokiol-induced tumor cell apoptosis. Honokiol was also confirmed to significantly prolong the survival of mice bearing xenograft tumors in a PIAS3-dependent fashion. Together, these findings highlight a novel pathway through which Honokiol can promote PIAS3 upregulation, in turn suppressing STAT3 Tyr705 phosphorylation and promoting the apoptotic death of tumor cells.
Collapse
Affiliation(s)
- Yue Fei
- Department of Lymphoma, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, China
| | - Xiaoyan Zhang
- State Key Laboratory of Experimental Hematology and Division of Pediatric Blood Diseases Center, Institute of Hematology and Blood Diseases Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Tianjin, 300060, China
| | - Xiaohui Wang
- Department of Lymphoma, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, China
| | - Yifei Sun
- Department of Lymphoma, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, China
| | - Jin He
- Department of Lymphoma, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, China
| | - Xia Liu
- Department of Lymphoma, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, China
| | - Zheng Song
- Department of Lymphoma, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, China
| | - Lanfang Li
- Department of Lymphoma, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, China
| | - Lihua Qiu
- Department of Lymphoma, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, China
| | - Zhengzi Qian
- Department of Lymphoma, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, China
| | - Shiyong Zhou
- Department of Lymphoma, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, China
| | - Xianming Liu
- Department of Lymphoma, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, China
| | - Huilai Zhang
- Department of Lymphoma, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, China.
| | - Xianhuo Wang
- Department of Lymphoma, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, China.
| |
Collapse
|
|
6
|
Lin FH, Hsu YC, Chang KC, Shyong YJ. Porous hydroxyapatite carrier enables localized and sustained delivery of honokiol for glioma treatment. Eur J Pharm Biopharm 2023:S0939-6411(23)00169-8. [PMID: 37391090 DOI: 10.1016/j.ejpb.2023.06.016] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 06/13/2023] [Accepted: 06/27/2023] [Indexed: 07/02/2023]
Abstract
The objective of this study is to develop hydroxyapatite (HAp) particles for targeted delivery of honokiol to tumor sites after glioma surgical management. Honokiol is released from the HAp-honokiol particles inside cancer cells through endocytosis and subsequent acid lysosomal dissolution. HAp is synthesized using a co-precipitation method, and egg white is added to create porous structures. The HAp is then surface-modified with stearic acid to enhance its hydrophobicity and loaded with honokiol to form HAp-honokiol particles. The synthesized particles are of appropriate size and characteristics for cancer cell uptake. Honokiol remains attached on to the HAp particles in neutral environments due to its hydrophobic nature, but undergoes rapid burst release in acidic environments such as lysosomes. The HAp-honokiol treatment shows a delayed effect on cell viability and cytotoxicity, indicating sustained drug release without compromising drug efficacy. Flow cytometry analysis demonstrates the apoptosis pathway induced by HAp-honokiol in ALTS1C1 glioma cells. In an in vivo study using a mouse glioma model, MRI results showed a 40% reduction in tumor size after HAp-honokiol treatment. These findings suggest that HAp-honokiol particles have potential as an effective drug delivery system for the treatment of glioma.
Collapse
Affiliation(s)
- Feng-Huei Lin
- Institute of Biomedical Engineering, National Taiwan University, Taipei, Taiwan
| | - Yu-Chen Hsu
- Institute of Biomedical Engineering, National Taiwan University, Taipei, Taiwan
| | - Kuo-Chi Chang
- Department of Chemical Engineering and Biotechnology, National Taipei University of Technology, Taipei, Taiwan
| | - Yan-Jye Shyong
- School of Pharmacy and Institute of Clinical Pharmacy and Pharmaceutical Sciences, National Cheng Kung University, Tainan City, Taiwan.
| |
Collapse
|
|
7
|
Lu SY, Wang HM, Feng N, Ma AJ. Total synthesis of bi-magnolignan. RSC Adv 2023; 13:8844-8846. [PMID: 36936845 PMCID: PMC10018648 DOI: 10.1039/d3ra01121f] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Accepted: 03/09/2023] [Indexed: 03/18/2023] Open
Abstract
Bi-magnolignan, isolated from the leaves of Magnolia officinalis, has shown excellent physiological activity against tumor cells. An efficient strategy for the first total synthesis of bi-magnolignan is reported. The bi-dibenzofuran skeleton was constructed via functional group interconversions of commercially available materials 1,2,4-trimethoxybenzene and 4-allylanisole. Then, the dibenzofuran skeleton was afforded by subsequent Suzuki coupling and intramolecular dehydration. The total synthesis of natural product was accomplished through FeCl3 catalyzed oxidative coupling.
Collapse
Affiliation(s)
- Si-Yuan Lu
- School of Biotechnology and Health Sciences, Wuyi University Jiangmen Guangdong 529020 People's Republic of China
| | - Hong-Mei Wang
- School of Biotechnology and Health Sciences, Wuyi University Jiangmen Guangdong 529020 People's Republic of China
| | - Na Feng
- School of Biotechnology and Health Sciences, Wuyi University Jiangmen Guangdong 529020 People's Republic of China
| | - Ai-Jun Ma
- School of Biotechnology and Health Sciences, Wuyi University Jiangmen Guangdong 529020 People's Republic of China
| |
Collapse
|
|
8
|
Das SS, Tambe S, Prasad Verma PR, Amin P, Singh N, Singh SK, Gupta PK. Molecular insights and therapeutic implications of nanoengineered dietary polyphenols for targeting lung carcinoma: part I. Nanomedicine (Lond) 2022; 17:1779-1798. [PMID: 36636930 DOI: 10.2217/nnm-2022-0133] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Lung cancer is the second leading cause of cancer-related mortality globally, and non-small-cell lung cancer accounts for most lung cancer cases. Nanotechnology-based drug-delivery systems have exhibited immense potential in lung cancer therapy due to their fascinating physicochemical characteristics, in vivo stability, bioavailability, prolonged and targeted delivery, gastrointestinal absorption and therapeutic efficiency of their numerous chemotherapeutic agents. However, traditional chemotherapeutics have systemic toxicity issues; therefore, dietary polyphenols might potentially replace them in lung cancer treatment. Polyphenol-based targeted nanotherapeutics have demonstrated interaction with a multitude of protein targets and cellular signaling pathways that affect major cellular processes. This review summarizes the various molecular mechanisms and targeted therapeutic potentials of nanoengineered dietary polyphenols in the effective management of lung cancer.
Collapse
Affiliation(s)
- Sabya Sachi Das
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, 835215, India.,School of Pharmaceutical and Population Health Informatics, DIT University, Dehradun, Uttarakhand, 248009, India
| | - Srushti Tambe
- Department of Pharmaceutical Science and Technology, Institute of Chemical Technology, Mumbai, Maharashtra, 400019, India
| | - Priya Ranjan Prasad Verma
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, 835215, India
| | - Purnima Amin
- Department of Pharmaceutical Science and Technology, Institute of Chemical Technology, Mumbai, Maharashtra, 400019, India
| | - Neeru Singh
- Department of Biomedical Laboratory Technology, University Polytechnic, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, 835215, India
| | - Sandeep Kumar Singh
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, 835215, India
| | - Piyush Kumar Gupta
- Department of Life Sciences, School of Basic Sciences and Research, Sharda University, Greater Noida, Uttar Pradesh, 201310, India.,Department of Biotechnology, Graphic Era Deemed to be University, Dehradun, Uttarakhand, 248002, India.,Faculty of Health and Life Sciences, INTI International University, Nilai 71800, Malaysia
| |
Collapse
|
|
9
|
Cheng X, Yan H, Pang S, Ya M, Qiu F, Qin P, Zeng C, Lu Y. Liposomes as Multifunctional Nano-Carriers for Medicinal Natural Products. Front Chem 2022; 10:963004. [PMID: 36003616 PMCID: PMC9393238 DOI: 10.3389/fchem.2022.963004] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 06/24/2022] [Indexed: 12/12/2022] Open
Abstract
Although medicinal natural products and their derivatives have shown promising effects in disease therapies, they usually suffer the drawbacks in low solubility and stability in the physiological environment, low delivery efficiency, side effects due to multi-targeting, and low site-specific distribution in the lesion. In this review, targeted delivery was well-guided by liposomal formulation in the aspects of preparation of functional liposomes, liposomal medicinal natural products, combined therapies, and image-guided therapy. This review is believed to provide useful guidance to enhance the targeted therapy of medicinal natural products and their derivatives.
Collapse
Affiliation(s)
- Xiamin Cheng
- Institute of Advanced Synthesis, School of Chemistry and Molecular Engineering, Jiangsu National Synergetic Innovation Center for Advanced Materials, Nanjing Tech University (Nanjing Tech), Nanjing, China
- *Correspondence: Xiamin Cheng, ; Chao Zeng, ; Yongna Lu,
| | - Hui Yan
- Institute of Advanced Synthesis, School of Chemistry and Molecular Engineering, Jiangsu National Synergetic Innovation Center for Advanced Materials, Nanjing Tech University (Nanjing Tech), Nanjing, China
| | - Songhao Pang
- Institute of Advanced Synthesis, School of Chemistry and Molecular Engineering, Jiangsu National Synergetic Innovation Center for Advanced Materials, Nanjing Tech University (Nanjing Tech), Nanjing, China
| | - Mingjun Ya
- Institute of Advanced Synthesis, School of Chemistry and Molecular Engineering, Jiangsu National Synergetic Innovation Center for Advanced Materials, Nanjing Tech University (Nanjing Tech), Nanjing, China
| | - Feng Qiu
- Institute of Advanced Synthesis, School of Chemistry and Molecular Engineering, Jiangsu National Synergetic Innovation Center for Advanced Materials, Nanjing Tech University (Nanjing Tech), Nanjing, China
| | - Pinzhu Qin
- School of Environment and Ecology, Jiangsu Open University, Nanjing, China
| | - Chao Zeng
- The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
- *Correspondence: Xiamin Cheng, ; Chao Zeng, ; Yongna Lu,
| | - Yongna Lu
- Institute of Advanced Synthesis, School of Chemistry and Molecular Engineering, Jiangsu National Synergetic Innovation Center for Advanced Materials, Nanjing Tech University (Nanjing Tech), Nanjing, China
- *Correspondence: Xiamin Cheng, ; Chao Zeng, ; Yongna Lu,
| |
Collapse
|
|
10
|
Xu T, Meng JR, Cheng W, Liu JZ, Chu J, Zhang Q, Ma N, Bai LP, Guo Y. Discovery of honokiol thioethers containing 1,3,4-oxadiazole moieties as potential α-glucosidase and SARS-CoV-2 entry inhibitors. Bioorg Med Chem 2022; 67:116838. [PMID: 35617790 PMCID: PMC9123836 DOI: 10.1016/j.bmc.2022.116838] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 05/15/2022] [Accepted: 05/16/2022] [Indexed: 11/26/2022]
Abstract
Honokiol, isolated from a traditional Chinese medicine (TCM) Magnolia officinalis, is a biphenolic compound with several biological activities. To improve and broaden its biological activity, herein, two series of honokiol thioethers bearing 1,3,4-oxadiazole moieties were prepared and assessed for their α-glucosidase and SARS-CoV-2 entry inhibitory activities. Among all the honokiol thioethers, compound 7l exhibited the strongest α-glucosidase inhibitory effect with an IC50 value of 18.9 ± 2.3 µM, which was superior to the reference drug acarbose (IC50 = 24.4 ± 0.3 µM). Some interesting results of structure–activity relationships (SARs) have also been discussed. Enzyme kinetic study demonstrated that 7l was a noncompetitive α-glucosidase inhibitor, which was further supported by the results of molecular docking. Moreover, honokiol thioethers 7e, 9a, 9e, and 9r exhibited potent antiviral activity against SARS-CoV-2 pseudovirus entering into HEK-293 T-ACE2h. Especially 9a displayed the strongest inhibitory activity against SARS-CoV-2 pseudovirus entry with an IC50 value of 16.96 ± 2.45 μM, which was lower than the positive control Evans blue (21.98 ± 1.98 μM). Biolayer interferometry (BLI) binding and docking studies suggested that 9a and 9r may effectively block the binding of SARS-CoV-2 to the host ACE2 receptor through dual recognition of SARS-CoV-2 spike RBD and human ACE2. Additionally, the potent honokiol thioethers 7l, 9a, and 9r displayed relatively no cytotoxicity to normal cells (LO2). These findings will provide a theoretical basis for the discovery of honokiol derivatives as potential both α-glucosidase and SARS-CoV-2 entry inhibitors.
Collapse
Affiliation(s)
- Ting Xu
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, Henan Province, PR China; State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Guangdong-Hong Kong-Macao Joint Laboratory of Respiratory Infectious Disease, Macau University of Science and Technology, Taipa, Macau
| | - Jie-Ru Meng
- State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Guangdong-Hong Kong-Macao Joint Laboratory of Respiratory Infectious Disease, Macau University of Science and Technology, Taipa, Macau
| | - Wanqing Cheng
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, Henan Province, PR China
| | - Jia-Zheng Liu
- State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Guangdong-Hong Kong-Macao Joint Laboratory of Respiratory Infectious Disease, Macau University of Science and Technology, Taipa, Macau
| | - Junyan Chu
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, Henan Province, PR China
| | - Qian Zhang
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, Henan Province, PR China
| | - Nannan Ma
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, Henan Province, PR China
| | - Li-Ping Bai
- State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Guangdong-Hong Kong-Macao Joint Laboratory of Respiratory Infectious Disease, Macau University of Science and Technology, Taipa, Macau.
| | - Yong Guo
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, Henan Province, PR China.
| |
Collapse
|
|
11
|
Ansari MJ, Bokov D, Markov A, Jalil AT, Shalaby MN, Suksatan W, Chupradit S, AL-Ghamdi HS, Shomali N, Zamani A, Mohammadi A, Dadashpour M. Cancer combination therapies by angiogenesis inhibitors; a comprehensive review. Cell Commun Signal 2022; 20:49. [PMID: 35392964 PMCID: PMC8991477 DOI: 10.1186/s12964-022-00838-y] [Citation(s) in RCA: 109] [Impact Index Per Article: 36.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 02/03/2022] [Indexed: 02/06/2023] Open
Abstract
Abnormal vasculature is one of the most conspicuous traits of tumor tissue, largely contributing to tumor immune evasion. The deregulation mainly arises from the potentiated pro-angiogenic factors secretion and can also target immune cells' biological events, such as migration and activation. Owing to this fact, angiogenesis blockade therapy was established to fight cancer by eliminating the nutrient and oxygen supply to the malignant cells by impairing the vascular network. Given the dominant role of vascular-endothelium growth factor (VEGF) in the angiogenesis process, the well-known anti-angiogenic agents mainly depend on the targeting of its actions. However, cancer cells mainly show resistance to anti-angiogenic agents by several mechanisms, and also potentiated local invasiveness and also distant metastasis have been observed following their administration. Herein, we will focus on clinical developments of angiogenesis blockade therapy, more particular, in combination with other conventional treatments, such as immunotherapy, chemoradiotherapy, targeted therapy, and also cancer vaccines. Video abstract.
Collapse
Affiliation(s)
- Mohammad Javed Ansari
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, Kingdom of Saudi Arabia
| | - Dmitry Bokov
- Institute of Pharmacy, Sechenov First Moscow State Medical University, 8 Trubetskaya St., bldg. 2, Moscow, 119991 Russian Federation
- Laboratory of Food Chemistry, Federal Research Center of Nutrition, Biotechnology and Food Safety, 2/14 Ustyinsky pr., Moscow, 109240 Russian Federation
| | - Alexander Markov
- Tyumen State Medical University, Tyumen, Russian Federation
- Industrial University, Tyumen, Russian Federation
| | - Abduladheem Turki Jalil
- Faculty of Biology and Ecology, Yanka Kupala State University of Grodno, 230023 Grodno, Belarus
- College of Technical Engineering, The Islamic University, Najaf, Iraq
- Department of Dentistry, Kut University College, Kut, Wasit 52001 Iraq
| | - Mohammed Nader Shalaby
- Biological Sciences and Sports Health Department, Faculty of Physical Education, Suez Canal University, Ismailia, Egypt
| | - Wanich Suksatan
- Faculty of Nursing, HRH Princess Chulabhorn College of Medical Science, Chulabhorn Royal Academy, Bangkok, Thailand
| | - Supat Chupradit
- Department of Occupational Therapy, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, 50200 Thailand
| | - Hasan S. AL-Ghamdi
- Internal Medicine Department, Division of Dermatology, Albaha University, Al Bahah, Kingdom of Saudi Arabia
| | - Navid Shomali
- Immunology Research Center (IRC), Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Zamani
- Shiraz Transplant Center, Abu Ali Sina Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ali Mohammadi
- Department of Neurology, Imam Khomeini Hospital, Urmia University of Medical Sciences, Urmia, Iran
| | - Mehdi Dadashpour
- Department of Medical Biotechnology, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| |
Collapse
|
|
12
|
Claisened Hexafluoro Inhibits Metastatic Spreading of Amoeboid Melanoma Cells. Cancers (Basel) 2021; 13:cancers13143551. [PMID: 34298765 PMCID: PMC8305480 DOI: 10.3390/cancers13143551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Revised: 06/30/2021] [Accepted: 07/13/2021] [Indexed: 11/17/2022] Open
Abstract
Metastatic melanoma is characterized by poor prognosis and a low free-survival rate. Thanks to their high plasticity, melanoma cells are able to migrate exploiting different cell motility strategies, such as the rounded/amoeboid-type motility and the elongated/mesenchymal-type motility. In particular, the amoeboid motility strongly contributes to the dissemination of highly invasive melanoma cells and no treatment targeting this process is currently available for clinical application. Here, we tested Claisened Hexafluoro as a novel inhibitor of the amoeboid motility. Reported data demonstrate that Claisened Hexafluoro specifically inhibits melanoma cells moving through amoeboid motility by deregulating mitochondrial activity and activating the AMPK signaling. Moreover, Claisened Hexafluoro is able to interfere with the adhesion abilities and the stemness features of melanoma cells, thus decreasing the in vivo metastatic process. This evidence may contribute to pave the way for future possible therapeutic applications of Claisened Hexafluoro to counteract metastatic melanoma dissemination.
Collapse
|
|
13
|
Martin JD, Miyazaki T, Cabral H. Remodeling tumor microenvironment with nanomedicines. WILEY INTERDISCIPLINARY REVIEWS-NANOMEDICINE AND NANOBIOTECHNOLOGY 2021; 13:e1730. [PMID: 34124849 DOI: 10.1002/wnan.1730] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 05/21/2021] [Accepted: 05/22/2021] [Indexed: 12/17/2022]
Abstract
The tumor microenvironment (TME) has been recognized as a major contributor to cancer malignancy and therapeutic resistance. Thus, strategies directed to re-engineer the TME are emerging as promising approaches for improving the efficacy of antitumor therapies by enhancing tumor perfusion and drug delivery, as well as alleviating the immunosuppressive TME. In this regard, nanomedicine has shown great potential for developing effective treatments capable of re-modeling the TME by controlling drug action in a spatiotemporal manner and allowing long-lasting modulatory effects on the TME. Herein, we review recent progress on TME re-engineering by using nanomedicine, particularly focusing on formulations controlling TME characteristics through targeted interaction with cellular components of the TME. Importantly, the TME should be re-engineering to a quiescent phenotype rather than be destroyed. Finally, immediate challenges and future perspectives of TME-re-engineering nanomedicines are discussed, anticipating further innovation in this growing field. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.
Collapse
Affiliation(s)
| | - Takuya Miyazaki
- Kanagawa Institute of Industrial Science and Technology, Ebina, Japan
| | - Horacio Cabral
- Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan
| |
Collapse
|
|
14
|
Liu B, Chen W, Li H, Li F, Jin X, Li Q. Radiosensitization of NSCLC cells to X-rays and carbon ions by the CHK1/CHK2 inhibitor AZD7762, Honokiol and Tunicamycin. RADIATION AND ENVIRONMENTAL BIOPHYSICS 2020; 59:723-732. [PMID: 32857208 DOI: 10.1007/s00411-020-00867-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/18/2019] [Accepted: 08/13/2020] [Indexed: 06/11/2023]
Abstract
Although radiotherapy, especially carbon-ion radiotherapy, is an effective treatment modality against non-small-cell lung cancer (NSCLC), studies using radiation combined with sensitizer for improving the efficacy of radiotherapy are still needed. In this work, we aimed to investigate in NSCLC A549 and H1299 cell lines the effects of different linear energy transfer (LET) radiations combined with diverse sensitizing compounds. Cells pretreated with the CHK1/CHK2 inhibitor AZD7762, Honokiol or Tunicamycin were irradiated with low-LET X-rays and high-LET carbon ions. Cell survival was assessed using the clonogenic cell survival assay. Cell cycle distribution and apoptosis were measured with flow cytometry, and DNA double strand break (DSB) and repair were detected using γ-H2AX immunofluorescence staining. Our results revealed that AZD7762, Honokiol and Tunicamycin demonstrated low cytotoxicity to NSCLC cells and a pronounced radiosensitizing effect on NSCLC cells exposed to carbon ions than X-rays. Unrepaired DNA DSB damages, the abrogation of G2/M arrest induced by irradiation, and finally apoptotic cell death were the main causes of the radiosensitizing effect. Thus, our data suggest that high-LET carbon ion combined with these compounds may be a potentially effective therapeutic strategy for locally advanced NSCLC.
Collapse
Affiliation(s)
- Bingtao Liu
- Institute of Modern Physics, Chinese Academy of Sciences, 509 Nanchang Road, Lanzhou, 730000, Gansu, China
- Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, 730000, China
- Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou, 730000, Gansu, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Weiqiang Chen
- Institute of Modern Physics, Chinese Academy of Sciences, 509 Nanchang Road, Lanzhou, 730000, Gansu, China
- Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, 730000, China
- Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou, 730000, Gansu, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Hongbin Li
- Institute of Modern Physics, Chinese Academy of Sciences, 509 Nanchang Road, Lanzhou, 730000, Gansu, China
- Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, 730000, China
- Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou, 730000, Gansu, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Feifei Li
- Institute of Modern Physics, Chinese Academy of Sciences, 509 Nanchang Road, Lanzhou, 730000, Gansu, China
- Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, 730000, China
- Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou, 730000, Gansu, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Xiaodong Jin
- Institute of Modern Physics, Chinese Academy of Sciences, 509 Nanchang Road, Lanzhou, 730000, Gansu, China.
- Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, 730000, China.
- Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou, 730000, Gansu, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
| | - Qiang Li
- Institute of Modern Physics, Chinese Academy of Sciences, 509 Nanchang Road, Lanzhou, 730000, Gansu, China.
- Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, 730000, China.
- Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou, 730000, Gansu, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
| |
Collapse
|
|
15
|
Mukherjee A, Madamsetty VS, Paul MK, Mukherjee S. Recent Advancements of Nanomedicine towards Antiangiogenic Therapy in Cancer. Int J Mol Sci 2020; 21:E455. [PMID: 31936832 PMCID: PMC7013812 DOI: 10.3390/ijms21020455] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Revised: 01/07/2020] [Accepted: 01/08/2020] [Indexed: 12/14/2022] Open
Abstract
Angiogenesis is a process of generation of de-novo blood vessels from already existing vasculature. It has a crucial role in different physiological process including wound healing, embryonic development, and tumor growth. The methods by which therapeutic drugs inhibit tumor angiogenesis are termed as anti-angiogenesis cancer therapy. Developments of angiogenic inhibiting drugs have various limitations causing a barrier for successful treatment of cancer, where angiogenesis plays an important role. In this context, investigators developed novel strategies using nanotechnological approaches that have demonstrated inherent antiangiogenic properties or used for the delivery of antiangiogenic agents in a targeted manner. In this present article, we decisively highlight the recent developments of various nanoparticles (NPs) including liposomes, lipid NPs, protein NPs, polymer NPs, inorganic NPs, viral and bio-inspired NPs for potential application in antiangiogenic cancer therapy. Additionally, the clinical perspectives, challenges of nanomedicine, and future perspectives are briefly analyzed.
Collapse
Affiliation(s)
- Anubhab Mukherjee
- Aavishkar Oral Strips Pvt Ltd., 109/3, IDA, Phase 2, Sector 2, Lane 6, Cherlapally, Hyderabad 500051, India;
| | - Vijay Sagar Madamsetty
- Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Jacksonville, FL 32224, USA;
| | - Manash K. Paul
- Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, The University of California, Los Angeles (UCLA), Factor Bldg. 10-240, 621 Charles E. Young Dr., Los Angeles, CA 90095, USA
| | - Sudip Mukherjee
- Department of Bioengineering, Rice University, Houston, TX 77030, USA
| |
Collapse
|
|
16
|
Ong CP, Lee WL, Tang YQ, Yap WH. Honokiol: A Review of Its Anticancer Potential and Mechanisms. Cancers (Basel) 2019; 12:E48. [PMID: 31877856 PMCID: PMC7016989 DOI: 10.3390/cancers12010048] [Citation(s) in RCA: 112] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Revised: 12/19/2019] [Accepted: 12/19/2019] [Indexed: 12/24/2022] Open
Abstract
Cancer is characterised by uncontrolled cell division and abnormal cell growth, which is largely caused by a variety of gene mutations. There are continuous efforts being made to develop effective cancer treatments as resistance to current anticancer drugs has been on the rise. Natural products represent a promising source in the search for anticancer treatments as they possess unique chemical structures and combinations of compounds that may be effective against cancer with a minimal toxicity profile or few side effects compared to standard anticancer therapy. Extensive research on natural products has shown that bioactive natural compounds target multiple cellular processes and pathways involved in cancer progression. In this review, we discuss honokiol, a plant bioactive compound that originates mainly from the Magnolia species. Various studies have proven that honokiol exerts broad-range anticancer activity in vitro and in vivo by regulating numerous signalling pathways. These include induction of G0/G1 and G2/M cell cycle arrest (via the regulation of cyclin-dependent kinase (CDK) and cyclin proteins), epithelial-mesenchymal transition inhibition via the downregulation of mesenchymal markers and upregulation of epithelial markers. Additionally, honokiol possesses the capability to supress cell migration and invasion via the downregulation of several matrix-metalloproteinases (activation of 5' AMP-activated protein kinase (AMPK) and KISS1/KISS1R signalling), inhibiting cell migration, invasion, and metastasis, as well as inducing anti-angiogenesis activity (via the down-regulation of vascular endothelial growth factor (VEGFR) and vascular endothelial growth factor (VEGF)). Combining these studies provides significant insights for the potential of honokiol to be a promising candidate natural compound for chemoprevention and treatment.
Collapse
Affiliation(s)
| | | | - Yin Quan Tang
- School of Biosciences, Faculty of Health and Medical Sciences, Taylor’s University Lakeside Campus, No. 1, Jalan Taylor’s, Subang Jaya 47500, Malaysia; (C.P.O.); (W.L.L.)
| | - Wei Hsum Yap
- School of Biosciences, Faculty of Health and Medical Sciences, Taylor’s University Lakeside Campus, No. 1, Jalan Taylor’s, Subang Jaya 47500, Malaysia; (C.P.O.); (W.L.L.)
| |
Collapse
|
|
17
|
A validated ultra-HPLC-MS/MS method for determination of honokiol in human plasma and its application to a clinical pharmacokinetic study. Bioanalysis 2019; 11:1085-1098. [PMID: 31251102 DOI: 10.4155/bio-2019-0030] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Aim: To investigate pharmacokinetics of honokiol after administration of honokiol liposome injection (HKLI) and support the clinical studies of HKLI; it is crucial to determine the concentration of honokiol in human biological samples. Experimental method & results: Human plasma samples were extracted by protein precipitation and analyzed by a new ultra-HPLC-MS/MS (UPLC-MS/MS) method with LLOQ of 0.5 ng/ml. The method was validated according to bioanalytical guidelines from the US FDA and EMA. Successful method validation proved that the method was sensitive and selective, and was suitable for determination of honokiol in clinical plasma samples. Conclusion: The method was successfully applied to evaluate the pharmacokinetics of honokiol after administration of HKLI to Chinese subjects with advanced non-small-cell lung cancer in a first in-human study.
Collapse
|
|
18
|
Zhu M, Li B, Ma H, Huang X, Wang H, Dai Y, Li Y, Li HM, Wu CZ. Synthesis and in vitro antitumor evaluation of honokiol derivatives. Bioorg Med Chem Lett 2019; 30:126849. [PMID: 31831382 DOI: 10.1016/j.bmcl.2019.126849] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 11/18/2019] [Accepted: 11/18/2019] [Indexed: 11/29/2022]
Abstract
Honokiol is a natural bioactive neolignan and has been widely researched and structural modified as an anticancer agent. In this paper, 18 honokiol derivatives were synthesized and investigated for their antitumor activity. Among these, the promising compound 5a exhibited much higher anti-proliferative activity with IC50 value of 10.41 μM. Transwell assays showed that 5a could significantly inhibit the invasion and migration of I-10 cells at 2.5 μM, which was further confirmed by the western blotting experiments with down-regulation of the HIF-1α and its associated downstream proteins MMP-2 and MMP-9. Overall, these results provided useful suggestion for further structural optimization of honokiol derivatives.
Collapse
Affiliation(s)
- Meilin Zhu
- School of Pharmacy, Bengbu Medical College, 2600 Donghai Road, Bengbu 233030, Anhui, China
| | - Bohan Li
- School of Pharmacy, Bengbu Medical College, 2600 Donghai Road, Bengbu 233030, Anhui, China
| | - Hui Ma
- School of Pharmacy, Bengbu Medical College, 2600 Donghai Road, Bengbu 233030, Anhui, China
| | - Xuenan Huang
- School of Pharmacy, Bengbu Medical College, 2600 Donghai Road, Bengbu 233030, Anhui, China
| | - Haotian Wang
- School of Pharmacy, Bengbu Medical College, 2600 Donghai Road, Bengbu 233030, Anhui, China
| | - Yiqun Dai
- School of Pharmacy, Bengbu Medical College, 2600 Donghai Road, Bengbu 233030, Anhui, China
| | - Yu Li
- School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China
| | - Hong-Mei Li
- School of Pharmacy, Bengbu Medical College, 2600 Donghai Road, Bengbu 233030, Anhui, China.
| | - Cheng-Zhu Wu
- School of Pharmacy, Bengbu Medical College, 2600 Donghai Road, Bengbu 233030, Anhui, China.
| |
Collapse
|
|
19
|
Liu JJ, Tang W, Fu M, Gong XQ, Kong L, Yao XM, Jing M, Cai FY, Li XT, Ju RJ. Development of R 8 modified epirubicin-dihydroartemisinin liposomes for treatment of non-small-cell lung cancer. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2019; 47:1947-1960. [PMID: 31079495 DOI: 10.1080/21691401.2019.1615932] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Presently, there are no few anticancer drugs that have been used clinically due to their poor targeting ability, short half-life period, non-selective distributions, generation of vasculogenic mimicry (VM) channels, high metastasis, and high recurrence rate. This study aimed to explore the effects of R8 modified epirubicin-dihydroartemisinin liposomes that could target non-small-cell lung cancer (NSCLC) cells, destroy VM channels, inhibit tumor metastasis, and explain the possible underlying mechanism. In vitro assays indicated that R8 modified epirubicin-dihydroartemisinin liposomes with ideal physicochemical characteristics could exhibit not only powerful cytotoxicity on A549 cells, but also the effective suppression of VM channels and tumor metastasis. Mechanistic studies manifested that R8 modified epirubicin-dihydroartemisinin liposomes could down-regulate the levels of VE-Cad, TGF-β1, MMP-2, and HIF-1α. In vivo assays indicated that R8 modified epirubicin-dihydroartemisinin liposomes could both increase the selective accumulation of chemotherapeutic drugs at tumor sites and show a targeting conspicuous of antitumor efficacy. In conclusion, the R8 modified epirubicin-dihydroartemisinin liposomes prepared in this study provide a treatment strategy with high efficiency for NSCLC.
Collapse
Affiliation(s)
- Jing-Jing Liu
- a School of Pharmacy , Liaoning University of Traditional Chinese Medicine , Dalian , China
| | - Wei Tang
- b Linyi Food and Drug Testing Center , Linyi , China
| | - Min Fu
- a School of Pharmacy , Liaoning University of Traditional Chinese Medicine , Dalian , China
| | - Xiao-Qing Gong
- c Department of Pharmaceutical Engineering , Beijing Institute of Petrochemical Technology , Beijing , China
| | - Liang Kong
- a School of Pharmacy , Liaoning University of Traditional Chinese Medicine , Dalian , China
| | - Xue-Min Yao
- a School of Pharmacy , Liaoning University of Traditional Chinese Medicine , Dalian , China
| | - Ming Jing
- a School of Pharmacy , Liaoning University of Traditional Chinese Medicine , Dalian , China
| | - Fu-Yi Cai
- a School of Pharmacy , Liaoning University of Traditional Chinese Medicine , Dalian , China
| | - Xue-Tao Li
- a School of Pharmacy , Liaoning University of Traditional Chinese Medicine , Dalian , China
| | - Rui-Jun Ju
- c Department of Pharmaceutical Engineering , Beijing Institute of Petrochemical Technology , Beijing , China
| |
Collapse
|
|
20
|
Lin D, Yan Z, Chen A, Ye J, Hu A, Liu J, Peng J, Wu X. Anti-proliferative activity and structure-activity relationship of honokiol derivatives. Bioorg Med Chem 2019; 27:3729-3734. [PMID: 31278004 DOI: 10.1016/j.bmc.2019.06.042] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 06/20/2019] [Accepted: 06/26/2019] [Indexed: 12/27/2022]
Abstract
As a known natural product with anti-tumor activity, honokiol has been widely researched and structural modified. Lots of honokiol derivatives have been found to possess good anti-proliferative activity and showed great potential in cancer therapy, but the SAR (structure-activity relationship) was still confused. Here in, the SAR were comprehensively researched by summary of reported derivatives and synthesis of novel derivatives. Amongst novel derivatives, the promising compounds A6 and A10 exhibited potent and selective anti-proliferative activities against K562 cell line with the IC50 values of 5.04 and 7.08 μM respectively. The SAR was discussed around honokiol and 79 derivatives by the means of CoMFA and theoretical calculation, which provided useful suggestion for further structural optimization of honokiol derivatives.
Collapse
Affiliation(s)
- Ding Lin
- College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China; Department of Traditional Chinese Medicine, Zhejiang A & F University, Hangzhou 311300, China
| | - Zhongzhong Yan
- College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China
| | - Aiyu Chen
- College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China
| | - Jiao Ye
- College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China
| | - Aixi Hu
- College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China.
| | - Juan Liu
- College of Pharmacy and Biological Science, University of South China, Hengyang 421000, China
| | - Junmei Peng
- College of Pharmacy and Biological Science, University of South China, Hengyang 421000, China
| | - Xiaoyun Wu
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Science, Southern Medical University, Guangzhou 510515, China
| |
Collapse
|
|
21
|
Banik K, Ranaware AM, Deshpande V, Nalawade SP, Padmavathi G, Bordoloi D, Sailo BL, Shanmugam MK, Fan L, Arfuso F, Sethi G, Kunnumakkara AB. Honokiol for cancer therapeutics: A traditional medicine that can modulate multiple oncogenic targets. Pharmacol Res 2019; 144:192-209. [DOI: 10.1016/j.phrs.2019.04.004] [Citation(s) in RCA: 87] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Revised: 03/18/2019] [Accepted: 04/02/2019] [Indexed: 02/07/2023]
|
|
22
|
Preya UH, Jeon C, Lee H, Kang Y, Wang Y, Choi J, Park JH. The Cytotoxic Activity of Honokiol‐Triazole Derivatives in Ovarian Cancer Cells. B KOREAN CHEM SOC 2019. [DOI: 10.1002/bkcs.11691] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Affiliation(s)
- Umma Hafsa Preya
- Department of Life and Nanopharmaceutical SciencesKyung Hee University Seoul 02447 South Korea
| | - Cheolmin Jeon
- Department of Chemical & Biological EngineeringHanbat National University Daejeon 34158 South Korea
| | - Haneul Lee
- Department of Chemical & Biological EngineeringHanbat National University Daejeon 34158 South Korea
| | - Yujung Kang
- Department of Chemical & Biological EngineeringHanbat National University Daejeon 34158 South Korea
| | - Yi‐Yue Wang
- Department of Life and Nanopharmaceutical SciencesKyung Hee University Seoul 02447 South Korea
| | - Jung‐Hye Choi
- Department of Life and Nanopharmaceutical SciencesKyung Hee University Seoul 02447 South Korea
| | - Jeong Ho Park
- Department of Chemical & Biological EngineeringHanbat National University Daejeon 34158 South Korea
| |
Collapse
|
|
23
|
Yu R, Zou Y, Liu B, Guo Y, Wang X, Han M. Surface modification of pH-sensitive honokiol nanoparticles based on dopamine coating for targeted therapy of breast cancer. Colloids Surf B Biointerfaces 2019; 177:1-10. [PMID: 30690424 DOI: 10.1016/j.colsurfb.2019.01.047] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2018] [Revised: 01/21/2019] [Accepted: 01/23/2019] [Indexed: 01/16/2023]
Abstract
At present, there is a higher demand for the efficacy of nanoparticle drugs. It is hoped that more drugs will reach the tumor site and that the drug will be less harmful to other normal cells of the body before reaching the tumor site. Most target research for nanomedicine can achieve better positioning through complex processes, such as synthesis. To overcome these difficulties, such as the complexity of the preparation method and lack of good targeting, we used simple polydopamine (PDA) as a pH-sensitive targeting anchor for nanoparticles (NPs). We successfully conjugated folic acid (FA) to the surface of honokiol (HK) nanoparticles coated with PDA using a typical surface modifier. After preparation into HK-PDA-FA-NPs, we characterized the particle size, potential and transmission electron microscope (TEM). The targeted nanoparticles (HK-PDA-FA-NPs) can be stably present in various physiological media and exhibit pH sensitivity during drug release in vitro. HK-PDA-FA-NPs have better targeting ability to 4T1 cells than HK-NPs. Targeted nanoparticles have a tumor inhibition rate of greater than 80% in vivo, which is significantly higher than ordinary HK-NPs. This experiment shows that surface modification of HK-NPs coated with PDA is a promising preparation method for targeted therapy.
Collapse
Affiliation(s)
- RunQi Yu
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, No. 151, Malianwa North Road, Haidian District, Beijing, PR China; School of Pharmacy, Heilongjiang University of Chinese Medicine, No. 24, Heping Road, Xiangfang District, Harbin, PR China
| | - Yuan Zou
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, No. 151, Malianwa North Road, Haidian District, Beijing, PR China
| | - Biao Liu
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, No. 151, Malianwa North Road, Haidian District, Beijing, PR China; Life Sciences and Environmental Sciences Center, Harbin University of Commerce, PR China
| | - Yifei Guo
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, No. 151, Malianwa North Road, Haidian District, Beijing, PR China
| | - Xiangtao Wang
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, No. 151, Malianwa North Road, Haidian District, Beijing, PR China.
| | - Meihua Han
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, No. 151, Malianwa North Road, Haidian District, Beijing, PR China.
| |
Collapse
|
|
24
|
Zhou C, Guo C, Li W, Zhao J, Yang Q, Tan T, Wan Z, Dong J, Song X, Gong T. A novel honokiol liposome: formulation, pharmacokinetics, and antitumor studies. Drug Dev Ind Pharm 2018; 44:2005-2012. [PMID: 30058387 DOI: 10.1080/03639045.2018.1506475] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Affiliation(s)
- Chuchu Zhou
- Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, Sichuan University, Chengdu, Sichuan Province, People’s Republic of China
| | - Chenqi Guo
- Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, Sichuan University, Chengdu, Sichuan Province, People’s Republic of China
| | - Wenhao Li
- Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, Sichuan University, Chengdu, Sichuan Province, People’s Republic of China
| | - Juan Zhao
- Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, Sichuan University, Chengdu, Sichuan Province, People’s Republic of China
| | - Qin Yang
- Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, Sichuan University, Chengdu, Sichuan Province, People’s Republic of China
| | - Tiantian Tan
- Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, Sichuan University, Chengdu, Sichuan Province, People’s Republic of China
| | - Zhuoya Wan
- School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA
| | - Jianxia Dong
- Department of Clinical Pharmacy, West China Hospital of Sichuan University, Chengdu, Sichuan Province, People’s Republic of China
| | - Xu Song
- Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, Sichuan University, Chengdu, Sichuan Province, People’s Republic of China
| | - Tao Gong
- Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, Sichuan University, Chengdu, Sichuan Province, People’s Republic of China
| |
Collapse
|
|
25
|
Wang X, Cheng L, Xie HJ, Ju RJ, Xiao Y, Fu M, Liu JJ, Li XT. Functional paclitaxel plus honokiol micelles destroying tumour metastasis in treatment of non-small-cell lung cancer. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2018; 46:1154-1169. [DOI: 10.1080/21691401.2018.1481082] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Xin Wang
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, China
| | - Lan Cheng
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, China
| | | | - Rui-Jun Ju
- Department of Pharmaceutical Engineering, Beijing Institute of Petrochemical Technology, Beijing, China
| | - Yao Xiao
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, China
| | - Min Fu
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, China
| | - Jing-Jing Liu
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, China
| | - Xue-Tao Li
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, China
| |
Collapse
|
|
26
|
Song XL, Ju RJ, Xiao Y, Wang X, Liu S, Fu M, Liu JJ, Gu LY, Li XT, Cheng L. Application of multifunctional targeting epirubicin liposomes in the treatment of non-small-cell lung cancer. Int J Nanomedicine 2017; 12:7433-7451. [PMID: 29066893 PMCID: PMC5644542 DOI: 10.2147/ijn.s141787] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Chemotherapy for aggressive non-small-cell lung cancer (NSCLC) usually results in a poor prognosis due to tumor metastasis, vasculogenic mimicry (VM) channels, limited killing of tumor cells, and severe systemic toxicity. Herein, we developed a kind of multifunctional targeting epirubicin liposomes to enhance antitumor efficacy for NSCLC. In the liposomes, octreotide was modified on liposomal surface for obtaining a receptor-mediated targeting effect, and honokiol was incorporated into the lipid bilayer for inhibiting tumor metastasis and eliminating VM channels. In vitro cellular assays showed that multifunctional targeting epirubicin liposomes not only exhibited the strongest cytotoxic effect on Lewis lung tumor cells but also showed the most efficient inhibition on VM channels. Action mechanism studies showed that multifunctional targeting epirubicin liposomes could downregulate PI3K, MMP-2, MMP-9, VE-Cadherin, and FAK and activate apoptotic enzyme caspase 3. In vivo results exhibited that multifunctional targeting epirubicin liposomes could accumulate selectively in tumor site and display an obvious antitumor efficacy. In addition, no significant toxicity of blood system and major organs was observed at a test dose. Therefore, multifunctional targeting epirubicin liposomes may provide a safe and efficient therapy strategy for NSCLC.
Collapse
Affiliation(s)
- Xiao-Li Song
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian
| | - Rui-Jun Ju
- Department of Pharmaceutical Engineering, Beijing Institute of Petrochemical Technology, Beijing, China
| | - Yao Xiao
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian
| | - Xin Wang
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian
| | - Shuang Liu
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian
| | - Min Fu
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian
| | - Jing-Jing Liu
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian
| | - Li-Yan Gu
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian
| | - Xue-Tao Li
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian
| | - Lan Cheng
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian
| |
Collapse
|
|
27
|
Godugu C, Doddapaneni R, Singh M. Honokiol nanomicellar formulation produced increased oral bioavailability and anticancer effects in triple negative breast cancer (TNBC). Colloids Surf B Biointerfaces 2017; 153:208-219. [PMID: 28249200 DOI: 10.1016/j.colsurfb.2017.01.038] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Revised: 01/16/2017] [Accepted: 01/21/2017] [Indexed: 12/28/2022]
Abstract
Triple negative breast cancer (TNBC), owing to its aggressive behavior and toxicity associated with available chemotherapy; currently no suitable therapy is available. Honokiol (HNK) is a promising anticancer drug but has poor bioavailability. In the current study, we evaluated the anticancer effects of an oral Honokiol nanomicellar (NM) formulation (size range of 20-40nm) in vitro against various TNBC cells lines. Cytotoxicity, clonogenic and wound healing assays demonstrated the promising anticancer effects. In vitro Caco-2 permeability studies suggested increased absorption of Honokiol. Compared to HNK-FD, nanomicellar formulations resulted in significant increase in the oral bioavailability. Cmax (4.06 and 3.60-fold) and AUC (6.26 and 5.83-fold) were significantly increased in comparison to oral 40 and 80mg/kg free drug respectively. Further, anticancer effects of these formulations were studied in BALB/c nude mice transplanted with orthotopic MDA-MB-231 cell induced xenografts. After 4 weeks of daily administration of HNK-NM formulation, significant reduction in the tumor volumes and weights compared to free drug (p<0.001) treated groups was observed. Surprisingly, in some of the animals (25%), the treatment resulted in complete eradication of tumors. Increased apoptosis and antiangiogenic effect was observed in HNK-NM groups compared to free drug and untreated control animals. This is the first report demonstrating that HNK-FD possesses anticancer effects against TNBC.
Collapse
Affiliation(s)
- Chandraiah Godugu
- College of Pharmacy Pharmaceutical Sciences, Florida A & M University, Tallahassee, FL 32307, USA; Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research, Balanagar, Hyderabad, Telangana 500037 India
| | - Ravi Doddapaneni
- College of Pharmacy Pharmaceutical Sciences, Florida A & M University, Tallahassee, FL 32307, USA; Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Mandip Singh
- College of Pharmacy Pharmaceutical Sciences, Florida A & M University, Tallahassee, FL 32307, USA.
| |
Collapse
|
|
28
|
Yang J, Pei H, Luo H, Fu A, Yang H, Hu J, Zhao C, Chai L, Chen X, Shao X, Wang C, Wu W, Wan L, Ye H, Qiu Q, Peng A, Wei Y, Yang L, Chen L. Non-toxic dose of liposomal honokiol suppresses metastasis of hepatocellular carcinoma through destabilizing EGFR and inhibiting the downstream pathways. Oncotarget 2016; 8:915-932. [PMID: 27906672 PMCID: PMC5352206 DOI: 10.18632/oncotarget.13687] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2015] [Accepted: 11/05/2016] [Indexed: 02/05/2023] Open
Abstract
At present, there is no specific anti-metastasis drug in HCC treatment. Drugs used for primary HCC tumors and tumor metastasis are very similar, among which cytotoxic drugs are prevalent, such as cisplatin, doxorubicin and 5-FU. The EGFR pathway plays an important role in promoting hepatocellular carcinoma (HCC) metastasis. Hence, development of non-toxic anti-metastasis drugs, such as EGFR or downstream pathways inhibitors, is of great importance. In our present study, we found non-toxic dose of liposomal honokiol (LH) could inhibit the HCC metastasis by destabilizing EGFR and inhibiting the downstream pathways. Non-toxic dose of LH significantly inhibited the motility, migration and lamellipodia formation of HepG2 cells in vitro and decreased extravasation of HepG2 cells in a novel metastasis model of transgenic zebrafish. In two lung metastasis models (HepG2 and B16F10) and a spontaneous metastasis model of HepG2 cells, LH remarkably inhibited pulmonary metastasis and regional lymph nodes metastasis without obvious toxicity. Further study showed that destabilizing EGFR and inhibiting the downstream pathways were the main mechanisms of non-toxic dose of LH on metastasis inhibition. Our results provide the preclinical rationale and the underlying mechanisms of LH to suppress HCC metastasis, implicating LH as a potential therapeutic agent to block HCC metastasis without severe side effects.
Collapse
Affiliation(s)
- Jianhong Yang
- 1 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, P.R. China
| | - Heying Pei
- 1 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, P.R. China
| | - Hong Luo
- 2 Department of Ultrasonic Medicine, West China Second Hospital, Sichuan University, Chengdu, China
| | - Afu Fu
- 1 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, P.R. China
| | - Hansuo Yang
- 1 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, P.R. China
| | - Jia Hu
- 1 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, P.R. China
| | - Chengjian Zhao
- 1 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, P.R. China
| | - LuLu Chai
- 1 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, P.R. China
| | - Xiang Chen
- 1 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, P.R. China
| | - Ximing Shao
- 1 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, P.R. China
| | - Chunyu Wang
- 1 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, P.R. China
| | - Wenshuang Wu
- 1 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, P.R. China
| | - Li Wan
- 3 School of Pharmacy, Chengdu University of TCM, The Ministry of Education Key Laboratory of Standardization of Chinese Herbal Medicine, State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu, China
| | - Haoyu Ye
- 1 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, P.R. China
| | - Qiang Qiu
- 1 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, P.R. China
| | - Aihua Peng
- 1 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, P.R. China
| | - Yuquan Wei
- 1 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, P.R. China
| | - Li Yang
- 1 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, P.R. China
| | - Lijuan Chen
- 1 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, P.R. China
| |
Collapse
|
|
29
|
Thulasiraman P, Johnson AB. Regulation of Mucin 1 and multidrug resistance protein 1 by honokiol enhances the efficacy of doxorubicin-mediated growth suppression in mammary carcinoma cells. Int J Oncol 2016; 49:479-86. [PMID: 27221150 PMCID: PMC4922838 DOI: 10.3892/ijo.2016.3534] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Accepted: 04/06/2016] [Indexed: 01/16/2023] Open
Abstract
Understanding the link between chemoresistance and cancer progression may identify future targeted therapy for breast cancer. One of the mechanisms by which chemoresistance is attained in cancer cells is mediated through the expression of multidrug resistance proteins (MRPs). Acquiring drug resistance has been correlated to the emergence of metastasis, accounting for the progression of the disease. One of the diagnostic markers of metastatic progression is the overexpression of a transmembrane protein called Mucin 1 (MUC1) which has been implicated in reduced survival rate. The objective of this study was to understand the relationship between MUC1 and MRP1 using natural phenolic compound isolated from Magnolia grandiflora, honokiol, in mammary carcinoma cells. We provide evidence that honokiol suppresses the expression level of MUC1 and MRP1 in mammary carcinoma cells. In a time-dependent manner, honokiol-mediated reduction of MUC1 is followed by a reduction of MRP1 expression in the breast cancer cells. Additionally, silencing MUC1 suppresses the expression level of MRP1 and enhances the efficacy of doxorubicin, an MRP1 substrate. Taken together, these findings suggest MUC1 regulates the expression of MRP1 and provides a direct link between cancer progression and chemoresistance in mammary carcinoma cells.
Collapse
Affiliation(s)
- Padmamalini Thulasiraman
- Department of Biomedical Sciences, College of Allied Health, University of South Alabama, Mobile, AL 36688, USA
| | - Andrea Butts Johnson
- Department of Biomedical Sciences, College of Allied Health, University of South Alabama, Mobile, AL 36688, USA
| |
Collapse
|
|
30
|
Honokiol targets mitochondria to halt cancer progression and metastasis. Mol Nutr Food Res 2016; 60:1383-95. [DOI: 10.1002/mnfr.201501007] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2015] [Revised: 03/22/2016] [Accepted: 03/25/2016] [Indexed: 12/16/2022]
|
|
31
|
Gao Y, Rankin GO, Tu Y, Chen YC. Inhibitory Effects of the Four Main Theaflavin Derivatives Found in Black Tea on Ovarian Cancer Cells. Anticancer Res 2016; 36:643-651. [PMID: 26851019 PMCID: PMC4899836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/05/2023]
Abstract
BACKGROUND Some polyphenols induce apoptosis and inhibit angiogenesis. Consumption of black tea, rich in polyphenols, has been found to reduce ovarian cancer risk. Theaflavin (TF1), theaflavin-3-gallate (TF2a), theaflavin-3'-gallate (TF2b) and theaflavin-3, 3'-digallate (TF3) are four main theaflavin derivatives found in black tea. MATERIALS AND METHODS Cell proliferation assay, Hoechst 33342 staining assay, Caspase-Glo Assay, western blot, human umbilical vein endothelial cell tube formation assay and vascular endothelial growth factor (VEGF) enzyme-linked immunosorbent assay were performed. RESULTS All four theaflavin derivatives reduced viability of ovarian cancer cells at lower concentrations than with normal ovarian cells. TF1 mainly mediated apoptosis via the intrinsic pathway, while the others via the intrinsic and extrinsic pathways. TF1 inhibited tube formation via reducing VEGF secretion in a hypoxia-inducible factor 1α-independent manner, while the others in a HIF1α-dependent way. CONCLUSION All four theaflavin derivatives inhibited ovarian cancer cells. Some of the effects and mechanisms of TF1 are different from those of the other three theaflavin derivatives.
Collapse
Affiliation(s)
- Ying Gao
- Department of Tea Science, Zhejiang University, Hangzhou, P.R. China College of Science, Technology and Mathematics, Alderson Broaddus University, Philippi, WV, U.S.A
| | - Gary O Rankin
- Department of Pharmacology, Physiology and Toxicology, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, U.S.A
| | - Youying Tu
- Department of Tea Science, Zhejiang University, Hangzhou, P.R. China
| | - Yi Charlie Chen
- College of Science, Technology and Mathematics, Alderson Broaddus University, Philippi, WV, U.S.A.
| |
Collapse
|
|
32
|
Glasgow MDK, Chougule MB. Recent Developments in Active Tumor Targeted Multifunctional Nanoparticles for Combination Chemotherapy in Cancer Treatment and Imaging. J Biomed Nanotechnol 2016; 11:1859-98. [PMID: 26554150 DOI: 10.1166/jbn.2015.2145] [Citation(s) in RCA: 88] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Nanotechnology and combination therapy are two major fields that show great promise in the treatment of cancer. The delivery of drugs via nanoparticles helps to improve drug's therapeutic effectiveness while reducing adverse side effects associated wifh high dosage by improving their pharmacokinetics. Taking advantage of molecular markers over-expressing on tumor tissues compared to normal cells, an "active" molecular marker targeted approach would be-beneficial for cancer therapy. These actively targeted nanoparticles would increase drug concentration at the tumor site, improving efficacy while further reducing chemo-resistance. The multidisciplinary approach may help to improve the overall efficacy in cancer therapy. This review article summarizes recent developments of targeted multifunctional nanoparticles in the delivery, of various drugs for a combinational chemotherapy approach to cancer treatment and imaging.
Collapse
|
|
33
|
Liou SF, Hua KT, Hsu CY, Weng MS. Honokiol from Magnolia spp. induces G1 arrest via disruption of EGFR stability through repressing HDAC6 deacetylated Hsp90 function in lung cancer cells. J Funct Foods 2015. [DOI: 10.1016/j.jff.2015.03.018] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
|
|
34
|
Sulakhiya K, Kumar P, Gurjar SS, Barua CC, Hazarika NK. Beneficial effect of honokiol on lipopolysaccharide induced anxiety-like behavior and liver damage in mice. Pharmacol Biochem Behav 2015; 132:79-87. [DOI: 10.1016/j.pbb.2015.02.015] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2014] [Revised: 02/11/2015] [Accepted: 02/16/2015] [Indexed: 01/12/2023]
|
|
35
|
Saeed M, Kuete V, Kadioglu O, Börtzler J, Khalid H, Greten HJ, Efferth T. Cytotoxicity of the bisphenolic honokiol from Magnolia officinalis against multiple drug-resistant tumor cells as determined by pharmacogenomics and molecular docking. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2014; 21:1525-1533. [PMID: 25442261 DOI: 10.1016/j.phymed.2014.07.011] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/31/2014] [Revised: 06/15/2014] [Accepted: 07/21/2014] [Indexed: 06/04/2023]
Abstract
A main problem in oncology is the development of drug-resistance. Some plant-derived lignans are established in cancer therapy, e.g. the semisynthetic epipodophyllotoxins etoposide and teniposide. Their activity is, unfortunately, hampered by the ATP-binding cassette (ABC) efflux transporter, P-glycoprotein. Here, we investigated the bisphenolic honokiol derived from Magnolia officinalis. P-glycoprotein-overexpressing CEM/ADR5000 cells were not cross-resistant to honokiol, but MDA-MB-231 BRCP cells transfected with another ABC-transporter, BCRP, revealed 3-fold resistance. Further drug resistance mechanisms analyzed study was the tumor suppressor TP53 and the epidermal growth factor receptor (EGFR). HCT116 p53(-/-) did not reveal resistance to honokiol, and EGFR-transfected U87.MG EGFR cells were collateral sensitive compared to wild-type cells (degree of resistance: 0.34). To gain insight into possible modes of collateral sensitivity, we performed in silico molecular docking studies of honokiol to EGFR and EGFR-related downstream signal proteins. Honokiol bound with comparable binding energies to EGFR (-7.30 ± 0.01 kcal/mol) as the control drugs erlotinib (-7.50 ± 0.30 kcal/mol) and gefitinib (-8.30 ± 0.10 kcal/mol). Similar binding affinities of AKT, MEK1, MEK2, STAT3 and mTOR were calculated for honokiol (range from -9.0 ± 0.01 to 7.40 ± 0.01 kcal/mol) compared to corresponding control inhibitor compounds for these signal transducers. This indicates that collateral sensitivity of EGFR-transfectant cells towards honokiol may be due to binding to EGFR and downstream signal transducers. COMPARE and hierarchical cluster analyses of microarray-based transcriptomic mRNA expression data of 59 tumor cell lines revealed a specific gene expression profile predicting sensitivity or resistance towards honokiol.
Collapse
Affiliation(s)
- Mohamed Saeed
- Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany
| | - Victor Kuete
- Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany; Department of Biochemistry, Faculty of Science, University of Dschang, Cameroon
| | - Onat Kadioglu
- Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany
| | - Jonas Börtzler
- Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany
| | - Hassan Khalid
- Medicinal and Aromatic Plants Research Institute (MAPRI), National Centre for Research, Khartoum, Sudan
| | - Henry Johannes Greten
- Abel Salazar Biomedical Sciences Institute, University of Porto, Portugal; Heidelberg School of Chinese Medicine, Heidelberg, Germany
| | - Thomas Efferth
- Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany.
| |
Collapse
|
|
36
|
Han M, Yu X, Guo Y, Wang Y, Kuang H, Wang X. Honokiol nanosuspensions: Preparation, increased oral bioavailability and dramatically enhanced biodistribution in the cardio-cerebro-vascular system. Colloids Surf B Biointerfaces 2014; 116:114-20. [DOI: 10.1016/j.colsurfb.2013.12.056] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2013] [Revised: 12/21/2013] [Accepted: 12/24/2013] [Indexed: 11/26/2022]
|
|
37
|
Characterization of metabolic profile of honokiol in rat feces using liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry and 13C stable isotope labeling. J Chromatogr B Analyt Technol Biomed Life Sci 2014; 953-954:20-9. [DOI: 10.1016/j.jchromb.2014.01.047] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2013] [Revised: 01/25/2014] [Accepted: 01/30/2014] [Indexed: 11/23/2022]
|
|
38
|
Honokiol analogs: a novel class of anticancer agents targeting cell signaling pathways and other bioactivities. Future Med Chem 2013; 5:809-29. [PMID: 23651094 DOI: 10.4155/fmc.13.32] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
Honokiol (3,5-di-(2-propenyl)-1,1-biphenyl-2,2-diol) is a natural bioactive neolignan isolated from the genus Magnolia. In recent studies, honokiol has been observed to have anti-angiogenic, anticancer, anti-inflammatory, neuroprotective and GABA-modulating properties in vitro and in preclinical models. Honokiol and its analogs target multiple signaling pathways including NF-κB, STAT3, EGFR, mTOR and caspase-mediated common pathway, which regulate cancer initiation and progression. Honokiol and its targets of action may be helpful in the development of effective analogs and targeted cancer therapy. In this review, recent data describing the molecular targets of honokiol and its analogs with anticancer and some other bioactivities are discussed.
Collapse
|
|
39
|
Lee NJ, Oh JH, Ban JO, Shim JH, Lee HP, Jung JK, Ahn BW, Yoon DY, Han SB, Ham YW, Hong JT. 4-O-methylhonokiol, a PPARγ agonist, inhibits prostate tumour growth: p21-mediated suppression of NF-κB activity. Br J Pharmacol 2013; 168:1133-45. [PMID: 23043610 DOI: 10.1111/j.1476-5381.2012.02235.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2012] [Revised: 08/22/2012] [Accepted: 09/05/2012] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND AND PURPOSE The effects of 4-O-methylhonokiol (MH), a constituent of Magnolia officinalis, were investigated on human prostate cancer cells and its mechanism of action elucidated. EXPERIMENTAL APPROACH The anti-cancer effects of MH were examined in prostate cancer and normal cells. The effects were validated in vivo using a mouse xenograft model. KEY RESULTS MH increased the expression of PPARγ in prostate PC-3 and LNCap cells. The pull-down assay and molecular docking study indicated that MH directly binds to PPARγ. MH also increased transcriptional activity of PPARγ but decreased NF-κB activity. MH inhibited the growth of human prostate cancer cells, an effect attenuated by the PPARγ antagonist GW9662. MH induced apoptotic cell death and this was related to G(0) -G(1) phase cell cycle arrest. MH increased the expression of the cell cycle regulator p21, and apoptotic proteins, whereas it decreased phosphorylation of Rb and anti-apoptotic proteins. Transfection of PC3 cells with p21 siRNA or a p21 mutant plasmid on the cyclin D1/ cycline-dependent kinase 4 binding site abolished the effects of MH on cell growth, cell viability and related protein expression. In the animal studies, MH inhibited tumour growth, NF-κB activity and expression of anti-apoptotic proteins, whereas it increased the transcriptional activity and expression of PPARγ, and the expression of apoptotic proteins and p21 in tumour tissues. CONCLUSIONS AND IMPLICATION MH inhibits growth of human prostate cancer cells through activation of PPARγ, suppression of NF-κB and arrest of the cell cycle. Thus, MH might be a useful tool for treatment of prostate cancer.
Collapse
Affiliation(s)
- N J Lee
- College of Pharmacy, Chungbuk National University, Chungbuk, South Korea
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
40
|
Recent trends in multifunctional liposomal nanocarriers for enhanced tumor targeting. JOURNAL OF DRUG DELIVERY 2013; 2013:705265. [PMID: 23533772 PMCID: PMC3606784 DOI: 10.1155/2013/705265] [Citation(s) in RCA: 152] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/25/2012] [Accepted: 02/06/2013] [Indexed: 12/30/2022]
Abstract
Liposomes are delivery systems that have been used to formulate a vast variety of therapeutic and imaging agents for the past several decades. They have significant advantages over their free forms in terms of pharmacokinetics, sensitivity for cancer diagnosis and therapeutic efficacy. The multifactorial nature of cancer and the complex physiology of the tumor microenvironment require the development of multifunctional nanocarriers. Multifunctional liposomal nanocarriers should combine long blood circulation to improve pharmacokinetics of the loaded agent and selective distribution to the tumor lesion relative to healthy tissues, remote-controlled or tumor stimuli-sensitive extravasation from blood at the tumor's vicinity, internalization motifs to move from tumor bounds and/or tumor intercellular space to the cytoplasm of cancer cells for effective tumor cell killing. This review will focus on current strategies used for cancer detection and therapy using liposomes with special attention to combination therapies.
Collapse
|
|
41
|
Kaushik G, Ramalingam S, Subramaniam D, Rangarajan P, Protti P, Rammamoorthy P, Anant S, Mammen JMV. Honokiol induces cytotoxic and cytostatic effects in malignant melanoma cancer cells. Am J Surg 2013; 204:868-73. [PMID: 23231930 DOI: 10.1016/j.amjsurg.2012.09.001] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2012] [Revised: 09/06/2012] [Accepted: 09/06/2012] [Indexed: 11/15/2022]
Abstract
BACKGROUND Melanomas are aggressive neoplasms with limited therapeutic options. Therefore, developing new therapies with low toxicity is of utmost importance. Honokiol is a natural compound that recently has shown promise as an effective anticancer agent. METHODS The effect of honokiol on melanoma cancer cells was assessed in vitro. Proliferation and physiologic changes were determined using hexosaminidase assay and transmission electron microscopy. Protein expression was assessed by immunoblotting. RESULTS Honokiol treatment inhibited cell proliferation and induced death. Electron microscopy showed autophagosome formation. Reduced levels of cyclin D1 accompanied cell-cycle arrest. Honokiol also decreased phosphorylation of AKT (known as protein kinase B) and mammalian target of rapamycin, and inhibited γ-secretase activity by down-regulating the expression of γ-secretase complex proteins, especially anterior pharynx-defective 1. CONCLUSIONS Honokiol is highly effective in inhibiting melanoma cancer cells by attenuating AKT/mammalian target of rapamycin and Notch signaling. These studies warrant further clinical evaluation for honokiol alone or with present chemotherapeutic regimens for the treatment of melanomas.
Collapse
Affiliation(s)
- Gaurav Kaushik
- Department of Surgery, University of Kansas Medical Center, Kansas City, KS, USA
| | | | | | | | | | | | | | | |
Collapse
|
|
42
|
Zhang L, Xie XY, Wang Y, Wang YH, Chen Y, Ren ZG. Treatment of radiation-induced hemorrhagic gastritis with prednisolone: A case report. World J Gastroenterol 2012; 18:7402-7404. [PMID: 23326152 PMCID: PMC3544049 DOI: 10.3748/wjg.v18.i48.7402] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2012] [Accepted: 09/28/2012] [Indexed: 02/06/2023] Open
Abstract
Radiation-induced gastritis is an infrequent cause of gastrointestinal bleeding. It is a serious complication arising from radiation therapy, and the standard treatment method has not been established. The initial injury is characteristically acute inflammation of gastric mucosa. We presented a 46-year-old male patient with hemorrhagic gastritis induced by external radiotherapy for metastatic retroperitoneal lymph node of hepatocellular carcinoma. The endoscopic examination showed diffuse edematous hyperemicmucosa with telangiectasias in the whole muscosa of the stomach and duodenal bulb. Multiple hemorrhagic patches with active oozing were found over the antrum. Anti-secretary therapy was initiated for hemostasis, but melena still occurred off and on. Finally, he was successfully treated by prednisolone therapy. We therefore strongly argue in favor of perdnisolone therapy to effectively treat patients with radiation-induced hemorrhagic gastritis.
Collapse
|
|
43
|
Ponnurangam S, Mammen JMV, Ramalingam S, He Z, Zhang Y, Umar S, Subramaniam D, Anant S. Honokiol in combination with radiation targets notch signaling to inhibit colon cancer stem cells. Mol Cancer Ther 2012; 11:963-72. [PMID: 22319203 DOI: 10.1158/1535-7163.mct-11-0999] [Citation(s) in RCA: 85] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Cancer stem cells are implicated in resistance to ionizing radiation (IR) and chemotherapy. Honokiol, a biphenolic compound has been used in traditional Chinese medicine for treating various ailments. In this study, we determined the ability of honokiol to enhance the sensitivity of colon cancer stem cells to IR. The combination of honokiol and IR suppressed proliferation and colony formation while inducing apoptosis of colon cancer cells in culture. There were also reduced numbers and size of spheroids, which was coupled with reduced expression of cancer stem cell marker protein DCLK1. Flow cytometry studies confirmed that the honokiol-IR combination reduced the number of DCLK1+ cells. In addition, there were reduced levels of activated Notch-1, its ligand Jagged-1, and the downstream target gene Hes-1. Furthermore, expression of components of the Notch-1 activating γ-secretase complex, presenilin 1, nicastrin, Pen2, and APH-1 was also suppressed. On the other hand, the honokiol effects were mitigated when the Notch intracellular domain was expressed. To determine the effect of honokiol-IR combination on tumor growth in vivo, nude mice tumor xenografts were administered honokiol intraperitoneally and exposed to IR. The honokiol-IR combination significantly inhibited tumor xenograft growth. In addition, there were reduced levels of DCLK1 and the Notch signaling-related proteins in the xenograft tissues. Together, these data suggest that honokiol is a potent inhibitor of colon cancer growth that targets the stem cells by inhibiting the γ-secretase complex and the Notch signaling pathway. These studies warrant further clinical evaluation for the combination of honokiol and IR for treating colon cancers.
Collapse
Affiliation(s)
- Sivapriya Ponnurangam
- Department of Molecular and Integrative Physiology, The University of Kansas Medical Center, Kansas City, Kansas 66160, USA
| | | | | | | | | | | | | | | |
Collapse
|
|
44
|
Hazra B, Ghosh S, Kumar A, Pandey BN. The prospective role of plant products in radiotherapy of cancer: a current overview. Front Pharmacol 2012; 2:94. [PMID: 22291649 PMCID: PMC3253585 DOI: 10.3389/fphar.2011.00094] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2011] [Accepted: 12/22/2011] [Indexed: 01/06/2023] Open
Abstract
Treatment of cancer often requires exposure to radiation, which has several limitations involving non-specific toxicity toward normal cells, reducing the efficacy of treatment. Efforts are going on to find chemical compounds which would effectively offer protection to the normal tissues after radiation exposure during radiotherapy of cancer. In this regard, plant-derived compounds might serve as “leads” to design ideal radioprotectors/radiosensitizers. This article reviews some of the recent findings on prospective medicinal plants, phytochemicals, and their analogs, based on both in vitro and in vivo tumor models especially focused with relevance to cancer radiotherapy. Also, pertinent discussion has been presented on the molecular mechanism of apoptotic death in relation to the oxidative stress in cancer cells induced by some of these plant samples and their active constituents.
Collapse
Affiliation(s)
- Banasri Hazra
- Department of Pharmaceutical Technology, Jadavpur University Kolkata, India.
| | | | | | | |
Collapse
|
|
45
|
Kim GD, Bae SY, Park HJ, Bae K, Lee SK. Honokiol Inhibits Vascular Vessel Formation of Mouse Embryonic Stem Cell-Derived Endothelial Cells via the Suppression of PECAM and MAPK/mTOR Signaling Pathway. Cell Physiol Biochem 2012; 30:758-70. [DOI: 10.1159/000341455] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/11/2012] [Indexed: 01/12/2023] Open
|
|
46
|
He Z, Subramaniam D, Ramalingam S, Dhar A, Postier RG, Umar S, Zhang Y, Anant S. Honokiol radiosensitizes colorectal cancer cells: enhanced activity in cells with mismatch repair defects. Am J Physiol Gastrointest Liver Physiol 2011; 301:G929-37. [PMID: 21836060 PMCID: PMC3220322 DOI: 10.1152/ajpgi.00159.2011] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2011] [Accepted: 08/04/2011] [Indexed: 01/31/2023]
Abstract
DNA mismatch repair is required for correcting any mismatches that are created during replication and recombination, and a defective mismatch repair system contributes to DNA damage-induced growth arrest. The colorectal cancer cell line HCT116 is known to have a mutation in the hMLH1 mismatch repair gene resulting in microsatellite instability and defective mismatch repair. Honokiol is a biphenolic compound that has been used in traditional Chinese medicine for treating various ailments including cancer. This study was designed to test the hypothesis that honokiol enhances the radiosensitivity of cancer cells with mismatch repair defect (HCT116) compared with those that are mismatch repair proficient (HCT116-CH3). We first determined that the combination of honokiol and γ-irradiation treatment resulted in dose-dependent inhibition of proliferation and colony formation in both cell lines. However, the effects were more pronounced in HCT116 cells. Similarly, the combination induced higher levels of apoptosis (caspase 3 activation, Bax to Bcl2 ratio) in the HCT116 cells compared with HCT116-CH3 cells. Cell cycle analyses revealed higher levels of dead cells in HCT116 cells. The combination treatment reduced expression of cyclin A1 and D1 and increased phosphorylated p53 in both cell lines, although there were significantly lower amounts of phosphorylated p53 in the HCT116-CH3 cells, suggesting that high levels of hMLH1 reduce radiosensitivity. These data demonstrate that honokiol is highly effective in radiosensitizing colorectal cancer cells, especially those with a mismatch repair defect.
Collapse
Affiliation(s)
- Zhiyun He
- Department of Medicine, Lanzhou University Second Hospital, Gansu Province, China
| | | | | | | | | | | | | | | |
Collapse
|
|
47
|
4-O-methylhonokiol inhibits colon tumor growth via p21-mediated suppression of NF-κB activity. J Nutr Biochem 2011; 23:706-15. [PMID: 21820300 DOI: 10.1016/j.jnutbio.2011.03.013] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2010] [Revised: 02/24/2011] [Accepted: 03/14/2011] [Indexed: 01/06/2023]
Abstract
Biphenolic components in the Magnolia family have shown several pharmacological activities such as antitumor effects. This study investigated the effects of 4-O-methylhonokiol (MH), a constituent of Magnolia officinalis, on human colon cancer cell growth and its action mechanism. 4-O-methylhonokiol (0-30 μM) decreased constitutive activated nuclear factor (NF)-κB DNA binding activity and inhibited growth of human colon (SW620 and HCT116) cancer cells. It also caused G₀-G₁ phase cell cycle arrest followed by an induction of apoptotic cell death. However, knockdown with small interfering RNA (siRNA) of p21 or transfection with cyclin D1/Cdk4 binding site-mutated p21 abrogated MH-induced cell growth inhibition, inhibition of NF-κB activity as well as expression of cyclin D1 and Cdk4. Conversely, inhibition of NF-κB with specific inhibitor or siRNA augmented MH-induced apoptotic cell death. 4-O-methylhonokiol inhibited tumor growth, NF-κB activity and expression of antiapoptotic proteins; however, it increased the expression of apoptotic proteins as well as p21 in xenograft nude mice bearing SW620 cancer cells. The present study reveals that MH causes p21-mediated human colon cancer cell growth inhibition through suppression of NF-κB and indicates that this compound by itself or in combination with other anticancer agents could be useful for the treatment of cancer.
Collapse
|
|
48
|
Wang X, Duan X, Yang G, Zhang X, Deng L, Zheng H, Deng C, Wen J, Wang N, Peng C, Zhao X, Wei Y, Chen L. Honokiol crosses BBB and BCSFB, and inhibits brain tumor growth in rat 9L intracerebral gliosarcoma model and human U251 xenograft glioma model. PLoS One 2011; 6:e18490. [PMID: 21559510 PMCID: PMC3084695 DOI: 10.1371/journal.pone.0018490] [Citation(s) in RCA: 99] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2010] [Accepted: 03/09/2011] [Indexed: 02/05/2023] Open
Abstract
Background Gliosarcoma is one of the most common malignant brain tumors, and anti-angiogenesis is a promising approach for the treatment of gliosarcoma. However, chemotherapy is obstructed by the physical obstacle formed by the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB). Honokiol has been known to possess potent activities in the central nervous system diseases, and anti-angiogenic and anti-tumor properties. Here, we hypothesized that honokiol could cross the BBB and BCSFB for the treatment of gliosarcoma. Methodologies We first evaluated the abilities of honokiol to cross the BBB and BCSFB by measuring the penetration of honokiol into brain and blood-cerebrospinal fluid, and compared the honokiol amount taken up by brain with that by other tissues. Then we investigated the effect of honokiol on the growth inhibition of rat 9L gliosarcoma cells and human U251 glioma cells in vitro. Finally we established rat 9L intracerebral gliosarcoma model in Fisher 344 rats and human U251 xenograft glioma model in nude mice to investigate the anti-tumor activity. Principal Findings We showed for the first time that honokiol could effectively cross BBB and BCSFB. The ratios of brain/plasma concentration were respectively 1.29, 2.54, 2.56 and 2.72 at 5, 30, 60 and 120 min. And about 10% of honokiol in plasma crossed BCSFB into cerebrospinal fluid (CSF). In vitro, honokiol produced dose-dependent inhibition of the growth of rat 9L gliosarcoma cells and human U251 glioma cells with IC50 of 15.61 µg/mL and 16.38 µg/mL, respectively. In vivo, treatment with 20 mg/kg body weight of honokiol (honokiol was given twice per week for 3 weeks by intravenous injection) resulted in significant reduction of tumor volume (112.70±10.16 mm3) compared with vehicle group (238.63±19.69 mm3, P = 0.000), with 52.77% inhibiting rate in rat 9L intracerebral gliosarcoma model, and (1450.83±348.36 mm3) compared with vehicle group (2914.17±780.52 mm3, P = 0.002), with 50.21% inhibiting rate in human U251 xenograft glioma model. Honokiol also significantly improved the survival over vehicle group in the two models (P<0.05). Conclusions/Significance This study provided the first evidence that honokiol could effectively cross BBB and BCSFB and inhibit brain tumor growth in rat 9L intracerebral gliosarcoma model and human U251 xenograft glioma model. It suggested a significant strategy for offering a potential new therapy for the treatment of gliosarcoma.
Collapse
Affiliation(s)
- Xianhuo Wang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Xingmei Duan
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Guangli Yang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Xiaoyan Zhang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Linyu Deng
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Hao Zheng
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Chongyang Deng
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Jiaolin Wen
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Ning Wang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Cheng Peng
- State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, People's Republic of China
| | - Xia Zhao
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Yuquan Wei
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Lijuan Chen
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
- State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, People's Republic of China
- * E-mail:
| |
Collapse
|
|
49
|
Wang XH, Cai LL, Zhang XY, Deng LY, Zheng H, Deng CY, Wen JL, Zhao X, Wei YQ, Chen LJ. Improved solubility and pharmacokinetics of PEGylated liposomal honokiol and human plasma protein binding ability of honokiol. Int J Pharm 2011; 410:169-74. [PMID: 21397675 DOI: 10.1016/j.ijpharm.2011.03.003] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2010] [Revised: 02/10/2011] [Accepted: 03/07/2011] [Indexed: 02/05/2023]
Abstract
PEGylated liposomal honokiol had been developed with the purpose of improving the solubility and pharmacokinetics compared with free honokiol. Human plasma protein binding ability of honokiol was also investigated. PEGylated liposomal honokiol was prepared by thin film evaporation-sonication method. Its mean particle size was 98.68 nm, mean zeta potential was -20.6 mV and encapsulation efficiency were 87.68±1.56%. The pharmacokinetics of PEGylated liposomal honokiol was studied after intravenous administration in Balb/c mice. There were significant differences of parameters T(1/2β) and AUC(0→∞) between them and liposome lengthened T(1/2β) and AUC(0→∞) values. The mean T(1/2β) value of PEGylated liposomal honokiol and free honokiol were 26.09 min and 13.46 min, respectively. The AUC(0→∞) ratio of PEGylated liposomal honokiol to free honokiol was about 1.85-fold (219.24 μg/mL min/118.68 μg/mL min) (P=0.000). Examination of protein binding ability showed that honokiol with 0.5, 8.0 and 20 μg/mL concentrations in human plasma achieved the percent of bound between 60% and 65%. The results suggested that PEGylated liposomal honokiol improved the solubility, increased the drug concentration in plasma, and withstanded the clearance. Besides, the percent of protein bound of honokiol in human plasma was between 60% and 65%.
Collapse
Affiliation(s)
- Xian-Huo Wang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
50
|
Lee YJ, Lee YM, Lee CK, Jung JK, Han SB, Hong JT. Therapeutic applications of compounds in the Magnolia family. Pharmacol Ther 2011; 130:157-76. [PMID: 21277893 DOI: 10.1016/j.pharmthera.2011.01.010] [Citation(s) in RCA: 332] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2011] [Accepted: 01/13/2011] [Indexed: 12/18/2022]
Abstract
The bark and/or seed cones of the Magnolia tree have been used in traditional herbal medicines in Korea, China and Japan. Bioactive ingredients such as magnolol, honokiol, 4-O-methylhonokiol and obovatol have received great attention, judging by the large number of investigators who have studied their pharmacological effects for the treatment of various diseases. Recently, many investigators reported the anti-cancer, anti-stress, anti-anxiety, anti-depressant, anti-oxidant, anti-inflammatory and hepatoprotective effects as well as toxicities and pharmacokinetics data, however, the mechanisms underlying these pharmacological activities are not clear. The aim of this study was to review a variety of experimental and clinical reports and, describe the effectiveness, toxicities and pharmacokinetics, and possible mechanisms of Magnolia and/or its constituents.
Collapse
Affiliation(s)
- Young-Jung Lee
- College of Pharmacy and Medical Research Center, Chungbuk National University, 12 Gaesin-dong, Heungduk-gu, Cheongju, Chungbuk 361-763, Republic of Korea
| | | | | | | | | | | |
Collapse
|