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1
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Zhang Z, Su R, Liu J, Chen K, Wu C, Sun P, Sun T. Tubulin/HDAC dual-target inhibitors: Insights from design strategies, SARs, and therapeutic potential. Eur J Med Chem 2025; 281:117022. [PMID: 39500063 DOI: 10.1016/j.ejmech.2024.117022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Revised: 10/21/2024] [Accepted: 10/30/2024] [Indexed: 12/02/2024]
Abstract
Microtubules, one of the cytoskeletons in eukaryotic cells, maintain the proper operation of several cellular functions. Additionally, they are regulated by the acetylation of HDAC6 and SIRT2 which affects microtubule dynamics. Given the fact that tubulin and HDAC inhibitors play a synergistic effect in the treatment of many cancers, the development of tubulin/HDAC dual-target inhibitors is conducive to addressing multiple limitations including drug resistance, dose toxicity, and unpredictable pharmacokinetic properties. At present, tubulin/HDAC dual-target inhibitors have been obtained in three main ways: uncleavable linked pharmacophores, cleavable linked pharmacophores, and modification of single-target drugs. Their therapeutic efficacy has been verified in vivo and in vitro assays. In this article, we reviewed the research progress of tubulin/HDAC dual inhibitors from design strategies, SARs, and biological activities, which may provide help for the discovery of novel tubulin/HDAC dual inhibitors.
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Affiliation(s)
- Zhen Zhang
- Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education. Shenyang 110016, PR China
| | - Rui Su
- Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education. Shenyang 110016, PR China
| | - Junao Liu
- Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education. Shenyang 110016, PR China
| | - Keyu Chen
- Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education. Shenyang 110016, PR China
| | - Chengjun Wu
- Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education. Shenyang 110016, PR China.
| | - Pinghua Sun
- Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education. Shenyang 110016, PR China; Key Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, School of Pharmacy, Shihezi University, Shihezi, 832003, PR China.
| | - Tiemin Sun
- Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education. Shenyang 110016, PR China.
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2
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Kong Y, Edler MC, Hamel E, Britton-Jenkins AR, Gillan O, Mooberry SL, Mu D, Brown ML. Synthesis and structure-activity relationship of boronic acid bioisosteres of combretastatin A-4 as anticancer agents. Bioorg Med Chem 2024; 116:117999. [PMID: 39546933 PMCID: PMC11645202 DOI: 10.1016/j.bmc.2024.117999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 10/18/2024] [Accepted: 11/08/2024] [Indexed: 11/17/2024]
Abstract
The boronic acid group plays an important role in drug discovery. Following our discovery of a boronic acid analog of combretastatin A-4 (CA-4), a series of analogs featuring a boronic acid group on the C phenyl ring of CA-4 was synthesized and evaluated for cytotoxicity, as well as for their ability to inhibit tubulin polymerization, inhibit the binding of [3H]colchicine to tubulin and cause depolymerization of cellular microtubules. Modifications on the C ring of CA-4, either eliminating the methoxy group or replacing the C phenyl ring with a pyridine ring, resulted in a reduced potency for inhibiting tubulin polymerization, colchicine binding and cytotoxic activities as compared to CA-4. Replacing the phenol group with a boronic acid group on the C ring of phenstatin led to a slight increase in cytotoxic potency but a decreased potency for inhibition of tubulin assembly and colchicine binding. Moreover, there was a significant decrease in activity by replacing the C phenyl ring with a pyridine ring. Our results indicate the critical importance of the methoxy group on the C ring as well as the importance of the C phenyl ring compared to a pyridine ring, despite the latter providing a nitrogen atom as a hydrogen bond donor/acceptor, which was predicted by molecular modeling to enhance interaction with the target. The decreased activities of our modified CA-4 boronic analogs may be attributed to weakened hydrogen bonding in our docking model based on the crystal structure of colchicine bound to αβ-tubulin. Notably, even though their effectiveness in inhibiting tubulin polymerization and colchicine binding and causing microtubule depolymerization in cells, the majority of these boronic acid analogs exhibited substantial cytotoxicity. This suggests that they may have additional cellular targets that contribute to their cytotoxicity, and this warrants further evaluation of these unique boronic acid compounds as potential anticancer agents.
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Affiliation(s)
- Yali Kong
- Department of Biomedical and Translational Sciences, Macon & Joan Brock Virginia Health Sciences at Old Dominion University, Norfolk, VA 23507, United States.
| | - Michael C Edler
- Department of Medical and Molecular Genetics, United States; School of Medicine, Indiana University, Indianapolis, IN 46202, United States
| | - Ernest Hamel
- Molecular Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, United States
| | - Asa R Britton-Jenkins
- Department of Biomedical and Translational Sciences, Macon & Joan Brock Virginia Health Sciences at Old Dominion University, Norfolk, VA 23507, United States
| | - Omar Gillan
- Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States
| | - Susan L Mooberry
- Department of Pharmacology, UT Health, San Antonio, TX 78229, United States
| | - David Mu
- Department of Biomedical and Translational Sciences, Macon & Joan Brock Virginia Health Sciences at Old Dominion University, Norfolk, VA 23507, United States; Leroy T. Canoles, Jr. Cancer Research Center, Macon & Joan Brock Virginia Health Sciences at Old Dominion University, Norfolk, VA 23507, United States
| | - Milton L Brown
- Department of Internal Medicine, Macon & Joan Brock Virginia Health Sciences at Old Dominion University, Norfolk, VA 23507, United States.
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Li J, Zhang T, Wu D, He C, Weng H, Zheng T, Liu J, Yao H, Chen J, Ren Y, Zhu Z, Xu J, Xu S. Palladium-Mediated Bioorthogonal System for Prodrug Activation of N-Benzylbenzamide-Containing Tubulin Polymerization Inhibitors for the Treatment of Solid Tumors. J Med Chem 2024; 67:19905-19924. [PMID: 39484713 DOI: 10.1021/acs.jmedchem.4c02419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2024]
Abstract
Bioorthogonal cleavage reactions have been developed as an intriguing strategy to enhance the safety of chemotherapeutics. Aiming to reduce the toxicity and improve the targeted release properties of the colchicine binding site inhibitors (CBSIs) based on previous work, a series of biologically inert prodrugs were further designed and synthesized through a bioorthogonal prodrug strategy. The therapeutic effects of prodrugs could be "turned-on" once combined with palladium resins. Particularly, prodrug 2b was 68.3-fold less cytotoxic compared to the parent compound, while its cytotoxicity was recovered in situ in the presence of palladium resins. Mechanism studies confirmed that 2b inhibited cell growth in the same manner as CBSIs. More importantly, in vivo efficacy studies demonstrated the efficient activation of 2b by palladium resins, resulting in significant inhibition of tumor growth (63.2%). These results suggest that prodrug 2b with improved safety and targeted release property catalyzed by a Pd-mediated bioorthogonal cleavage reaction deserves further investigation.
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Affiliation(s)
- Jinlong Li
- School of Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, P.R. China
| | - Tong Zhang
- School of Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, P.R. China
| | - Di Wu
- School of Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, P.R. China
| | - Chen He
- School of Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, P.R. China
| | - Haoxiang Weng
- School of Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, P.R. China
| | - Tiandong Zheng
- School of Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, P.R. China
| | - Jie Liu
- School of Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, P.R. China
| | - Hong Yao
- School of Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, P.R. China
| | - Jichao Chen
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China
| | - Yansong Ren
- School of Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, P.R. China
| | - Zheying Zhu
- Division of Molecular Therapeutics & Formulation, School of Pharmacy, The University of Nottingham, Nottingham NG7 2RD, U.K
| | - Jinyi Xu
- School of Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, P.R. China
| | - Shengtao Xu
- School of Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, P.R. China
- Department of Hepatobiliary Surgery, The First People's Hospital of Kunshan, Suzhou 215132, P.R. China
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Liu Y, Zhang J, Tian J, Wang C, Wang T, Gong J, Hu L. Structure-activity relationship study of new carbazole sulfonamide derivatives as anticancer agents with dual-target mechanism. Eur J Med Chem 2024; 273:116509. [PMID: 38781920 DOI: 10.1016/j.ejmech.2024.116509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 05/04/2024] [Accepted: 05/15/2024] [Indexed: 05/25/2024]
Abstract
A series of novel carbazole sulfonamide derivatives were synthesized and evaluated for antiproliferative activity. Among them, compounds 7 and 15 showed strong potency (IC50 values of 0.81-31.19 nM) against five different cancer cells including multidrug-resistant MCF7/ADR cells. Compound 15 displayed a high cancer cell selectivity (IC50(L02)/average IC50: SI = 7.7). The l-valine prodrug 7a and the phosphate prodrug 15a exerted rohust in vivo antitumor efficacies and accepted safety prolifes. Further mechanism studies revealed that 7 and 15 directly bind to the colchicine site in tubulin to block tubulin polymerization, promote microtubule fragmentation at the cellular level, and induce apoptosis with G2/M cell cycle arrest. These compounds also inhibit HEMC-1 cells migration and vascular tube formation. Additionally, compound 7 displayed a selective inhibition of Topo I. Collectively, these studies suggest that 7 and 15 represents a promising new generation of tubulin inhibitors for cancer treatment.
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Affiliation(s)
- Yonghua Liu
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Junyi Zhang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jiaqi Tian
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chengxi Wang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Tianqi Wang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jianhua Gong
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Laixing Hu
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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Montero V, Montana M, Carré M, Vanelle P. Quinoxaline derivatives: Recent discoveries and development strategies towards anticancer agents. Eur J Med Chem 2024; 271:116360. [PMID: 38614060 DOI: 10.1016/j.ejmech.2024.116360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 03/19/2024] [Accepted: 03/25/2024] [Indexed: 04/15/2024]
Abstract
Cancer is a leading cause of death and a major health problem worldwide. While many effective anticancer agents are available, most drugs currently on the market are not specific, raising issues like the common side effects of chemotherapy. However, recent research hold promises for the development of more efficient and safer anticancer drugs. Quinoxaline and its derivatives are becoming recognized as a novel class of chemotherapeutic agents with activity against different tumors. The present review compiles and discusses studies concerning the therapeutic potential of the anticancer activity of quinoxaline derivatives, covering articles published between January 2018 and January 2023.
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Affiliation(s)
- Vincent Montero
- Aix Marseille Univ, CNRS, ICR UMR 7273, Equipe Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, CEDEX 05, 13385, Marseille, France; AP-HM, Service de Pharmacologie Clinique et Pharmacovigilance, Hôpital de la Timone, Marseille CEDEX 05, 13385, France.
| | - Marc Montana
- Aix Marseille Univ, CNRS, ICR UMR 7273, Equipe Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, CEDEX 05, 13385, Marseille, France; AP-HM, Oncopharma, Hôpital Nord, Marseille, France
| | - Manon Carré
- Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm UMR1068, CNRS UMR7258, Aix-Marseille Université UM105, Institut Paoli Calmettes - Faculté de Pharmacie, Marseille, France
| | - Patrice Vanelle
- Aix Marseille Univ, CNRS, ICR UMR 7273, Equipe Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, CEDEX 05, 13385, Marseille, France; AP-HM, Service Central de la Qualité et de l'Information Pharmaceutiques, Hôpital Conception, Marseille, 13005, France
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6
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Singh SB. Discovery, synthesis, activities, structure-activity relationships, and clinical development of combretastatins and analogs as anticancer drugs. A comprehensive review. Nat Prod Rep 2024; 41:298-322. [PMID: 38009216 DOI: 10.1039/d3np00053b] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2023]
Abstract
Covering: 1982 to up to the end of 2022Bioassay guided purification of the extracts of Combretum caffrum led to the discovery of six series of combretastatins A-D with cytotoxic activities ranging from sub nM to >50 μM ED50's against a wide variety of cancer cell lines. Of these, cis-stilbenes combretastatins A-4 and A-1 were the most potent, exhibiting in vivo efficacy against a wide variety of tumor types in murine models. These antimitotic agents inhibited tubulin polymerization by reversibly binding to the colchicine binding sites. They inhibited tumor growth by a novel antivascular and antineogenesis mechanism in which they stopped blood flows to the blood vessels causing necrosis. Over 20 clinical trials of the phosphate prodrugs of combretastatin A-4 (CA4P) and A-1 (CA1P) showed objective and stable responses against many tumor types, with increased survival times of many patients along with the confirmed cure of certain patients inflicted with anaplastic thyroid cancers. Medicinal chemistry efforts led to the identification of three new leads (AVE8062, BNC105P, SCB01A) with improved in vitro and in vivo potency and an often-improved cellular spectrum. Unfortunately, these preclinical improvements did not translate clinically in any meaningful way. Objectively, CA4P remained the best compound and has garnered many Orphan drug designations by FDA. Clinical trials with tumor genetic mapping, particularly from previous responders, may help boost the success of these compounds in future studies. A comprehensive review of combretastatin series A-D, including bioassay guided discovery, total syntheses, and structure-activity relationship (SAR) studies, biological and mechanistic studies, and preclinical and clinical evaluations of the isolated combretastatins and analogs, along with the personal perspective of the author who originated this project, is presented.
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Affiliation(s)
- Sheo B Singh
- Charles A Dana Research Institute for Scientists Emeriti (RISE), Drew University, Madison, NJ 07940, USA.
- Department of Chemistry and Chemical Biology, Stevens Institute of Technology, Hoboken, NJ 07030, USA.
- SBS Pharma Consulting LLC, Edison, NJ 08820, USA
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7
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Huo XS, Tang-Yang J, Zeng WB, Jian XE, Ma XX, Yue-Yang P, Wen-Wei Y, Zhao PL. Synthesis and biological evaluation of novel 5-substituted/unsubstituted triazolothiadiazines as tubulin depolymerizing and vascular disrupting agents with promising antitumor activity. Drug Dev Res 2023; 84:975-987. [PMID: 37089026 DOI: 10.1002/ddr.22066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 03/21/2023] [Accepted: 04/09/2023] [Indexed: 04/25/2023]
Abstract
A novel series of 5-substituted/unsubstituted [1,2,4]triazolo[3,4-b][1,3,4] thiadiazine compounds has been achieved successfully through chemoselective reduction of the C = N bond, based on our prior work. Initial biological evaluation illustrated that the most active derivative 7j exhibited significant cell growth inhibitory activity toward MCF-7, A549, HCT116, and A2780 with the IC50 values of 0.75, 0.94, 2.90, and 4.15 μM, respectively. Most importantly, all the representative analogs did not demonstrate obvious cytotoxic activity against the non-tumoural cell line HEK-293 (IC50 > 100 μM). The mechanism study revealed that 7j caused the G2 /M phase arrest, induced cell apoptosis in HeLa cells in a concentration-dependent manner, and also showed potent tubulin polymerization inhibitory effect. Meanwhile, 7j exerted significant antivascular activity in the wound-healing and tube formation assays. These observations indicate that 5-unsubstituted 6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine scaffold might be considered as a potential lead for antitubulin inhibitors to develop highly efficient anticancer agents with potent selectivity over normal human cells.
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Affiliation(s)
- Xian-Sen Huo
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Science, Southern Medical University, Guangzhou, P.R.China
| | - Ji Tang-Yang
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Science, Southern Medical University, Guangzhou, P.R.China
| | - Wen-Bin Zeng
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Science, Southern Medical University, Guangzhou, P.R.China
| | - Xie-Er Jian
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Science, Southern Medical University, Guangzhou, P.R.China
| | - Xuan-Xuan Ma
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Science, Southern Medical University, Guangzhou, P.R.China
| | - Peng Yue-Yang
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Science, Southern Medical University, Guangzhou, P.R.China
| | - You Wen-Wei
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Science, Southern Medical University, Guangzhou, P.R.China
| | - Pei-Liang Zhao
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Science, Southern Medical University, Guangzhou, P.R.China
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Fang Y, Luo X, Xu Y, Liu Z, Mintz RL, Yu H, Yu X, Li K, Ju E, Wang H, Tang Z, Tao Y, Li M. Sandwich-Structured Implants to Obstruct Multipath Energy Supply and Trigger Self-Enhanced Hypoxia-Initiated Chemotherapy Against Postsurgical Tumor Recurrence and Metastasis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023:e2300899. [PMID: 37156756 PMCID: PMC10401165 DOI: 10.1002/advs.202300899] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 04/03/2023] [Indexed: 05/10/2023]
Abstract
As a currently common strategy to treat cancer, surgical resection may cause tumor recurrence and metastasis due to residual postoperative tumors. Herein, an implantable sandwich-structured dual-drug depot is developed to trigger a self-intensified starvation therapy and hypoxia-induced chemotherapy sequentially. The two outer layers are 3D-printed using a calcium-crosslinked mixture ink containing soy protein isolate, polyvinyl alcohol, sodium alginate, and combretastatin A4 phosphate (CA4P). The inner layer is one patch of poly (lactic-co-glycolic acid)-based electrospun fibers loaded with tirapazamine (TPZ). The preferentially released CA4P destroys the preexisting blood vessels and prevents neovascularization, which obstructs the external energy supply to cancer cells but aggravates hypoxic condition. The subsequently released TPZ is bioreduced to cytotoxic benzotriazinyl under hypoxia, further damaging DNA, generating reactive oxygen species, disrupting mitochondria, and downregulating hypoxia-inducible factor 1α, vascular endothelial growth factor, and matrix metalloproteinase 9. Together these processes induce apoptosis, block the intracellular energy supply, counteract the disadvantage of CA4P in favoring intratumor angiogenesis, and suppress tumor metastasis. The in vivo and in vitro results and the transcriptome analysis demonstrate that the postsurgical adjuvant treatment with the dual-drug-loaded sandwich-like implants efficiently inhibits tumor recurrence and metastasis, showing great potential for clinical translation.
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Affiliation(s)
- Youqiang Fang
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, Department of Urology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, P. R. China
| | - Xing Luo
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, Department of Urology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, P. R. China
| | - Yanteng Xu
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, Department of Urology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, P. R. China
| | - Zheng Liu
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, Department of Urology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, P. R. China
| | - Rachel L Mintz
- Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, 63110, USA
| | - Haiyang Yu
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, P. R. China
| | - Xuan Yu
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, Department of Urology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, P. R. China
- Department of Ultrasound, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, P. R. China
| | - Kai Li
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, Department of Urology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, P. R. China
- Department of Ultrasound, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, P. R. China
| | - Enguo Ju
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, Department of Urology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, P. R. China
| | - Haixia Wang
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, Department of Urology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, P. R. China
| | - Zhaohui Tang
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, P. R. China
| | - Yu Tao
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, Department of Urology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, P. R. China
- Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, 510630, P. R. China
| | - Mingqiang Li
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, Department of Urology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, P. R. China
- Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, 510630, P. R. China
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9
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Orihara H, Ma M, Nagashima Y, Tochinai R, Sekizawa SI, Kato D, Shinada M, Aoki S, Fujita N, Nakagawa T, Tsuru Y, Tatewaki Y, Mutoh T, Taki Y, Nishimura R, Kuwahara M. Co-administration of JQ1, a bromodomain-containing protein 4 inhibitor, enhances the antitumor effect of combretastatin A4, a microtubule inhibitor, while attenuating its cardiotoxicity. Biomed Pharmacother 2023; 160:114353. [PMID: 36736274 DOI: 10.1016/j.biopha.2023.114353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 01/26/2023] [Accepted: 01/31/2023] [Indexed: 02/04/2023] Open
Abstract
Combretastatin A4 (CA4) inhibits microtubule polymerization, and clinical trials of the prodrug, CA4 disodium phosphate (CA4DP), as an anti-cancer agent have been conducted. However, CA4DP has not been marketed to date because the margin between the effective dose and the cardiotoxic dose is insufficient. Meanwhile, bromodomain-containing protein 4 (BRD4) has been reported to be required for recovery from mitotic arrests induced by anti-microtubule drugs. BRD4 has also been reported to be involved in the progression of heart failure. Therefore, we hypothesized that the combined use of CA4DP with BRD4 inhibitors can enhance the antitumor effect and attenuate CA4DP-induced cardiotoxicity. In this study, the antitumor effect and cardiotoxicity caused by the co-administration of CA4DP with JQ1, a BRD4 inhibitor, were evaluated. CA4 or JQ1 alone reduced the viability of cultured canine mammary tumor cells (CHMp-13a). Viability was further reduced by co-administration, through the suppression of c-Myc. BRD4 positivity in CHMp-13a cytoplasm showed a significant increase when treated with CA4 alone, while the increase was not significant following co-administration. In CHMp-13a xenograft-transplanted mice, co-administration of CA4DP and JQ1 suppressed tumor growth significantly. In CA4DP-induced cardiac injury model rats, echocardiography showed a CA4DP-induced decrease in cardiac function and histopathology showed cardiomyocyte necrosis. Meanwhile, these cardiac changes tended to be milder following the co-administration of CA4DP and JQ1. These results suggest that CA4DP-JQ1 co-administration enhances the antitumor effect of CA4DP while attenuating its cardiotoxicity and therefore potentially open the doors to the development of a novel cancer chemotherapy with reduced cardiotoxicity risks.
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Affiliation(s)
- Haruka Orihara
- Department of Veterinary Pathophysiology and Animal Health, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
| | - Min Ma
- Department of Veterinary Pathophysiology and Animal Health, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
| | - Yoshiyasu Nagashima
- Department of Veterinary Pathophysiology and Animal Health, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
| | - Ryota Tochinai
- Department of Veterinary Pathophysiology and Animal Health, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan; Department of Aging Research and Geriatric Medicine, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-cho, Aobaku, Sendai-shi, Miyagi 980-8575, Japan; Research Institute for Brain and Blood Vessels, Akita Cerebrospinal and Cardiovascular Center, 6-10 Sensyu-Kubota-machi, Akita-shi, Akita 010-0874, Japan.
| | - Shin-Ichi Sekizawa
- Department of Veterinary Pathophysiology and Animal Health, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
| | - Daiki Kato
- Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
| | - Masahiro Shinada
- Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
| | - Susumu Aoki
- Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
| | - Naoki Fujita
- Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
| | - Takayuki Nakagawa
- Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
| | - Yoshiharu Tsuru
- Primetech Corp. Life Science Laboratory, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
| | - Yasuko Tatewaki
- Department of Aging Research and Geriatric Medicine, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-cho, Aobaku, Sendai-shi, Miyagi 980-8575, Japan
| | - Tatsushi Mutoh
- Department of Aging Research and Geriatric Medicine, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-cho, Aobaku, Sendai-shi, Miyagi 980-8575, Japan; Research Institute for Brain and Blood Vessels, Akita Cerebrospinal and Cardiovascular Center, 6-10 Sensyu-Kubota-machi, Akita-shi, Akita 010-0874, Japan
| | - Yasuyuki Taki
- Department of Aging Research and Geriatric Medicine, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-cho, Aobaku, Sendai-shi, Miyagi 980-8575, Japan
| | - Ryohei Nishimura
- Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
| | - Masayoshi Kuwahara
- Department of Veterinary Pathophysiology and Animal Health, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
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10
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Abdul Hussein SA, Razzak Mahmood AA, Tahtamouni LH, Balakit AA, Yaseen YS, Al-Hasani RA. New Combretastatin Analogs as Anticancer Agents: Design, Synthesis, Microtubules Polymerization Inhibition, and Molecular Docking Studies. Chem Biodivers 2023; 20:e202201206. [PMID: 36890635 DOI: 10.1002/cbdv.202201206] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Accepted: 02/16/2023] [Indexed: 03/10/2023]
Abstract
A new series of 4-(4-methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-4H-1,2,4-triazole-3-thiol derivatives were synthesized as analogs for the anticancer drug combretastatin A-4 (CA-4) and characterized using FT-IR, 1 H-NMR, 13 CNMR, and HR-MS techniques. The new CA-4 analogs were designed to meet the structural requirements of the highest expected anticancer activity of CA-4 analogs by maintaining ring A 3,4,5-trimethoxyphenyl moiety, and at the same time varying the substituents effect of the triazole moiety (ring B). In silico analysis indicated that compound 3 has higher total energy and dipole moment than colchicine and the other analogs, and it has excellent distribution of electron density and is more stable, resulting in an increased binding affinity during tubulin inhibition. Additionally, compound 3 was found to interact with three apoptotic markers, namely p53, Bcl-2, and caspase 3. Compound 3 showed strong similarity to colchicine, and it has excellent pharmacokinetics properties and a good dynamic profile. The in vitro anti-proliferation studies showed that compound 3 is the most cytotoxic CA-4 analog against cancer cells (IC50 of 6.35 μM against Hep G2 hepatocarcinoma cells), and based on its selectivity index (4.7), compound 3 is a cancer cytotoxic-selective agent. As expected and similar to colchicine, compound 3-treated Hep G2 hepatocarcinoma cells were arrested at the G2/M phase resulting in induction of apoptosis. Compound 3 tubulin polymerization IC50 (9.50 μM) and effect on Vmax of tubulin polymerization was comparable to that of colchicine (5.49 μM). Taken together, the findings of the current study suggest that compound 3, through its binding to the colchicine-binding site at β-tubulin, is a promising microtubule-disrupting agent with excellent potential to be used as cancer therapeutic agent.
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Affiliation(s)
- Shaker A Abdul Hussein
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Babylon, 51001, Babylon, Iraq
| | - Ammar A Razzak Mahmood
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Baghdad, 10001, Baghdad, Iraq
| | - Lubna H Tahtamouni
- Department of Biology and Biotechnology, Faculty of Science, The Hashemite University, 13133, Zarqa, Jordan
- Department of Biochemistry and Molecular Biology, College of Natural Sciences, Colorado State University, Fort Collins, 80523 Colorado, USA
| | - Asim A Balakit
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Babylon, 51001, Babylon, Iraq
| | - Yahya S Yaseen
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Tikrit, 34001, Tikrit, Iraq
| | - Rehab A Al-Hasani
- Department of Chemistry, College of Science, Al-Mustansiriyah University, 10052, Baghdad, Iraq
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11
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Choudhary S, Kaku K, Robles AJ, Hamel E, Mooberry SL, Gangjee A. Simple monocyclic pyrimidine analogs as microtubule targeting agents binding to the colchicine site. Bioorg Med Chem 2023; 82:117217. [PMID: 36889150 PMCID: PMC10084637 DOI: 10.1016/j.bmc.2023.117217] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Revised: 02/20/2023] [Accepted: 02/20/2023] [Indexed: 03/08/2023]
Abstract
Complex natural products that bind to tubulin/microtubules come under the broad category of microtubule binding agents. The design of simplified analogs of previously reported bicyclic, microtubule depolymerizer, pyrrolo[2,3-d]pyrimidine, provided valuable structure-activity relationship data and led to the identification of novel monocyclic pyrimidine analogs of which 12 was 47-fold more potent (EC50 123 nM) for cellular microtubule depolymerization activity and 7.5-fold more potent (IC50 24.4 nM) at inhibiting the growth of MDA-MB-435 cancer cells, suggesting significantly better binding of the target within the colchicine site of tubulin compared to lead compound 1. This compound and others of this series of monocyclic pyrimidine analogs were able to overcome multidrug resistance due to the expression of the βIII-isotype of tubulin and P-glycoprotein. In vivo evaluation of the most potent analog 12 in an MDA-MB-435 xenograft mouse model indicated, along with paclitaxel, that both compounds showed a trend towards lower tumor volume however neither compound showed significant antitumor activity in the trial. To our knowledge these are the first examples of simple substituted monocyclic pyrimidines as colchicine site binding antitubulin compounds with potent antitumor activity.
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Affiliation(s)
- Shruti Choudhary
- Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh PA 15282, United States
| | - Krishna Kaku
- Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh PA 15282, United States
| | - Andrew J Robles
- Department of Pharmacology and the Mays Cancer Center, University of Texas Health Science Center, San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, United States
| | - Ernest Hamel
- Molecular Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, United States
| | - Susan L Mooberry
- Department of Pharmacology and the Mays Cancer Center, University of Texas Health Science Center, San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, United States.
| | - Aleem Gangjee
- Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh PA 15282, United States.
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12
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Lin S, Du T, Zhang J, Wu D, Tian H, Zhang K, Jiang L, Lu D, Sheng L, Li Y, Ji M, Chen X, Xu H. Optimization of Benzamide Derivatives as Potent and Orally Active Tubulin Inhibitors Targeting the Colchicine Binding Site. J Med Chem 2022; 65:16372-16391. [PMID: 36511661 DOI: 10.1021/acs.jmedchem.2c01208] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Targeting the colchicine binding site on tubulin is a promising strategy to develop cancer therapeutics. Herein, we describe our systematic structure-activity relationship studies of benzamide derivatives that lead to an identification of a potent and orally active tubulin inhibitor 48, which occupied all three zones of the colchicine binding site in the X-ray co-crystal structure, inhibited tubulin polymerization, promoted mitotic blockade and apoptosis, and exhibited significant antiproliferative activities against various cancer cell lines. Compound 48 demonstrated favorable pharmacokinetic profiles, robust in vivo antitumor efficacies, and acceptable safety profiles. Furthermore, 48 overcame drug resistance in the paclitaxel-resistant A549 xenograft model. Collectively, 48 has been advanced into further preclinical evaluation for the development of next-generation microtubule-targeting drugs.
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Affiliation(s)
- Songwen Lin
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.,Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.,CAMS Key Laboratory of Small Molecule Immuno-Oncology Drug Discovery, Chinese Academy of Medical Sciences, Beijing 100050, China
| | - Tingting Du
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.,CAMS Key Laboratory of Small Molecule Immuno-Oncology Drug Discovery, Chinese Academy of Medical Sciences, Beijing 100050, China
| | - Jingbo Zhang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.,Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.,CAMS Key Laboratory of Small Molecule Immuno-Oncology Drug Discovery, Chinese Academy of Medical Sciences, Beijing 100050, China
| | - Deyu Wu
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.,Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.,CAMS Key Laboratory of Small Molecule Immuno-Oncology Drug Discovery, Chinese Academy of Medical Sciences, Beijing 100050, China
| | - Hua Tian
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.,Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Kehui Zhang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.,Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.,CAMS Key Laboratory of Small Molecule Immuno-Oncology Drug Discovery, Chinese Academy of Medical Sciences, Beijing 100050, China
| | - Lin Jiang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.,Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Duo Lu
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Li Sheng
- Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Yan Li
- Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Ming Ji
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.,CAMS Key Laboratory of Small Molecule Immuno-Oncology Drug Discovery, Chinese Academy of Medical Sciences, Beijing 100050, China
| | - Xiaoguang Chen
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.,CAMS Key Laboratory of Small Molecule Immuno-Oncology Drug Discovery, Chinese Academy of Medical Sciences, Beijing 100050, China
| | - Heng Xu
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.,Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.,CAMS Key Laboratory of Small Molecule Immuno-Oncology Drug Discovery, Chinese Academy of Medical Sciences, Beijing 100050, China
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13
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Ahmed MB, Islam SU, Alghamdi AAA, Kamran M, Ahsan H, Lee YS. Phytochemicals as Chemo-Preventive Agents and Signaling Molecule Modulators: Current Role in Cancer Therapeutics and Inflammation. Int J Mol Sci 2022; 23:15765. [PMID: 36555406 PMCID: PMC9779495 DOI: 10.3390/ijms232415765] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 12/02/2022] [Accepted: 12/09/2022] [Indexed: 12/15/2022] Open
Abstract
Cancer is one of the deadliest non communicable diseases. Numerous anticancer medications have been developed to target the molecular pathways driving cancer. However, there has been no discernible increase in the overall survival rate in cancer patients. Therefore, innovative chemo-preventive techniques and agents are required to supplement standard cancer treatments and boost their efficacy. Fruits and vegetables should be tapped into as a source of compounds that can serve as cancer therapy. Phytochemicals play an important role as sources of new medication in cancer treatment. Some synthetic and natural chemicals are effective for cancer chemoprevention, i.e., the use of exogenous medicine to inhibit or impede tumor development. They help regulate molecular pathways linked to the development and spread of cancer. They can enhance antioxidant status, inactivating carcinogens, suppressing proliferation, inducing cell cycle arrest and death, and regulating the immune system. While focusing on four main categories of plant-based anticancer agents, i.e., epipodophyllotoxin, camptothecin derivatives, taxane diterpenoids, and vinca alkaloids and their mode of action, we review the anticancer effects of phytochemicals, like quercetin, curcumin, piperine, epigallocatechin gallate (EGCG), and gingerol. We examine the different signaling pathways associated with cancer and how inflammation as a key mechanism is linked to cancer growth.
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Affiliation(s)
- Muhammad Bilal Ahmed
- BK21 FOUR KNU Creative BioResearch Group, School of Life Sciences, Kyungpook National University, Daegu 41566, Republic of Korea
| | - Salman Ul Islam
- Department of Pharmacy, Cecos University, Peshawar, Street 1, Sector F 5 Phase 6 Hayatabad, Peshawar 25000, Pakistan
| | | | - Muhammad Kamran
- School of Molecular Sciences, The University of Western Australia, M310, 35 Stirling Hwy, Perth, WA 6009, Australia
| | - Haseeb Ahsan
- Department of Pharmacy, Faculty of Life and Environmental Sciences, University of Peshawar, Peshawar 25120, Pakistan
| | - Young Sup Lee
- BK21 FOUR KNU Creative BioResearch Group, School of Life Sciences, Kyungpook National University, Daegu 41566, Republic of Korea
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14
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Qin J, Li H, Wang X, Zhang Y, Duan Y, Yao Y, Yang H, Sun M. Discovery of a novel piperlongumine analogue as a microtubule polymerization inhibitor with potent anti-angiogenic and anti-metastatic efficacy. Eur J Med Chem 2022; 243:114738. [PMID: 36162214 DOI: 10.1016/j.ejmech.2022.114738] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Revised: 08/06/2022] [Accepted: 08/31/2022] [Indexed: 11/04/2022]
Abstract
In an effort to discover anticancer agents with simultaneous effects on tubulin and angiogenesis, we designed and synthesized two series of piperlongumie (PL) derivatives by replacing of phenyl group with a variety of benzoheterocycle (series II) or cyclizing the C7-C8 olefin into an aromatic heterocycle (series I). Most of the new compounds showed better antiproliferative activities against six cancer cell lines than the parent drug PL. Compound II-14b had the best cytotoxic profile of these two series in cancer cells, whilst being relatively low cytotoxicity against normal human cells and high potency against drug-resistant cells. It disrupted cellular microtubule networks and inhibited tubulin assembly with an IC50 value of 5.8 μM. Further studies elucidated that II-14b showed antitumor activities through multiple mechanisms, including the pruduction of abundant ROS, the dissipation of mitochondrial membrane potential, the accumulation of DNA double-strand breaks, and the induction of cell cycle in G2/M phase. More importantly, we have observed that it possesses potential anti-angiogenesis capabilities, including suppression of HUVECs cell migration, invasion, and endothelial tube formation in vitro and in vivo. In vivo assessment indicated that II-14b inhibits the growth and metastasis of MGC-803 xenograft tumour in zebrafish. These findings show that II-14b is a high-efficacy and non-toxic antitumor agent.
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Affiliation(s)
- Jinling Qin
- School of Pharmaceutical Sciences, And Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Hongliang Li
- School of Pharmaceutical Sciences, And Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Xuan Wang
- School of Pharmaceutical Sciences, And Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Yixin Zhang
- School of Pharmaceutical Sciences, And Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Yongtao Duan
- Henan Provincial Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou, 450018, China
| | - Yongfang Yao
- School of Pharmaceutical Sciences, And Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
| | - Hua Yang
- School of Pharmaceutical Sciences, And Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
| | - Moran Sun
- School of Pharmaceutical Sciences, And Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
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15
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Wang D, Feng C, Xiao Z, Huang C, Chen Z, Fang W, Ma X, Wang X, Luo L, Hu K, Tao W. Therapeutic hydrogel for enhanced immunotherapy: A powerful combination of MnO2 nanosheets and vascular disruption. NANO TODAY 2022; 47:101673. [DOI: 10.1016/j.nantod.2022.101673] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/05/2025]
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16
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Tong S, Zhao W, Zhao D, Zhang W, Zhang Z. Biomaterials-Mediated Tumor Infarction Therapy. Front Bioeng Biotechnol 2022; 10:916926. [PMID: 35757801 PMCID: PMC9218593 DOI: 10.3389/fbioe.2022.916926] [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: 04/10/2022] [Accepted: 05/23/2022] [Indexed: 11/19/2022] Open
Abstract
Agents for tumor vascular infarction are recently developed therapeutic agents for the vascular destruction of tumors. They can suppress the progression of the tumor by preventing the flow of nutrition and oxygen to its tissues. Agents of tumor vascular infarction can be divided into three categories according to the differences in their pathways of action: those that use the thrombin-activating pathway, fibrin-activating pathway, and platelet-activating pathway. However, poor targeting ability, low permeation, and potential side-effects restrict the development of the corresponding drugs. Biomaterials can subtly avoid these drawbacks to suppress the tumor. In this article, the authors summarize currently used biomaterials for tumor infarction therapy with the goal of identifying its mechanism, and discuss outstanding deficiencies in methods of this kind.
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Affiliation(s)
| | | | | | | | - Zhiyu Zhang
- Department of Orthopedics, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
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17
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Sun M, Yuan M, Kang Y, Qin J, Zhang Y, Duan Y, Wang L, Yao Y. Identification of novel non-toxic and anti-angiogenic α-fluorinated chalcones as potent colchicine binding site inhibitors. J Enzyme Inhib Med Chem 2022; 37:339-354. [PMID: 34979843 PMCID: PMC8741257 DOI: 10.1080/14756366.2021.2014831] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
Abstract
α-Fluorinated chalcones were prepared and evaluated for their cell growth inhibitory properties against six human cancer cell lines. The most potent chalcone 4c demonstrated excellent selective toxicity against cancer cells versus normal human cells, with IC50 values at nanomolar concentration ranges against 5 cancer cell lines. A further study revealed that 4c could bind to the colchicine site of tubulin, disrupt the cell microtubule networks, and effectively inhibit tubulin polymerisation. Cellular-based mechanism studies elucidated that 4c arrested MGC-803 cell cycle at G2/M phase. In addition, 4c dose-dependently caused Caspase-induced apoptosis of MGC-803 cells through mitochondrial dysfunction. Notably, compound 4c was found to inhibit the HUVECs tube formation, migration, and invasion in vitro. Furthermore, our data suggested that treatment with 4c significantly reduced MGC-803 cells metastasis and proliferation in vitro. Overall, this work showed that chalcone hybrid 4c is a potent inhibitor of tubulin assembly with prominent anti-angiogenesis and anti-cancer properties.
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Affiliation(s)
- Moran Sun
- Henan Provincial Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou, China.,Key Laboratory of Advanced Drug Preparation Technologies, School of Pharmaceutical Sciences, Ministry of Education, Zhengzhou University, Zhengzhou, China
| | - Minghua Yuan
- Key Laboratory of Advanced Drug Preparation Technologies, School of Pharmaceutical Sciences, Ministry of Education, Zhengzhou University, Zhengzhou, China
| | - Yingying Kang
- Key Laboratory of Advanced Drug Preparation Technologies, School of Pharmaceutical Sciences, Ministry of Education, Zhengzhou University, Zhengzhou, China
| | - Jinling Qin
- Key Laboratory of Advanced Drug Preparation Technologies, School of Pharmaceutical Sciences, Ministry of Education, Zhengzhou University, Zhengzhou, China
| | - Yixin Zhang
- Key Laboratory of Advanced Drug Preparation Technologies, School of Pharmaceutical Sciences, Ministry of Education, Zhengzhou University, Zhengzhou, China
| | - Yongtao Duan
- Henan Provincial Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Longfei Wang
- Henan Provincial Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Yongfang Yao
- Henan Provincial Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou, China.,Key Laboratory of Advanced Drug Preparation Technologies, School of Pharmaceutical Sciences, Ministry of Education, Zhengzhou University, Zhengzhou, China.,State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
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18
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Sun YX, Song J, Kong LJ, Sha BB, Tian XY, Liu XJ, Hu T, Chen P, Zhang SY. Design, synthesis and evaluation of novel bis-substituted aromatic amide dithiocarbamate derivatives as colchicine site tubulin polymerization inhibitors with potent anticancer activities. Eur J Med Chem 2021; 229:114069. [PMID: 34971875 DOI: 10.1016/j.ejmech.2021.114069] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 12/18/2021] [Accepted: 12/19/2021] [Indexed: 12/12/2022]
Abstract
As the continuation of our work on the development of tubulin inhibitors with potential anticancer activities, novel bis-substituted aromatic amide dithiocarbamate derivatives were designed by contacting bis-substituted aryl scaffolds (potential anti-tubulin fragments) with N-containing heterocycles (potential anti-tubulin fragments) in one hybrid using the anticancer dithioformate unit as the linker. The antiproliferative activity against three digestive tract tumor cells was evaluated and preliminary structure activity relationships were summarized. Among these compounds, compound 20q exhibited most potent antiproliferative activity against MGC-803, HCT-116, Kyse30 and Kyse450 cells with IC50 values of 0.084, 0.227, 0.069 and 0.078 μM, respectively. In further studies, compound 20q was identified as a novel tubulin inhibitor targeting the colchicine binding site. Compound 20q could inhibit the microtubule assembly and disrupt cytoskeleton in Kyse30 and Kyse450 cells. The results of molecular docking suggested that compound 20q could tightly bind into the colchicine binding site of tubulin by hydrogen bonds and hydrophobic interactions. Compound 20q dose-dependently inhibited the cell growth and colony formation, effectively arrested cells at the G2/M phase and induce mitochondrial apoptosis in Kyse30 and Kyse450 cells. In addition, Compound 20q could regulate the expression of G2/M phase and mitochondrial apoptosis related proteins. Collectively, compound 20q was here reported as a novel tubulin inhibitor with potential anticancer activities.
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Affiliation(s)
- Ya-Xin Sun
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Jian Song
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China; School of Pharmaceutical Sciences, Institute of Drug Discovery & Development, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Zhengzhou, 450001, China
| | - Li-Jun Kong
- School of Pharmaceutical Sciences, Institute of Drug Discovery & Development, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Zhengzhou, 450001, China
| | - Bei-Bei Sha
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Xin-Yi Tian
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Xiu-Juan Liu
- School of Pharmaceutical Sciences, Institute of Drug Discovery & Development, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Zhengzhou, 450001, China
| | - Tao Hu
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Ping Chen
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
| | - Sai-Yang Zhang
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China; School of Pharmaceutical Sciences, Institute of Drug Discovery & Development, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Zhengzhou, 450001, China; Henan Institute of Advanced Technology, Zhengzhou University, Zhengzhou, 450001, China; State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, 210023, Jiangsu, People's Republic of China.
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19
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Ibrahim TS, Hawwas MM, Malebari AM, Taher ES, Omar AM, Neamatallah T, Abdel-Samii ZK, Safo MK, Elshaier YAMM. Discovery of novel quinoline-based analogues of combretastatin A-4 as tubulin polymerisation inhibitors with apoptosis inducing activity and potent anticancer effect. J Enzyme Inhib Med Chem 2021; 36:802-818. [PMID: 33730937 PMCID: PMC7993375 DOI: 10.1080/14756366.2021.1899168] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Revised: 01/27/2021] [Accepted: 02/27/2021] [Indexed: 02/08/2023] Open
Abstract
A new series of quinoline derivatives of combretastatin A-4 have been designed, synthesised and demonstrated as tubulin polymerisation inhibitors. These novel compounds showed significant antiproliferative activities, among them, 12c exhibited the most potent inhibitory activity against different cancer cell lines (MCF-7, HL-60, HCT-116 and HeLa) with IC50 ranging from 0.010 to 0.042 µM, and with selectivity profile against MCF-10A non-cancer cells. Further mechanistic studies suggest that 12c can inhibit tubulin polymerisation and cell migration, leading to G2/M phase arrest. Besides, 12c induces apoptosis via a mitochondrial-dependant apoptosis pathway and caused reactive oxygen stress generation in MCF-7 cells. These results provide guidance for further rational development of potent tubulin polymerisation inhibitors for the treatment of cancer.HighlightsA novel series of quinoline derivatives of combretastatin A-4 have been designed and synthesised.Compound 12c showed significant antiproliferative activities against different cancer cell lines.Compound 12c effectively inhibited tubulin polymerisation and competed with [3H] colchicine in binding to tubulin.Compound 12c arrested the cell cycle at G2/M phase, effectively inducing apoptosis and inhibition of cell migration.
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Affiliation(s)
- Tarek S. Ibrahim
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
| | - Mohamed M. Hawwas
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut, Egypt
| | - Azizah M. Malebari
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Ehab S. Taher
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut, Egypt
| | - Abdelsattar M. Omar
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
| | - Thikryat Neamatallah
- Department of Pharmacology and toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Zakaria K. Abdel-Samii
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
| | - Martin K. Safo
- Institute for Structural Biology, Drug Discovery and Development, Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, USA
| | - Yaseen A. M. M. Elshaier
- Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Sadat City, Menoufia, Egypt
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Zheng L, Ren R, Sun X, Zou Y, Shi Y, Di B, Niu MM. Discovery of a Dual Tubulin and Poly(ADP-Ribose) Polymerase-1 Inhibitor by Structure-Based Pharmacophore Modeling, Virtual Screening, Molecular Docking, and Biological Evaluation. J Med Chem 2021; 64:15702-15715. [PMID: 34670362 DOI: 10.1021/acs.jmedchem.1c00932] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Dual inhibition of tubulin and poly(ADP-ribose) polymerase-1 (PARP-1) may become an attractive approach for cancer therapy. Here, we discover a dual tubulin/PARP-1 inhibitor (termed as TP-3) using structure-based virtual screening. TP-3 shows strong dual inhibitory effects on both tubulin and PARP-1. Cellular assays reveal that TP-3 shows superior antiproliferative activities against human cancer cells, including breast, liver, ovarian, and cervical cancers. Further studies indicate that TP-3 plays an antitumor role through multiple mechanisms, including the disturbance of the microtubule network and the PARP-1 DNA repairing function, accumulation of DNA double-strand breaks, inhibition of the tube formation, and induction of G2/M cell cycle arrest and apoptosis. In vivo assessment indicates that TP-3 inhibits the growth of MDA-MB-231 xenograft tumors in nude mouse with no notable side effects. These data demonstrate that TP-3 is a dual-targeting, high-efficacy, and low-toxic antitumor agent.
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Affiliation(s)
- Lufeng Zheng
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, China
| | - Ren Ren
- Key Laboratory of Drug Quality Control and Pharmacovigilance, Jiangsu Key Laboratory of Drug Design and Optimization, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China
| | - Xiaolian Sun
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Quality Control and Pharmacovigilance, Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing 210009, China
| | - Yunting Zou
- Key Laboratory of Drug Quality Control and Pharmacovigilance, Jiangsu Key Laboratory of Drug Design and Optimization, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China
| | - Yiru Shi
- Key Laboratory of Drug Quality Control and Pharmacovigilance, Jiangsu Key Laboratory of Drug Design and Optimization, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China
| | - Bin Di
- Key Laboratory of Drug Quality Control and Pharmacovigilance, Jiangsu Key Laboratory of Drug Design and Optimization, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China
| | - Miao-Miao Niu
- Key Laboratory of Drug Quality Control and Pharmacovigilance, Jiangsu Key Laboratory of Drug Design and Optimization, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China
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21
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Marchetti C, De Felice F, Romito A, Iacobelli V, Sassu CM, Corrado G, Ricci C, Scambia G, Fagotti A. Chemotherapy resistance in epithelial ovarian cancer: Mechanisms and emerging treatments. Semin Cancer Biol 2021; 77:144-166. [PMID: 34464704 DOI: 10.1016/j.semcancer.2021.08.011] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Revised: 08/24/2021] [Accepted: 08/26/2021] [Indexed: 12/12/2022]
Abstract
Ovarian cancer (OC) remains a fatal malignancy because most patients experience recurrent disease, which is resistant to chemotherapy. The outcomes for patients with platinum-resistant OC are poor, response rates to further chemotherapy are low and median survival is lower than 12 months. The complexity of platinum-resistant OC, which comprises a heterogeneous spectrum of diseases, is indeed far from being completely understood. Therefore, comprehending tumors' biological behaviour to identify reliable biomarkers, which may predict responses to therapies, is a demanding challenge to improve OC management. In the age of precision medicine, efforts to overcome platinum resistance in OC represent a dynamic and vast field in which innovative drugs and clinical trials rapidly develop. This review will present the exceptional biochemical environment implicated in OC and highlights mechanisms of chemoresistance. Furthermore, innovative molecules and new therapeutic opportunities are presented, along with currently available therapies and ongoing clinical trials.
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Affiliation(s)
- Claudia Marchetti
- Division of Gynecologic Oncology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy.
| | - Francesca De Felice
- Division of Radiotherapy and Oncology, Policlinico Umberto I, Roma, Italy; Università La Sapienza, Roma, Italy
| | - Alessia Romito
- Gynecology and Breast Care Center, Mater Olbia Hospital, Olbia, Italy
| | - Valentina Iacobelli
- Division of Gynecologic Oncology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy; Department Woman and Child Health Sciences, Catholic University of the Sacred Heart, Rome, Italy
| | - Carolina Maria Sassu
- Department of Maternal and Child Health and Urological Sciences, "Sapienza" University of Rome, Polyclinic Umberto I, Rome, Italy
| | - Giacomo Corrado
- Division of Gynecologic Oncology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy
| | - Caterina Ricci
- Division of Gynecologic Oncology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy
| | - Giovanni Scambia
- Division of Gynecologic Oncology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy; Department Woman and Child Health Sciences, Catholic University of the Sacred Heart, Rome, Italy
| | - Anna Fagotti
- Division of Gynecologic Oncology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy; Department Woman and Child Health Sciences, Catholic University of the Sacred Heart, Rome, Italy
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22
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Dai G, Zheng D, Liu G, Song Q. Synergistic Anticancer Effects of Cisplatin Combined with Combretastatin A4 Phosphate on Human Osteosarcoma-Xenografted Mice. Cells Tissues Organs 2021; 210:293-300. [PMID: 34433168 DOI: 10.1159/000517446] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 04/12/2021] [Indexed: 11/19/2022] Open
Abstract
This study aimed to investigate the effectiveness of anticancer therapy combining a cytotoxic chemotherapeutic agent, cisplatin (DDP), and a vascular disruptive drug, combretastatin A4 phosphate (CA4P), in osteosarcoma. First, a human osteosarcoma-xenografted mice model was established. Second, the transplanted tumor models were treated with DDP and CA4P in combination or as monotherapy. Third, the therapeutic effects and the mechanism of the drug combination in the inhibition of transplanted tumors was studied. Finally, the toxic effects of the drugs were observed and recorded. The results showed that DDP combined with CA4P significantly inhibited the growth and lung metastasis of transplanted tumors compared with the monotherapy drug group and vehicle control group. Histopathological analysis revealed that apoptotic and necrotic cell death significantly increased in the combination group, and combined treatment significantly inhibited the proliferation of osteosarcoma cells compared with either agent alone or the vehicle control. Additionally, no obvious toxic effects were observed in the combination group. These results indicate that the combined effects of DDP and CA4P on the progression of human osteosarcoma in vivo were superior to that of either agent alone. DDP combined with CA4P exerted synergistic effects at lower concentrations and promoted apoptosis and necrosis, as well as inhibited proliferation of osteosarcoma cells, but it did not increase the systemic toxic effects of chemotherapy. Our findings highlight CA4P as an effective anticancer agent candidate for combination with DDP in clinical applications to treat osteosarcoma.
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Affiliation(s)
- Guo Dai
- Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Di Zheng
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, China
| | - Gaiwei Liu
- Department of Orthopedics, Jingzhou Central Hospital, Jingzhou, China
| | - Qi Song
- Department of Trauma Surgery, Wuhan No. 1 Hospital, Wuhan, China
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Meng F, Zou B, Yang R, Duan Q, Qian T. The diagnostic efficiency of the perfusion-related parameters in assessing the vascular disrupting agent (CA4P) response in a rabbit VX2 liver tumor model. Acta Radiol 2021; 63:1147-1156. [PMID: 34279135 DOI: 10.1177/02841851211032450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND There are inconsistencies when concomitantly using dynamic contrast enhancement (DCE) and intravoxel incoherent motion (IVIM) to evaluate diagnostic efficiency. PURPOSE To evaluate the diagnostic efficiency of perfusion-related parameters in assessing the effect of Combretastatin-A4-phosphate (CA4P) in a rabbit VX2 liver tumor model using DCE and IVIM. MATERIAL AND METHODS Twenty rabbits implanted with VX2 tumors were included in the study. The perfusion-parameters of DCE (Ktrans and iAUC60) and IVIM (f and D*) were measured at baseline and 4 h after administration of CA4P. Subsequently, the rabbits were euthanized. Pre- and post-treatment perfusion parameters were analyzed using paired t-test. Correlation between the various perfusion parameters and correlation of perfusion parameters with microvascular density (MVD) were assessed using Pearson correlation analysis. The diagnostic efficiency was evaluated using receiver operating characteristic (ROC) curve analysis. RESULTS All perfusion parameters (Ktrans, iAUC60, f and D*) showed significant decrease after 4 h of CA4P administration (all P < 0.001). Post-treatment perfusion parameters showed a moderate correlation with MVD (r = 0.663, r = 0.567, r = 0.685, r = 0.618, respectively; all P < 0.05). At baseline and after treatment, Ktrans values and iAUC60 showed correlation with f and D* (all P < 0.05). Concomitant use of perfusion parameters of DCE and IVIM showed the best diagnostic performance, which was slightly greater than that observed with individual application of DCE or IVIM (AUC = 0.915, 0.880, and 0.895, respectively). CONCLUSION Although concomitant application of DCE and IVIM can slightly improve the diagnostic value in assessing the effect of CA4P, the values were relatively small.
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Affiliation(s)
- Fanhua Meng
- Department of Radiology, Shanghai Fifth People’s Hospital, Fudan University, Shanghai, PR China
| | - Biao Zou
- Department of Radiology, Shanghai Fifth People’s Hospital, Fudan University, Shanghai, PR China
| | - Rong Yang
- Department of Radiology, Shanghai Fifth People’s Hospital, Fudan University, Shanghai, PR China
| | - Qingqing Duan
- Department of Radiology, Shanghai Fifth People’s Hospital, Fudan University, Shanghai, PR China
| | - Ting Qian
- Department of Radiology, International Peace Maternity and Child Health Hospital, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
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Akkol EK, Dereli FTG, Sobarzo-Sánchez E, Khan H. Roles of Medicinal Plants and Constituents in Gynecological Cancer Therapy: Current Literature and Future Directions. Curr Top Med Chem 2021; 20:1772-1790. [PMID: 32297581 DOI: 10.2174/1568026620666200416084440] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 03/05/2020] [Accepted: 03/16/2020] [Indexed: 12/20/2022]
Abstract
Gynecologic cancers, including cervical, primary peritoneal, ovarian, uterine/endometrial, vaginal and vulvar cancers and gestational trophoblastic disease, are characterized by abnormal cell proliferation in female reproductive cells. Due to the variable pathology of these cancers and the lack of appropriate screening tests in developing countries, cancer diagnosis can be reported in advanced stages in most women and this situation adversely affects prognosis and clinical outcomes of illness. For this reason, many researchers in the field of gynecological oncology have carried out many studies. The treatment of various gynecological problems, which cause physical, biological and psychosocial conditions such as fear, shame, blame and anger, has been important throughout the history. Treatment with herbs has become popular nowadays due to the serious side effects of the synthetic drugs used in treatment and the medical and economical problems caused by them. Many scientists have identified various active drug substances through in vivo and in vitro biological activity studies on medicinal plants from the past to the present. While the intrinsic complexity of natural product-based drug discoveries requires highly integrated interdisciplinary approaches, scientific and technological advances and research trends clearly show that natural products will be among the most important new drug sources in the future. In this review, an overview of the studies conducted for the discovery of multitargeted drug molecules in the rational treatment of gynecological cancers is presented.
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Affiliation(s)
- Esra Küpeli Akkol
- Department of Pharmacognosy, Faculty of Pharmacy, Gazi University, Etiler 06330, Ankara, Turkey
| | | | - Eduardo Sobarzo-Sánchez
- Instituto de Investigación e Innovación en Salud, Facultad de Ciencias de la Salud, Universidad Central de Chile, 8330507 Santiago, Spain
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University, Mardan 23200, Pakistan
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25
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Huo XS, Jian XE, Ou-Yang J, Chen L, Yang F, Lv DX, You WW, Rao JJ, Zhao PL. Discovery of highly potent tubulin polymerization inhibitors: Design, synthesis, and structure-activity relationships of novel 2,7-diaryl-[1,2,4]triazolo[1,5-a]pyrimidines. Eur J Med Chem 2021; 220:113449. [PMID: 33895499 DOI: 10.1016/j.ejmech.2021.113449] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 04/03/2021] [Accepted: 04/04/2021] [Indexed: 02/08/2023]
Abstract
By removing 5-methyl and 6-acetyl groups in our previously reported compound 3, we designed a series of novel 2,7-diaryl-[1,2,4]triazolo[1,5-a]pyrimidine derivatives as potential tubulin polymerization inhibitors. Among them, compound 5e displayed low nanomolar antiproliferative efficacy on HeLa cells which was 166-fold higher than the lead analogue 3. Interestingly, 5e displayed significant selectivity in inhibiting cancer cells over HEK-293 (normal human embryonic kidney cells). In addition, 5e dose-dependently arrested HeLa in G2/M phase through the alterations of the expression levels of p-cdc2 and cyclin B1, and caused HeLa cells apoptosis by regulation of expressions of cleaved PARP. Further evidence demonstrated that 5e effectively inhibited tubulin polymerization and was 3-fold more powerful than positive control CA-4. Moreover, molecular docking analysis indicated that 5e overlapped well with CA-4 in the colchicine-binding site. These studies demonstrated that 2,7-diaryl-[1,2,4]triazolo[1,5-a]pyrimidine skeleton might be used as the leading unit to develop novel tubulin polymerization inhibitors as potential anticancer agents.
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Affiliation(s)
- Xian-Sen Huo
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Science, Southern Medical University, Guangzhou, 510515, PR China
| | - Xie-Er Jian
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Science, Southern Medical University, Guangzhou, 510515, PR China
| | - Jie Ou-Yang
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Science, Southern Medical University, Guangzhou, 510515, PR China
| | - Lin Chen
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Science, Southern Medical University, Guangzhou, 510515, PR China
| | - Fang Yang
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Science, Southern Medical University, Guangzhou, 510515, PR China
| | - Dong-Xin Lv
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Science, Southern Medical University, Guangzhou, 510515, PR China
| | - Wen-Wei You
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Science, Southern Medical University, Guangzhou, 510515, PR China
| | - Jin-Jun Rao
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Science, Southern Medical University, Guangzhou, 510515, PR China.
| | - Pei-Liang Zhao
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Science, Southern Medical University, Guangzhou, 510515, PR China.
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26
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Wu MK, Man RJ, Liao YJ, Zhu HL, Zhou ZG. Discovery of novel indole-1,2,4-triazole derivatives as tubulin polymerization inhibitors. Drug Dev Res 2021; 82:1008-1020. [PMID: 33675542 DOI: 10.1002/ddr.21805] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Revised: 02/01/2021] [Accepted: 02/05/2021] [Indexed: 11/08/2022]
Abstract
A series of novel indole-1,2,4-triazole derivatives have been designed, synthesized, and evaluated as potential tubulin polymerization inhibitors. The top hit 12, bearing the 3,4,5-trimethoxyphenyl moiety, exhibited substantial anti-proliferative activity against HepG2, HeLa, MCF-7, and A549 cells in vitro with IC50 values of 0.23 ± 0.08 μM, 0.15 ± 0.18 μM, 0.38 ± 0.12 μM, and 0.30 ± 0.13 μM, respectively. It also inhibited tubulin polymerization with the IC50 value of 2.1 ± 0.12 μM, which was comparable with that of the positive controls. Furthermore, compound 12 regulated the expression of cell cycle-related proteins (Cyclin B1, Cdc25c, and Cdc2) and apoptosis-related proteins (Bcl-2, Bcl-x, and Mcl-1). Mechanistically, compound 12 could arrest cell cycle at the G2/M phase, thus induce an increase of apoptotic cell death. In addition, molecular docking hinted the possible interaction mode of compound 12 into the colchicine binding site of tubulin heterodimers. According to the applications of microtubule-targeting agents in both direct and synergistic cancer therapies, we hope this work might be of significance for future researches.
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Affiliation(s)
- Meng-Ke Wu
- Guangxi Biological Polysaccharide Separation, Purification and Modification Research Platform, Guangxi University for Nationalities, Nanning, China
| | - Ruo-Jun Man
- Guangxi Biological Polysaccharide Separation, Purification and Modification Research Platform, Guangxi University for Nationalities, Nanning, China
| | - Yan-Juan Liao
- Guangxi Biological Polysaccharide Separation, Purification and Modification Research Platform, Guangxi University for Nationalities, Nanning, China
| | - Hai-Liang Zhu
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China
| | - Zhu-Gui Zhou
- College of Chemistry and Chemical Engineering, Guangxi Key Laboratory of Polysaccharide Materials and Modifications, Guangxi University for Nationalities, Nanning, China
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Yang X, Gao M, Miao M, Jiang C, Zhang D, Yin Z, Ni Y, Chen J, Zhang J. Combining combretastatin A4 phosphate with ginsenoside Rd synergistically inhibited hepatocellular carcinoma by reducing HIF-1α via PI3K/AKT/mTOR signalling pathway. J Pharm Pharmacol 2021; 73:263-271. [PMID: 33793802 DOI: 10.1093/jpp/rgaa006] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 11/02/2020] [Indexed: 01/02/2023]
Abstract
OBJECTIVES Combretastatin A4 phosphate (CA4P), a vascular disrupting agent (VDA), can cause rapid tumour vessel occlusion. Subsequently, extensive necrosis is discovered in the tumour center, which induces widespread hypoxia and the rise of the α subunit of hypoxia-inducible factor-1 (HIF-1α). The aim of this study was to evaluate the inhibition of hepatocellular carcinoma growth by combining CA4P with HIF-1 α inhibitor and investigate the mechanism of this combination. METHODS Ginsenoside Rd (Rd) was used in combination with CA4P to estimate the inhibition effect in HepG2 cells and HepG2 xenograft mouse model. The efficacy of anti-tumour was evaluated by tumour growth curve. The protein expression of HIF-1α and PI3K/AKT/mTOR signalling pathway were analysed by western blot. KEY FINDINGS Combination of CA4P and Rd inhibited HepG2 cell proliferation and induced apoptosis in vivo and in vitro. It also increased the necrotic area of the tumour and delayed the tumour growth. Moreover, Rd down-regulated HIF-1α protein expression by inhibiting PI3K/AKT/mTOR signalling pathway. CONCLUSIONS Combination of CA4P and Rd had synergistic anti-tumour effects. The mechanism may be related to the inhibition of HIF-1α by PI3K/AKT/mTOR signalling pathway. This strategy provides a new thought for the combinative therapy of VDAs.
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Affiliation(s)
- Xinxiu Yang
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, P.R. China
| | - Meng Gao
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, P.R. China
- Laboratories of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, Jiangsu Province, P.R. China
| | - Mengqi Miao
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, P.R. China
| | - Cuihua Jiang
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, P.R. China
- Laboratories of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, Jiangsu Province, P.R. China
| | - Dongjian Zhang
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, P.R. China
- Laboratories of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, Jiangsu Province, P.R. China
| | - Zhiqi Yin
- Department of TCMs Pharmaceuticals & State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu Province, P.R. China
| | - Yicheng Ni
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, P.R. China
- Laboratories of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, Jiangsu Province, P.R. China
| | - Jing Chen
- Department of Radiotherapy, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, P.R. China
| | - Jian Zhang
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, P.R. China
- Laboratories of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, Jiangsu Province, P.R. China
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Utilisation of Chick Embryo Chorioallantoic Membrane as a Model Platform for Imaging-Navigated Biomedical Research. Cells 2021; 10:cells10020463. [PMID: 33671534 PMCID: PMC7926796 DOI: 10.3390/cells10020463] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 02/15/2021] [Accepted: 02/19/2021] [Indexed: 02/07/2023] Open
Abstract
The fertilised chick egg and particularly its chorioallantoic membrane (CAM) have drawn continuing interest in biomedicine and bioengineering fields, especially for research on vascular study, cancer, drug screening and development, cell factors, stem cells, etc. This literature review systemically introduces the CAM's structural evolution, functions, vascular features and the circulation system, and cell regulatory factors. It also presents the major and updated applications of the CAM in assays for pharmacokinetics and biodistribution, drug efficacy and toxicology testing/screening in preclinical pharmacological research. The time course of CAM applications for different assays and their advantages and limitations are summarised. Among these applications, two aspects are emphasised: (1) potential utility of the CAM for preclinical studies on vascular-disrupting agents (VDAs), promising for anti-cancer vascular-targeted therapy, and (2) modern imaging technologies, including modalities and their applications for real-time visualisation, monitoring and evaluation of the changes in CAM vasculature as well as the interactions occurring after introducing the tested medical, pharmaceutical and biological agents into the system. The aim of this article is to help those working in the biomedical field to familiarise themselves with the chick embryo CAM as an alternative platform and to utilise it to design and optimise experimental settings for their specific research topics.
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Hao SY, Qi ZY, Wang S, Wang XR, Chen SW. Synthesis and bioevaluation of N-(3,4,5-trimethoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-amines as tubulin polymerization inhibitors with anti-angiogenic effects. Bioorg Med Chem 2021; 31:115985. [DOI: 10.1016/j.bmc.2020.115985] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 12/21/2020] [Accepted: 12/24/2020] [Indexed: 02/08/2023]
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Sinha K, Chaudhury SS, Ruidas B, Majumder R, Pal T, Sur TK, Sarkar PK, Mukhopadhyay CD. Role of Modern Biological Techniques in Evidence-Based Validation of Ayurvedic Herbometallic Preparations. EVIDENCE BASED VALIDATION OF TRADITIONAL MEDICINES 2021:313-336. [DOI: 10.1007/978-981-15-8127-4_16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/19/2023]
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Ibrahim TS, Hawwas MM, Malebari AM, Taher ES, Omar AM, O’Boyle NM, McLoughlin E, Abdel-Samii ZK, Elshaier YAMM. Potent Quinoline-Containing Combretastatin A-4 Analogues: Design, Synthesis, Antiproliferative, and Anti-Tubulin Activity. Pharmaceuticals (Basel) 2020; 13:E393. [PMID: 33203182 PMCID: PMC7698209 DOI: 10.3390/ph13110393] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 11/11/2020] [Accepted: 11/12/2020] [Indexed: 01/03/2023] Open
Abstract
A novel series of quinoline derivatives of combretastatin A-4 incorporating rigid hydrazone and a cyclic oxadiazole linkers were synthesized and have demonstrated potent tubulin polymerization inhibitory properties. Many of these novel derivatives have shown significant antiproliferative activities in the submicromolar range. The most potent compound, 19h, demonstrated superior IC50 values ranging from 0.02 to 0.04 µM against four cancer cell lines while maintaining low cytotoxicity in MCF-10A non-cancer cells, thereby suggesting 19h's selectivity towards proliferating cancer cells. In addition to tubulin polymerization inhibition, 19h caused cell cycle arrest in MCF-7 cells at the G2/M phase and induced apoptosis. Collectively, these findings indicate that 19h holds potential for further investigation as a potent chemotherapeutic agent targeting tubulin.
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Affiliation(s)
- Tarek S. Ibrahim
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (A.M.M.); (A.M.O.)
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt;
| | - Mohamed M. Hawwas
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut 71524, Egypt; (M.M.H.); (E.S.T.)
| | - Azizah M. Malebari
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (A.M.M.); (A.M.O.)
| | - Ehab S. Taher
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut 71524, Egypt; (M.M.H.); (E.S.T.)
| | - Abdelsattar M. Omar
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (A.M.M.); (A.M.O.)
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt
| | - Niamh M. O’Boyle
- School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Trinity Biomedical Sciences Institute, 152-160 Pearse Street, Dublin 2, Ireland; (N.M.O.); (E.M.)
| | - Eavan McLoughlin
- School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Trinity Biomedical Sciences Institute, 152-160 Pearse Street, Dublin 2, Ireland; (N.M.O.); (E.M.)
| | - Zakaria K. Abdel-Samii
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt;
| | - Yaseen A. M. M. Elshaier
- Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Sadat City, Sadat City 32958, Egypt;
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Yetkin-Arik B, Kastelein AW, Klaassen I, Jansen CHJR, Latul YP, Vittori M, Biri A, Kahraman K, Griffioen AW, Amant F, Lok CAR, Schlingemann RO, van Noorden CJF. Angiogenesis in gynecological cancers and the options for anti-angiogenesis therapy. Biochim Biophys Acta Rev Cancer 2020; 1875:188446. [PMID: 33058997 DOI: 10.1016/j.bbcan.2020.188446] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 10/02/2020] [Accepted: 10/04/2020] [Indexed: 02/06/2023]
Abstract
Angiogenesis is required in cancer, including gynecological cancers, for the growth of primary tumors and secondary metastases. Development of anti-angiogenesis therapy in gynecological cancers and improvement of its efficacy have been a major focus of fundamental and clinical research. However, survival benefits of current anti-angiogenic agents, such as bevacizumab, in patients with gynecological cancer, are modest. Therefore, a better understanding of angiogenesis and the tumor microenvironment in gynecological cancers is urgently needed to develop more effective anti-angiogenic therapies, either or not in combination with other therapeutic approaches. We describe the molecular aspects of (tumor) blood vessel formation and the tumor microenvironment and provide an extensive clinical overview of current anti-angiogenic therapies for gynecological cancers. We discuss the different phenotypes of angiogenic endothelial cells as potential therapeutic targets, strategies aimed at intervention in their metabolism, and approaches targeting their (inflammatory) tumor microenvironment.
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Affiliation(s)
- Bahar Yetkin-Arik
- Ocular Angiogenesis Group, Department of Ophthalmology, Amsterdam Cardiovascular Sciences, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam, the Netherlands; Department of Medical Biology, Amsterdam Cardiovascular Sciences, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam, the Netherlands
| | - Arnoud W Kastelein
- Department of Obstetrics and Gynaecology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam, the Netherlands.
| | - Ingeborg Klaassen
- Ocular Angiogenesis Group, Department of Ophthalmology, Amsterdam Cardiovascular Sciences, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam, the Netherlands; Department of Medical Biology, Amsterdam Cardiovascular Sciences, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam, the Netherlands
| | - Charlotte H J R Jansen
- Department of Obstetrics and Gynaecology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam, the Netherlands
| | - Yani P Latul
- Department of Obstetrics and Gynaecology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam, the Netherlands
| | - Miloš Vittori
- Biotechnical Faculty, University of Ljubljana, Ljubljana, Slovenia
| | - Aydan Biri
- Department of Obstetrics and Gynecology, Koru Ankara Hospital, Ankara, Turkey
| | - Korhan Kahraman
- Department of Obstetrics and Gynecology, Bahcesehir University School of Medicine, Istanbul, Turkey
| | - Arjan W Griffioen
- Angiogenesis Laboratory, Department of Medical Oncology, Amsterdam UMC, Cancer Center Amsterdam, Amsterdam, the Netherlands
| | - Frederic Amant
- Department of Oncology, KU Leuven, Leuven, Belgium; Center for Gynaecological Oncology, Antoni van Leeuwenhoek, Amsterdam, the Netherlands; Center for Gynaecological Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Center for Gynaecological Oncology, Amsterdam University Medical Centers, Amsterdam, the Netherlands
| | - Christianne A R Lok
- Center for Gynaecological Oncology, Antoni van Leeuwenhoek, Amsterdam, the Netherlands
| | - Reinier O Schlingemann
- Ocular Angiogenesis Group, Department of Ophthalmology, Amsterdam Cardiovascular Sciences, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam, the Netherlands; Department of Ophthalmology, University of Lausanne, Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, Lausanne, Switzerland
| | - Cornelis J F van Noorden
- Department of Medical Biology, Amsterdam Cardiovascular Sciences, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam, the Netherlands; Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Ljubljana, Slovenia
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Carrozzo M, Eriksen JG, Bensadoun RJ, Boers-Doets CB, Lalla RV, Peterson DE. Oral Mucosal Injury Caused by Targeted Cancer Therapies. J Natl Cancer Inst Monogr 2020; 2019:5551364. [PMID: 31425602 DOI: 10.1093/jncimonographs/lgz012] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 03/14/2019] [Accepted: 05/01/2019] [Indexed: 02/06/2023] Open
Abstract
Targeted cancer therapies have fundamentally transformed the treatment of many types of cancers over the past decade, including breast, colorectal, lung, and pancreatic cancers, as well as lymphoma, leukemia, and multiple myeloma. The unique mechanisms of action of these agents have resulted in many patients experiencing enhanced tumor response together with a reduced adverse event profile as well. Toxicities do continue to occur, however, and in selected cases can be clinically challenging to manage. Of particular importance in the context of this monograph is that the pathobiology for oral mucosal lesions caused by targeted cancer therapies has only been preliminarily investigated. There is distinct need for novel basic, translational, and clinical research strategies to enhance design of preventive and therapeutic approaches for patients at risk for development of these lesions. The research modeling can be conceptually enhanced by extrapolating "lessons learned" from selected oral mucosal conditions in patients without cancer as well. This approach may permit determination of the extent to which pathobiology and clinical management are either similar to or uniquely distinct from oral mucosal lesions caused by targeted cancer therapies. Modeling associated with oral mucosal disease in non-oncology patients is thus presented in this context as well. This article addresses this emerging paradigm, with emphasis on current mechanistic modeling and clinical treatment. This approach is in turn designed to foster delineation of new research strategies, with the goal of enhancing cancer patient treatment in the future.
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Affiliation(s)
- M Carrozzo
- Center for Oral Health Research, Oral Medicine Department, School of Dental Sciences, Newcastle University, UK
| | - J Grau Eriksen
- Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus, Denmark
| | - R-J Bensadoun
- Institut Niçois de Cancérologie (INC), Centre de Haute Energie, Nice, France
| | - C B Boers-Doets
- CancerMed, Department of Medical Strategy, Wormer, The Netherlands.,Impaqtt Foundation, Department of Adverse Event Research & Valorisation, Wormer, The Netherlands
| | - R V Lalla
- Section of Oral Medicine, Department of Oral Health & Diagnostic Sciences, School of Dental Medicine, UConn Health, Farmington, CT
| | - D E Peterson
- Section of Oral Medicine, Department of Oral Health & Diagnostic Sciences, School of Dental Medicine & Neag Comprehensive Cancer Center, UConn Health, Farmington, CT
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Maklad RM, AbdelHafez ESMN, Abdelhamid D, Aly OM. Tubulin inhibitors: Discovery of a new scaffold targeting extra-binding residues within the colchicine site through anchoring substituents properly adapted to their pocket by a semi-flexible linker. Bioorg Chem 2020; 99:103767. [PMID: 32325332 DOI: 10.1016/j.bioorg.2020.103767] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2019] [Revised: 03/06/2020] [Accepted: 03/15/2020] [Indexed: 02/08/2023]
Abstract
Bis-hydrazides 13a-h were designed and synthesized as potential tubulin inhibitors selectively targeting the colchicine site between α- and β-tubulin subunits. The newly designed ring-B substituents were assisted at their ends by 'anchor groups' which are expected to exert binding interaction(s) with new additional amino acid residues in the colchicine site (beyond those amino acids previously reported to interact with reference inhibitors as CA-4 and colchicine). Conformational flexibility of bis-hydrazide linker assisted these 'extra-binding' properties through reliving ligands' strains in the final ligand-receptor complexes. Compound 13f displayed the most promising computational and biological study results in the series: MM/GBSA binding energy of -62.362 kcal/mol (extra-binding to Arg α:221, Thr β:353 & Lys β:254); 34% NCI-H522 cells' death (at 10 µM), IC50 = 0.073 µM (MTT assay); significant cell cycle arrest at G2/M phase; 11.6% preG1 apoptosis induction and 83.1% in vitro tubulin inhibition (at concentration = IC50). Future researchers in bis-hydrazide tubulin inhibitors are advised to consider the 2-chloro-N-(4-substituted-phenyl)acetamide derivatives as compound 13f due to extra-binding properties of their ring B.
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Affiliation(s)
- Raed M Maklad
- Institute of Drug Discovery and Development, Kafrelsheikh University, Kafrelsheikh, Egypt; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt; Zewail City of Science and Technology, 6th of October, Giza, Egypt.
| | | | - Dalia Abdelhamid
- Medicinal Chemistry Department, Faculty of Pharmacy, Minia University, Minia, Egypt
| | - Omar M Aly
- Medicinal Chemistry Department, Faculty of Pharmacy, Minia University, Minia, Egypt
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Predicting Clinical Efficacy of Vascular Disrupting Agents in Rodent Models of Primary and Secondary Liver Cancers: An Overview with Imaging-Histopathology Correlation. Diagnostics (Basel) 2020; 10:diagnostics10020078. [PMID: 32024029 PMCID: PMC7168934 DOI: 10.3390/diagnostics10020078] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 01/24/2020] [Accepted: 01/28/2020] [Indexed: 12/16/2022] Open
Abstract
Vascular disrupting agents (VDAs) have entered clinical trials for over 15 years. As the leading VDA, combretastatin A4 phosphate (CA4P) has been evaluated in combination with chemotherapy and molecular targeting agents among patients with ovarian cancer, lung cancer and thyroid cancer, but still remains rarely explored in human liver cancers. To overcome tumor residues and regrowth after CA4P monotherapy, a novel dual targeting pan-anticancer theragnostic strategy, i.e., OncoCiDia, has been developed and shown promise previously in secondary liver tumor models. Animal model of primary liver cancer is time consuming to induce, but of value for more closely mimicking human liver cancers in terms of tumor angiogenesis, histopathological heterogeneity, cellular differentiation, tumor components, cancer progression and therapeutic response. Being increasingly adopted in VDA researches, multiparametric magnetic resonance imaging (MRI) provides imaging biomarkers to reflect in vivo tumor responses to drugs. In this article as a chapter of a doctoral thesis, we overview the construction and clinical relevance of primary and secondary liver cancer models in rodents. Target selection for CA4P therapy assisted by enhanced MRI using hepatobiliary contrast agents (CAs), and therapeutic efficacy evaluated by using MRI with a non-specific contrast agent, dynamic contrast enhanced (DCE) imaging, diffusion weighted imaging (DWI) are also described. We then summarize diverse responses among primary hepatocellular carcinomas (HCCs), secondary liver and pancreatic tumors to CA4P, which appeared to be related to tumor size, vascularity, and cellular differentiation. In general, imaging-histopathology correlation studies allow to conclude that CA4P tends to be more effective in secondary liver tumors and in more differentiated HCCs, but less effective in less differentiated HCCs and implanted pancreatic tumor. Notably, cirrhotic liver may be responsive to CA4P as well. All these could be instructive for future clinical trials of VDAs.
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36
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Jiang L, Goto M, Zhu DQ, Hsu PL, Li KP, Cui M, He X, Morris-Natschke SL, Lee KH, Xie L. Scaffold Hopping-Driven Optimization of 4-(Quinazolin-4-yl)-3,4-dihydroquinoxalin-2(1 H)-ones as Novel Tubulin Inhibitors. ACS Med Chem Lett 2020; 11:83-89. [PMID: 31938468 DOI: 10.1021/acsmedchemlett.9b00352] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Accepted: 12/16/2019] [Indexed: 11/28/2022] Open
Abstract
Scaffold hopping-driven lead optimizations were performed based on our prior lead 7-methoxy-4-(2-methylquinazolin-4-yl)-3,4-dihydroquinoxalin-2(1H)-one (2a) by C-ring expansion and isometric replacement of the A/B-ring, successively, aimed at finding new potential alternative drug candidates with different scaffold(s), high antitumor activity, and other improved properties to replace prior, once promising drug candidates that failed in further studies. Two series of new compounds 7 (a-d) and 13 (a-j) were synthesized and evaluated for antitumor activity, leading to the discovery of three highly potent compounds 13c, 13d, and 13e with different scaffolds. They exhibited similar high antitumor activity with single digital low nanomolar GI50 values (4.6-9.6 nM) in cellular assays, comparable to lead 2a, clinical drug candidate CA-4, and paclitaxel in the same assays. Further biological evaluations identified new active compounds as tubulin polymerization inhibitors targeting the colchicine binding site. Moreover, 13d showed better aqueous solubility than 2a and a similar log P value.
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Affiliation(s)
- Li Jiang
- Beijing Institute of Pharmacology and Toxicology, 27 Tai-Ping Road, Beijing 100850, China
| | - Masuo Goto
- Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, United States
| | - Dong-Qing Zhu
- Beijing Institute of Pharmacology and Toxicology, 27 Tai-Ping Road, Beijing 100850, China
| | - Pei-Ling Hsu
- Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, United States
| | - Kang-Po Li
- Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, United States
| | - Mutian Cui
- Beijing Institute of Pharmacology and Toxicology, 27 Tai-Ping Road, Beijing 100850, China
| | - Xiaoyang He
- Beijing Institute of Radiation Medicine, 27 Tai-Ping Road, Beijing 100850, China
| | - Susan Lynne Morris-Natschke
- Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, United States
| | - Kuo-Hsiung Lee
- Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, United States
- Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, Taiwan
| | - Lan Xie
- Beijing Institute of Pharmacology and Toxicology, 27 Tai-Ping Road, Beijing 100850, China
- Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, United States
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Synthesis and biological evaluation of 1-(benzofuran-3-yl)-4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazole derivatives as tubulin polymerization inhibitors. Bioorg Chem 2020; 94:103392. [DOI: 10.1016/j.bioorg.2019.103392] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2019] [Revised: 09/04/2019] [Accepted: 10/21/2019] [Indexed: 12/13/2022]
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Design, synthesis, and biological evaluation of novel benzodiazepine derivatives as anticancer agents through inhibition of tubulin polymerization in vitro and in vivo. Eur J Med Chem 2019; 182:111670. [DOI: 10.1016/j.ejmech.2019.111670] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Revised: 08/20/2019] [Accepted: 08/30/2019] [Indexed: 11/21/2022]
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Novel [1,2,4]triazolo[1,5-a]pyrimidine derivatives as potent antitubulin agents: Design, multicomponent synthesis and antiproliferative activities. Bioorg Chem 2019; 92:103260. [PMID: 31525523 DOI: 10.1016/j.bioorg.2019.103260] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2019] [Revised: 08/27/2019] [Accepted: 09/05/2019] [Indexed: 12/15/2022]
Abstract
As restricted CA-4 analogues, a novel series of [1,2,4]triazolo[1,5-a]pyrimidines possessing 3,4,5-trimethoxylphenyl groups has been achieved successfully via an efficient one-pot three-component reaction of 3-(3,4,5-trimethoxyphenyl)-1H-1,2,4-triazol-5-amine, 1,3-dicarbonyl compounds and aldehydes. Initial biological evaluation demonstrated some of target compounds displayed potent antitumor activity in vitro against three cancer cell lines. Among them, the most highly active analogue 26 inhibited the growth of HeLa, and A549 cell lines with IC50 values at 0.75, and 1.02 μM, respectively, indicating excellent selectivity over non-tumoural cell line HEK-293 (IC50 = 29.94 μM) which suggested that the target compounds might possess a high safety index. Moreover, cell cycle analysis illustrated that the analogue 26 significantly induced HeLa cells arrest in G2/M phase, meanwhile the compound could dramatically affect cell morphology and microtubule networks. In addition, compound 28 exhibited potent anti-tubulin activity with IC50 values of 9.90 μM, and molecular docking studies revealed the analogue occupied the colchicine-binding site of tubulin. These observations suggest that [1,2,4]triazolo[1,5-a]pyrimidines represent a new class of tubulin polymerization inhibitors and well worth further investigation aiming to generate potential anticancer agents.
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40
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Gill JH, Rockley KL, De Santis C, Mohamed AK. Vascular Disrupting Agents in cancer treatment: Cardiovascular toxicity and implications for co-administration with other cancer chemotherapeutics. Pharmacol Ther 2019; 202:18-31. [PMID: 31173840 DOI: 10.1016/j.pharmthera.2019.06.001] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Accepted: 05/30/2019] [Indexed: 02/08/2023]
Abstract
Destruction of the established tumour vasculature by a class of compound termed Vascular Disrupting Agents (VDAs) is showing considerable promise as a viable approach for the management of solid tumours. VDAs induce a rapid shutdown and collapse of tumour blood vessels, leading to ischaemia and consequent necrosis of the tumour mass. Their efficacy is hindered by the persistence of a viable rim of tumour cells, supported by the peripheral normal vasculature, necessitating their co-administration with additional chemotherapeutics for maximal therapeutic benefit. However, a major limitation for the use of many cancer therapeutics is the development of life-threatening cardiovascular toxicities, with significant consequences for treatment response and the patient's quality of life. The aim of this review is to outline VDAs as a cancer therapeutic approach and define the mechanistic basis of cardiovascular toxicities of current chemotherapeutics, with the overall objective of discussing whether VDA combinations with specific chemotherapeutic classes would be good or bad in terms of cardiovascular toxicity.
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Affiliation(s)
- Jason H Gill
- Northern Institute for Cancer Research (NICR), Faculty of Medical Sciences, Newcastle University, UK; School of Pharmacy, Faculty of Medical Sciences, Newcastle University, UK.
| | - Kimberly L Rockley
- Northern Institute for Cancer Research (NICR), Faculty of Medical Sciences, Newcastle University, UK
| | - Carol De Santis
- Northern Institute for Cancer Research (NICR), Faculty of Medical Sciences, Newcastle University, UK
| | - Asma K Mohamed
- Northern Institute for Cancer Research (NICR), Faculty of Medical Sciences, Newcastle University, UK
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Liang J, Ma R, Chen H, Zhang D, Ye W, Shi C, Luo L. Detection of Hyperacute Reactions of Desacetylvinblastine Monohydrazide in a Xenograft Model Using Intravoxel Incoherent Motion DWI and R2* Mapping. AJR Am J Roentgenol 2019; 212:717-726. [PMID: 30699010 DOI: 10.2214/ajr.18.20517] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
OBJECTIVE This study aimed to investigate the feasibility of intravoxel incoherent motion (IVIM) DWI and R2* (transverse relaxation rate) mapping to monitor the hyperacute therapeutic efficacy of desacetylvinblastine monohydrazide (DAVLBH) on an experimental hepatocellular carcinoma mouse model within 24 hours. MATERIALS AND METHODS Forty-four mice were implanted with hepatocellular carcinoma and divided into three random groups. A treatment group and a control group underwent IVIM-DWI and R2* mapping examinations before and after a single injection of DAVLBH or saline at 1, 2, 4, and 24 hours. The pathology group was set for pathologic analysis, including H and E staining and CD31 and hypoxia-inducible factor (HIF)-1α immunohistochemical staining. RESULTS DAVLBH caused hyperacute disruptions on the tumor capillaries in the treatment group. Water molecule diffusion (D), microcirculation perfusion (D*), and perfusion fraction (f) decreased initially but then gradually recovered to the baseline level by 24 hours after the first injection of DAVLBH. In contrast, R2* increased dramatically at 1 hour and then gradually decreased from 1 hour to 24 hours after treatment. D*, f, and D showed similar trends and were positively correlated with CD31 expression (r = 0.868, 0.721, and 0.730, respectively), but were negatively correlated with HIF-1α expression (r = -0.784, -0.737, and -0.673, respectively). R2* showed a negative correlation with CD31 expression (r = -0.823) and a positive correlation with HIF-1α expression (r = 0.791). CONCLUSION Both IVIM-DWI and R2* mapping can adequately detect the vascular-disrupting effect of DAVLBH as early as 1 hour after injection in a mouse xenograft model. Moreover, D* and R2* are the two most sensitive hemodynamic parameters and can monitor the hyperacute changes associated with DAVLBH treatment in vivo.
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Affiliation(s)
- Jianye Liang
- 1 Medical Imaging Center, The First Affiliated Hospital of Jinan University, No. 613, Huangpu Rd West, Tianhe District, Guangzhou, Guangdong 510630, China
| | - Rong Ma
- 2 Department of Radiology, The First Affiliated Hospital of Hunan Normal University, Changsha, China
| | - Heru Chen
- 3 College of Pharmacy, Jinan University, Guangzhou, China
| | - Dongmei Zhang
- 3 College of Pharmacy, Jinan University, Guangzhou, China
| | - Wencai Ye
- 3 College of Pharmacy, Jinan University, Guangzhou, China
| | - Changzheng Shi
- 1 Medical Imaging Center, The First Affiliated Hospital of Jinan University, No. 613, Huangpu Rd West, Tianhe District, Guangzhou, Guangdong 510630, China
| | - Liangping Luo
- 1 Medical Imaging Center, The First Affiliated Hospital of Jinan University, No. 613, Huangpu Rd West, Tianhe District, Guangzhou, Guangdong 510630, China
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A class of novel tubulin polymerization inhibitors exert effective anti-tumor activity via mitotic catastrophe. Eur J Med Chem 2019; 163:896-910. [DOI: 10.1016/j.ejmech.2018.12.030] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Revised: 12/10/2018] [Accepted: 12/12/2018] [Indexed: 02/08/2023]
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43
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Blagden SP, Hamilton AL, Mileshkin L, Wong S, Michael A, Hall M, Goh JC, Lisyanskaya AS, DeSilvio M, Frangou E, Stronach EA, Gopalakrishna P, Meniawy TM, Gabra H. Phase IB Dose Escalation and Expansion Study of AKT Inhibitor Afuresertib with Carboplatin and Paclitaxel in Recurrent Platinum-resistant Ovarian Cancer. Clin Cancer Res 2018; 25:1472-1478. [PMID: 30563934 DOI: 10.1158/1078-0432.ccr-18-2277] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Revised: 09/24/2018] [Accepted: 11/30/2018] [Indexed: 11/16/2022]
Abstract
PURPOSE Preclinically, AKT kinase inhibition restores drug sensitivity in platinum-resistant tumors. Here the pan-AKT kinase inhibitor afuresertib was given in combination with paclitaxel and carboplatin (PC) in patients with recurrent platinum-resistant epithelial ovarian cancer (PROC) and primary platinum-refractory ovarian cancer (PPROC). PATIENTS AND METHODS Part I was a combination 3+3 dose escalation study for recurrent ovarian cancer. Patients received daily continuous oral afuresertib at 50-150 mg/day with intravenous paclitaxel (175 mg/m2) and carboplatin (AUC5) every 3 weeks for six cycles followed by maintenance afuresertib at 125 mg/day until progression or toxicity. Part II was a single-arm evaluation of the clinical activity of this combination in recurrent PROC (Cohort A) or PPROC (Cohort B). Patients received oral afuresertib at the MTD defined in Part I in combination with PC for six cycles, followed by maintenance afuresertib. Primary endpoints were safety and tolerability of afuresertib in combination with PC (Part I, dose escalation), and investigator-assessed overall response rate (ORR) as per RECIST version 1.1 (Part II). RESULTS Twenty-nine patients enrolled into Part I, and 30 into Part II. Three dose-limiting toxicities of grade 3 rash were observed, one at 125 mg and two at 150 mg afuresertib. The MTD of afuresertib in combination with PC was therefore identified as 125 mg/day. The most common (≥50%) drug-related adverse events observed in Part I of the study were nausea, diarrhea, vomiting, alopecia, fatigue, and neutropenia and, in Part II, were diarrhea, fatigue, nausea, and alopecia. The Part II ORR in the intention to treat patients was 32% [95% confidence interval (CI), 15.9-52.4] by RECIST 1.1 and 52% (95% CI, 31.3-72.2) by GCIG CA125 criteria. Median progression-free survival was 7.1 months (95% CI, 6.3-9.0 months). CONCLUSIONS Afuresertib plus PC demonstrated efficacy in recurrent PROC with the MTD of afuresertib defined as 125 mg/day.
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Affiliation(s)
- Sarah P Blagden
- Ovarian Cancer Action Research Centre, Imperial College London, United Kingdom. .,Department of Oncology, University of Oxford, United Kingdom
| | - Anne L Hamilton
- Royal Women's Hospital, Melbourne, Victoria, Australia.,Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Linda Mileshkin
- Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Shirley Wong
- Western Hospital, Melbourne, Victoria, Australia
| | | | - Marcia Hall
- Mount Vernon Cancer Centre, Middlesex, United Kingdom
| | - Jeffrey C Goh
- Royal Brisbane & Women's Hospital, Queensland, Australia.,University of Queensland, Saint Lucia, Queensland, Australia
| | | | | | - Eleni Frangou
- Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
| | - Euan A Stronach
- Ovarian Cancer Action Research Centre, Imperial College London, United Kingdom
| | | | - Tarek M Meniawy
- Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.,University of Western Australia, Crawley, Western Australia, Australia
| | - Hani Gabra
- Ovarian Cancer Action Research Centre, Imperial College London, United Kingdom.,Early Clinical Development, IMED Biotech Unit, AstraZeneca, Cambridge, United Kingdom
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44
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Lichota A, Gwozdzinski K. Anticancer Activity of Natural Compounds from Plant and Marine Environment. Int J Mol Sci 2018; 19:E3533. [PMID: 30423952 PMCID: PMC6275022 DOI: 10.3390/ijms19113533] [Citation(s) in RCA: 246] [Impact Index Per Article: 35.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Revised: 11/05/2018] [Accepted: 11/06/2018] [Indexed: 02/07/2023] Open
Abstract
This paper describes the substances of plant and marine origin that have anticancer properties. The chemical structure of the molecules of these substances, their properties, mechanisms of action, their structure⁻activity relationships, along with their anticancer properties and their potential as chemotherapeutic drugs are discussed in this paper. This paper presents natural substances from plants, animals, and their aquatic environments. These substances include the vinca alkaloids, mistletoe plant extracts, podophyllotoxin derivatives, taxanes, camptothecin, combretastatin, and others including geniposide, colchicine, artesunate, homoharringtonine, salvicine, ellipticine, roscovitine, maytanasin, tapsigargin, and bruceantin. Compounds (psammaplin, didemnin, dolastin, ecteinascidin, and halichondrin) isolated from the marine plants and animals such as microalgae, cyanobacteria, heterotrophic bacteria, invertebrates (e.g., sponges, tunicates, and soft corals) as well as certain other substances that have been tested on cells and experimental animals and used in human chemotherapy.
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Affiliation(s)
- Anna Lichota
- Department of Molecular Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, 90-136 Lodz, Poland.
| | - Krzysztof Gwozdzinski
- Department of Molecular Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, 90-136 Lodz, Poland.
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Prasad B, Lakshma Nayak V, Srikanth PS, Baig MF, Subba Reddy NV, Babu KS, Kamal A. Synthesis and biological evaluation of 1-benzyl-N-(2-(phenylamino)pyridin-3-yl)-1H-1,2,3-triazole-4-carboxamides as antimitotic agents. Bioorg Chem 2018; 83:535-548. [PMID: 30472555 DOI: 10.1016/j.bioorg.2018.11.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 10/31/2018] [Accepted: 11/01/2018] [Indexed: 01/11/2023]
Abstract
A library of 1-benzyl-N-(2-(phenylamino)pyridin-3-yl)-1H-1,2,3-triazole-4-carboxamides (7a-al) have been designed, synthesized and screened for their anti-proliferative activity against some selected human cancer cell lines namely DU-145, A-549, MCF-7 and HeLa. Most of them have shown promising cytotoxicity against lung cancer cell line (A549), amongst them 7f was found to be the most potent anti-proliferative congener. Furthermore, 7f exhibited comparable tubulin polymerization inhibition (IC50 value 2.04 µM) to the standard E7010 (IC50 value 2.15 µM). Moreover, flow cytometric analysis revealed that this compound induced apoptosis via cell cycle arrest at G2/M phase in A549 cells. Induction of apoptosis was further observed by examining the mitochondrial membrane potential and was also confirmed by Hoechst staining as well as Annexin V-FITC assays. Furthermore, molecular docking studies indicated that compound 7f binds to the colchicine binding site of the β-tubulin. Thus, 7f exhibits anti-proliferative properties by inhibiting the tubulin polymerization through the binding at the colchicine active site and by induction of apoptosis.
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Affiliation(s)
- Budaganaboyina Prasad
- Medicinal Chemistry and Biotechnology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India; Department of Chemistry, Osmania University, Hyderabad 500007, Telangana, India
| | - V Lakshma Nayak
- Medicinal Chemistry and Biotechnology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
| | - P S Srikanth
- Medicinal Chemistry and Biotechnology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
| | - Mirza Feroz Baig
- Medicinal Chemistry and Biotechnology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
| | - N V Subba Reddy
- Medicinal Chemistry and Biotechnology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
| | - Korrapati Suresh Babu
- Medicinal Chemistry and Biotechnology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India; Department of Chemistry, Osmania University, Hyderabad 500007, Telangana, India
| | - Ahmed Kamal
- Medicinal Chemistry and Biotechnology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India; School of Pharmaceutical Education and Research (SPER), Jamia Hamdard, 110 062 New Delhi, India.
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Lindemann K, Beale PJ, Rossi E, Goh JC, Vaughan MM, Tenney ME, Martyn JK, Sommeijer D, Iglesias JL, Kremmidiotis G, Simpson J, Doolin E, Lavranos TC, Leske A, Veillard AS, Espinoza D, Stockler MR, Rischin D. Phase I study of BNC105P, carboplatin and gemcitabine in partially platinum-sensitive ovarian cancer patients in first or second relapse (ANZGOG-1103). Cancer Chemother Pharmacol 2018; 83:97-105. [DOI: 10.1007/s00280-018-3706-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Accepted: 08/27/2018] [Indexed: 12/27/2022]
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47
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Lai Q, Wang Y, Wang R, Lai W, Tang L, Tao Y, Liu Y, Zhang R, Huang L, Xiang H, Zeng S, Gou L, Chen H, Yao Y, Yang J. Design, synthesis and biological evaluation of a novel tubulin inhibitor 7a3 targeting the colchicine binding site. Eur J Med Chem 2018; 156:162-179. [DOI: 10.1016/j.ejmech.2018.05.010] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Revised: 04/20/2018] [Accepted: 05/07/2018] [Indexed: 11/29/2022]
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48
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Liu YW, De Keyzer F, Feng YB, Chen F, Song SL, Swinnen J, Bormans G, Oyen R, Huang G, Ni YC. Intra-individual comparison of therapeutic responses to vascular disrupting agent CA4P between rodent primary and secondary liver cancers. World J Gastroenterol 2018; 24:2710-2721. [PMID: 29991876 PMCID: PMC6034151 DOI: 10.3748/wjg.v24.i25.2710] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Revised: 04/01/2018] [Accepted: 04/09/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To compare therapeutic responses of a vascular-disrupting-agent, combretastatin-A4-phosphate (CA4P), among hepatocellular carcinomas (HCCs) and implanted rhabdomyosarcoma (R1) in the same rats by magnetic-resonance-imaging (MRI), microangiography and histopathology.
METHODS Thirty-six HCCs were created by diethylnitrosamine gavage in 14 rats that were also intrahepatically implanted with one R1 per rat as monitored by T2-/T1-weighted images (T2WI/T1WI) on a 3.0T clinical MRI-scanner. Vascular response and tumoral necrosis were detected by dynamic contrast-enhanced (DCE-) and CE-MRI before, 1 h after and 12 h after CA4P iv at 10 mg/kg (treatment group n = 7) or phosphate-buffered saline at 1.0 mL/kg (control group n = 7). Tumor blood supply was calculated by a semiquantitative DCE parameter of area under the time signal intensity curve (AUC30). In vivo MRI findings were verified by postmortem techniques.
RESULTS On CE-T1WIs, unlike the negative response in all tumors of control animals, in treatment group CA4P caused rapid extensive vascular shutdown in all R1-tumors, but mildly or spottily in HCCs at 1 h. Consequently, tumor necrosis occurred massively in R1-tumors but patchily in HCCs at 12 h. AUC30 revealed vascular closure (66%) in R1-tumors at 1 h (P < 0.05), followed by further perfusion decrease at 12 h (P < 0.01), while less significant vascular clogging occurred in HCCs. Histomorphologically, CA4P induced more extensive necrosis in R1-tumors (92.6%) than in HCCs (50.2%) (P < 0.01); tumor vascularity heterogeneously scored +~+++ in HCCs but homogeneously scored ++ in R1-tumors.
CONCLUSION This study suggests superior performance of CA4P in metastatic over primary liver cancers, which could guide future clinical applications of vascular-disrupting-agents.
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MESH Headings
- Angiography
- Animals
- Antineoplastic Agents, Phytogenic/pharmacology
- Antineoplastic Agents, Phytogenic/therapeutic use
- Carcinoma, Hepatocellular/blood supply
- Carcinoma, Hepatocellular/chemically induced
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/pathology
- Contrast Media/administration & dosage
- Diethylnitrosamine/toxicity
- Humans
- Liver/diagnostic imaging
- Liver/pathology
- Liver Neoplasms/blood supply
- Liver Neoplasms/chemically induced
- Liver Neoplasms/drug therapy
- Liver Neoplasms/pathology
- Liver Neoplasms, Experimental/chemically induced
- Liver Neoplasms, Experimental/diagnostic imaging
- Liver Neoplasms, Experimental/drug therapy
- Liver Neoplasms, Experimental/pathology
- Magnetic Resonance Imaging/methods
- Male
- Neovascularization, Pathologic/drug therapy
- Neovascularization, Pathologic/pathology
- Rats
- Rhabdomyosarcoma/blood supply
- Rhabdomyosarcoma/drug therapy
- Rhabdomyosarcoma/pathology
- Rhabdomyosarcoma/secondary
- Stilbenes/pharmacology
- Stilbenes/therapeutic use
- Treatment Outcome
- Tumor Microenvironment/drug effects
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Ye-Wei Liu
- Shanghai Key Laboratory for Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China
- Biomedical Group, Campus Gasthuisberg, KU Leuven, Leuven 3000, Belgium
- Institute of Clinical Nuclear Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
- Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) & Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai 200025, China
| | | | - Yuan-Bo Feng
- Biomedical Group, Campus Gasthuisberg, KU Leuven, Leuven 3000, Belgium
| | - Feng Chen
- Biomedical Group, Campus Gasthuisberg, KU Leuven, Leuven 3000, Belgium
| | - Shao-Li Song
- Institute of Clinical Nuclear Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Johan Swinnen
- Biomedical Group, Campus Gasthuisberg, KU Leuven, Leuven 3000, Belgium
| | - Guy Bormans
- Biomedical Group, Campus Gasthuisberg, KU Leuven, Leuven 3000, Belgium
| | - Raymond Oyen
- Biomedical Group, Campus Gasthuisberg, KU Leuven, Leuven 3000, Belgium
| | - Gang Huang
- Shanghai Key Laboratory for Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China
- Institute of Clinical Nuclear Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
- Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) & Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai 200025, China
| | - Yi-Cheng Ni
- Biomedical Group, Campus Gasthuisberg, KU Leuven, Leuven 3000, Belgium
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Liu Y, De Keyzer F, Wang Y, Wang F, Feng Y, Chen F, Yu J, Liu J, Song S, Swinnen J, Bormans G, Oyen R, Huang G, Ni Y. The first study on therapeutic efficacies of a vascular disrupting agent CA4P among primary hepatocellular carcinomas with a full spectrum of differentiation and vascularity: Correlation of MRI-microangiography-histopathology in rats. Int J Cancer 2018; 143:1817-1828. [PMID: 29707770 DOI: 10.1002/ijc.31567] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Revised: 03/27/2018] [Accepted: 04/10/2018] [Indexed: 12/19/2022]
Abstract
To better inform the next clinical trials of vascular disrupting agent combretastatin-A4-phosphate (CA4P) in patients with hepatic malignancies, this preclinical study aimed at evaluating CA4P therapeutic efficacy in rats with primary hepatocellular carcinomas (HCCs) of a full spectrum of differentiation and vascularity by magnetic resonance imaging (MRI), microangiography and histopathology. Ninety-six HCCs were raised in 25 rats by diethylnitrosamine gavage. Tumor growth was monitored by T2-/T1-weighted-MRI (T2WI, T1WI) using a 3.0 T scanner. Early vascular response and later intratumoral necrosis were detected by dynamic-contrast-enhanced (DCE) MRI and diffusion-weighted-imaging (DWI) before, 1 and 12 hr after CA4P iv-administration. In vivo MRI-findings were validated by postmortem-techniques. Multi-parametric MRI revealed rapid CA4P-induced tumor vascular shutdown within 1 hr, followed by variable intratumoral necrosis at 12 hr. Tumor volumes decreased by 10% at 1 hr (p < 0.05), but resumed at 12 hr. Correlations of semi-quantitative DCE parameter initial-area-under-the-gadolinium-curve (IAUGC30) with histopathology proved partial vascular closure and compensational reopening (p < 0.05). The higher grades of vascularity prevented those residual tumor tissues from CA4P-caused ischemic necrosis. By histopathology using a 4-scale cellular-differentiation criteria and a 4-grade tumor-vascularity classification, percentage of CA4P-induced necrosis negatively correlated with HCC differentiation (r = -0.404, p < 0.001) and tumor vascularity (r = -0.370, p < 0.001). Ordinal-logistic-regression helped to predict early tumor responses to CA4P in terms of tumoral differentiation and vascularity. Our study demonstrated that CA4P could induce vascular shutdown in primary HCCs within 1 hr, resulting in various degrees of tumor necrosis at 12 hr. MRI as a real-time imaging biomarker may help to define tumor vascularity and differentiation and further to predict CA4P therapeutic outcomes.
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Affiliation(s)
- Yewei Liu
- Biomedical Group, Campus Gasthuisberg, KU Leuven, Leuven, Belgium.,Shanghai Key Laboratory for Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai, China.,Institute of Clinical Nuclear Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) & Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai, China
| | | | - Yixin Wang
- Biomedical Group, Campus Gasthuisberg, KU Leuven, Leuven, Belgium
| | - Fengna Wang
- Biomedical Group, Campus Gasthuisberg, KU Leuven, Leuven, Belgium
| | - Yuanbo Feng
- Biomedical Group, Campus Gasthuisberg, KU Leuven, Leuven, Belgium
| | - Feng Chen
- Biomedical Group, Campus Gasthuisberg, KU Leuven, Leuven, Belgium
| | - Jie Yu
- Biomedical Group, Campus Gasthuisberg, KU Leuven, Leuven, Belgium
| | - Jianjun Liu
- Institute of Clinical Nuclear Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shaoli Song
- Institute of Clinical Nuclear Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Johan Swinnen
- Biomedical Group, Campus Gasthuisberg, KU Leuven, Leuven, Belgium
| | - Guy Bormans
- Biomedical Group, Campus Gasthuisberg, KU Leuven, Leuven, Belgium
| | - Raymond Oyen
- Biomedical Group, Campus Gasthuisberg, KU Leuven, Leuven, Belgium
| | - Gang Huang
- Shanghai Key Laboratory for Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai, China.,Institute of Clinical Nuclear Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) & Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai, China
| | - Yicheng Ni
- Biomedical Group, Campus Gasthuisberg, KU Leuven, Leuven, Belgium
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El Bairi K, Amrani M, Afqir S. Starvation tactics using natural compounds for advanced cancers: pharmacodynamics, clinical efficacy, and predictive biomarkers. Cancer Med 2018; 7:2221-2246. [PMID: 29732738 PMCID: PMC6010871 DOI: 10.1002/cam4.1467] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Revised: 02/21/2018] [Accepted: 02/28/2018] [Indexed: 02/05/2023] Open
Abstract
The high mortality associated with oncological diseases is mostly due to tumors in advanced stages, and their management is a major challenge in modern oncology. Angiogenesis is a defined hallmark of cancer and predisposes to metastatic invasion and dissemination and is therefore an important druggable target for cancer drug discovery. Recently, because of drug resistance and poor prognosis, new anticancer drugs from natural sources targeting tumor vessels have attracted more attention and have been used in several randomized and controlled clinical trials as therapeutic options. Here, we outline and discuss potential natural compounds as salvage treatment for advanced cancers from recent and ongoing clinical trials and real-world studies. We also discuss predictive biomarkers for patients' selection to optimize the use of these potential anticancer drugs.
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Affiliation(s)
- Khalid El Bairi
- Faculty of Medicine and PharmacyMohamed Ist UniversityOujdaMorocco
| | - Mariam Amrani
- Equipe de Recherche en Virologie et Onco‐biologieFaculty of MedicinePathology DepartmentNational Institute of OncologyUniversité Mohamed VRabatMorocco
| | - Said Afqir
- Department of Medical OncologyMohamed VI University HospitalOujdaMorocco
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