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Wang X, Tian W, Wang N, Yang X, Liu Z, Li L, Zhao T, Wang C, Zhang H, Yang H, Jia Y. Transcriptome analysis reveals the anticancer effects of fenbendazole on ovarian cancer: an in vitro and in vivo study. BMC Cancer 2024; 24:1593. [PMID: 39736624 DOI: 10.1186/s12885-024-13361-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Accepted: 12/17/2024] [Indexed: 01/01/2025] Open
Abstract
New treatment strategies for ovarian cancer, which is the deadliest female reproductive tract malignancy, are urgently needed. Here, we investigated the anticancer effects of fenbendazole (FBZ), a benzimidazole compound, on the regulation of apoptosis and mitotic catastrophe in A2780 and SKOV3 human epithelial ovarian cancer cells. Functional experiments, including Cell Counting Kit 8 (CCK-8), colony formation, and flow cytometry assays, were conducted to explore the effects of FBZ on the malignant biological behavior of A2780 and SKOV3 cells. RNA sequencing and western blotting were utilized to elucidate the underlying mechanisms by which FBZ affects cell apoptosis. We found that FBZ inhibited the proliferation and promoted the apoptosis of ovarian cancer cells in a dose-dependent manner. Furthermore, we reported the transcriptome profiling of FBZ-treated SKOV3 ovarian cancer cells. In all, 1747 differentially expressed genes (DEGs) were identified, including 944 downregulated and 803 upregulated genes. KEGG enrichment and Reactome enrichment analyses revealed that the DEGs were associated mainly with mitosis- and cell cycle-related pathways. Additionally, we found that FBZ may promote apoptosis via mitotic catastrophe. Finally, oral administration of FBZ inhibited tumor growth in a mouse model of xenograft ovarian cancer. Overall, these findings suggest that FBZ has therapeutic potential for the treatment of ovarian cancer.
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Affiliation(s)
- Xin Wang
- Department of Gynecology, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan, Kunming, 650118, Yunnan, P. R. China
| | - Wenda Tian
- Department of Gynecology, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan, Kunming, 650118, Yunnan, P. R. China
| | - Ning Wang
- Department of Obstetrics and Gynecology, Dehong Affiliated Hospital of Kunming Medical University, Dehong People's Hospital of Yunnan Province, Kunming, 678400, Yunnan, P. R. China
| | - Xiangqun Yang
- Department of Gynecology, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan, Kunming, 650118, Yunnan, P. R. China
| | - Zhenyan Liu
- Department of Gynecology, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan, Kunming, 650118, Yunnan, P. R. China
| | - Lvzhou Li
- Department of Obstetrics and Gynecology, Dehong Affiliated Hospital of Kunming Medical University, Dehong People's Hospital of Yunnan Province, Kunming, 678400, Yunnan, P. R. China
| | - Taoyu Zhao
- Department of Obstetrics and Gynecology, Dehong Affiliated Hospital of Kunming Medical University, Dehong People's Hospital of Yunnan Province, Kunming, 678400, Yunnan, P. R. China
| | - Chuanlin Wang
- Department of Clinical Nutrition, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan, Kunming, 650118, Yunnan, P. R. China
| | - Hongping Zhang
- Department of Gynecology, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan, Kunming, 650118, Yunnan, P. R. China.
| | - Hongying Yang
- Department of Gynecology, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan, Kunming, 650118, Yunnan, P. R. China.
| | - Yue Jia
- Department of Gynecology, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan, Kunming, 650118, Yunnan, P. R. China.
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Xing X, Zhou Z, Peng H, Cheng S. Anticancer role of flubendazole: Effects and molecular mechanisms (Review). Oncol Lett 2024; 28:558. [PMID: 39355784 PMCID: PMC11443308 DOI: 10.3892/ol.2024.14691] [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: 07/12/2024] [Accepted: 08/29/2024] [Indexed: 10/03/2024] Open
Abstract
Flubendazole, an anthelmintic agent with a well-established safety profile, has emerged as a promising anticancer drug that has demonstrated efficacy against a spectrum of cancer types over the past decade. Its anticancer properties encompass a multifaceted mechanism of action, including the inhibition of cancer cell proliferation, disruption of microtubule dynamics, regulation of cell cycle, autophagy, apoptosis, suppression of cancer stem cell characteristics, promotion of ferroptosis and inhibition of angiogenesis. The present review aimed to provide a comprehensive overview of the molecular underpinnings of the anticancer activity of flubendazole, highlighting key molecules and regulatory pathways. Given the breadth of the potential of flubendazole, further research is imperative to identify additional cancer types sensitive to flubendazole, refine experimental methodologies for enhancing its reliability, uncover synergistic drug combinations, improve its bioavailability and explore innovative administration methods. The present review provided a foundation for future studies on the role of flubendazole in oncology and described its molecular mechanisms of action.
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Affiliation(s)
- Xing Xing
- Department of Urology, The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei 434000, P.R. China
| | - Zongning Zhou
- Human Genetic Resources Preservation Center of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Hongwei Peng
- Human Genetic Resources Preservation Center of Wuhan University, Wuhan, Hubei 430071, P.R. China
- Hubei Key Laboratory of Urological Diseases, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Shaoping Cheng
- Department of Urology, The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei 434000, P.R. China
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Liang M, Wang Y, Liu L, Deng D, Yan Z, Feng L, Kong C, Li C, Li Y, Li G. Synergistic intravesical instillation for bladder cancer: CRISPR-Cas13a and fenbendazole combination therapy. J Exp Clin Cancer Res 2024; 43:223. [PMID: 39128990 PMCID: PMC11318243 DOI: 10.1186/s13046-024-03146-0] [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: 01/30/2024] [Accepted: 07/30/2024] [Indexed: 08/13/2024] Open
Abstract
BACKGROUND CRISPR-Cas13a is renowned for its precise and potent RNA editing capabilities in cancer therapy. While various material systems have demonstrated efficacy in supporting CRISPR-Cas13a to execute cellular functions in vitro efficiently and specifically, the development of CRISPR-Cas13a-based therapeutic agents for intravesical instillation in bladder cancer (BCa) remains unexplored. METHODS In this study, we introduce a CRISPR-Cas13a nanoplatform, which effectively inhibits PDL1 expression following intravesical instillation. This system utilizes a fusion protein CAST, created through the genetic fusion of CRISPR-Cas13 and the transmembrane peptide TAT. CAST acts as a potent transmembrane RNA editor and is assembled with the transepithelial delivery carrier fluorinated chitosan (FCS). Upon intravesical administration into the bladder, the CAST-crRNAa/FCS nanoparticles (NPs) exhibit remarkable transepithelial capabilities, significantly suppressing PDL1 expression in tumor tissues.To augment immune activation within the tumor microenvironment, we integrated a fenbendazole (FBZ) intravesical system (FBZ@BSA/FCS NPs). This system is formulated through BSA encapsulation followed by FCS coating, positioning FBZ as a powerful chemo-immunological agent. RESULTS In an orthotropic BCa model, the FBZ@BSA/FCS NPs demonstrated pronounced tumor cell apoptosis, synergistically reduced PDL1 expression, and restructured the immune microenvironment. This culminated in an enhanced synergistic intravesical instillation approach for BCa. Consequently, our study unveils a novel RNA editor nanoagent formulation and proposes a potential synergistic therapeutic strategy. This approach significantly bolsters therapeutic efficacy, holding promise for the clinical translation of CRISPR-Cas13-based cancer perfusion treatments.
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Affiliation(s)
- Mingkang Liang
- Institute of Urology, The Affiliated Luohu Hospital of Shenzhen University, Shenzhen University, Shenzhen, Guangdong, 518000, China
- Institute of Urology, Luohu Clinical College of Shantou University Medical College, Shantou University Medical College, Shantou, Guangdong, 515000, China
| | - Yongqiang Wang
- Department of Urology, Health Science Center, South China Hospital, Shenzhen University, Shenzhen, Guangdomg, 518116, China
| | - Lisha Liu
- Institute of Urology, The Affiliated Luohu Hospital of Shenzhen University, Shenzhen University, Shenzhen, Guangdong, 518000, China
| | - Dashi Deng
- Institute of Urology, The Affiliated Luohu Hospital of Shenzhen University, Shenzhen University, Shenzhen, Guangdong, 518000, China
| | - Zeqin Yan
- Department of Urology, Health Science Center, South China Hospital, Shenzhen University, Shenzhen, Guangdomg, 518116, China
| | - Lida Feng
- Institute of Urology, The Affiliated Luohu Hospital of Shenzhen University, Shenzhen University, Shenzhen, Guangdong, 518000, China
| | - Chenfan Kong
- Institute of Urology, The Affiliated Luohu Hospital of Shenzhen University, Shenzhen University, Shenzhen, Guangdong, 518000, China
| | - Chenchen Li
- Institute of Urology, The Affiliated Luohu Hospital of Shenzhen University, Shenzhen University, Shenzhen, Guangdong, 518000, China
| | - Yuqing Li
- Institute of Urology, Luohu Clinical College of Shantou University Medical College, Shantou University Medical College, Shantou, Guangdong, 515000, China.
- Department of Urology, Health Science Center, South China Hospital, Shenzhen University, Shenzhen, Guangdomg, 518116, China.
| | - Guangzhi Li
- Institute of Urology, The Affiliated Luohu Hospital of Shenzhen University, Shenzhen University, Shenzhen, Guangdong, 518000, China.
- Institute of Urology, Luohu Clinical College of Shantou University Medical College, Shantou University Medical College, Shantou, Guangdong, 515000, China.
- Department of Urology, Health Science Center, South China Hospital, Shenzhen University, Shenzhen, Guangdomg, 518116, China.
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Zhang B, Zhao J, Kang D, Wang Z, Xu L, Zheng R, Liu A. Flubendazole suppresses VEGF-induced angiogenesis in HUVECs and exerts antitumor effects in PC-3 cells. Chem Biol Drug Des 2024; 103:e14503. [PMID: 38480495 DOI: 10.1111/cbdd.14503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 01/17/2024] [Accepted: 02/07/2024] [Indexed: 03/27/2024]
Abstract
Flubendazole, an FDA-approved anthelmintic, has been predicted to show strong VEGFR2 inhibitory activity in silico screening combined with in vitro experimental validation, and it has shown anti-cancer effects on some human cancer cell lines, but little is known about the anti-angiogenesis effects and anti-prostate cancer effects. In this study, we analyzed the binding modes and kinetic analysis of flubendazole with VEGFR2 and first demonstrated that flubendazole suppressed VEGF-stimulated cell proliferation, wound-healing migration, cell invasion and tube formation of HUVEC cells, and decreased the phosphorylation of extracellular signal-regulated kinase and serine/threonine kinase Akt, which are the downstream proteins of VEGFR2 that are important for cell growth. What's more, our results showed that flubendazole decreased PC-3 cell viability and proliferation ability, and suppressed PC-3 cell wound healing migration and invasion across a Matrigel-coated Transwell membrane in a concentration-dependent manner. The antiproliferative effects of flubendazole were due to induction of G2-M phase cell cycle arrest in PC-3 cells with decreasing expression of the Cyclin D1 and induction of cell apoptosis with the number of apoptotic cells increased after flubendazole treatment. These results indicated that flubendazole could exert anti-angiogenic and anticancer effects by inhibiting cell cycle and inducing cell apoptosis.
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Affiliation(s)
- Baoyue 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, China
- Department of Pharmacy, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, Shandong, China
| | - Jun Zhao
- 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, China
| | - De Kang
- 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, China
| | - Zhe Wang
- 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, China
| | - Lvjie 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, China
| | - RuiFang Zheng
- Xinjiang Key Laboratory of Uighur Medicines, Xinjiang Institute of Materia Medica, Urumchi, Xinjiang, China
| | - Ailin Liu
- 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, China
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Zhou Y, Liao M, Li Z, Ye J, Wu L, Mou Y, Fu L, Zhen Y. Flubendazole Enhances the Inhibitory Effect of Paclitaxel via HIF1α/PI3K/AKT Signaling Pathways in Breast Cancer. Int J Mol Sci 2023; 24:15121. [PMID: 37894802 PMCID: PMC10606573 DOI: 10.3390/ijms242015121] [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: 08/09/2023] [Revised: 09/27/2023] [Accepted: 10/04/2023] [Indexed: 10/29/2023] Open
Abstract
Paclitaxel, a natural anticancer drug, is widely recognized and extensively utilized in the treatment of breast cancer (BC). However, it may lead to certain side effects or drug resistance. Fortunately, combination therapy with another anti-tumor agent has been explored as an option to improve the efficacy of paclitaxel in the treatment of BC. Herein, we first evaluated the synergistic effects of paclitaxel and flubendazole through combination index (CI) calculations. Secondly, flubendazole was demonstrated to synergize paclitaxel-mediated BC cell killing in vitro and in vivo. Moreover, we discovered that flubendazole could reverse the drug resistance of paclitaxel-resistant BC cells. Mechanistically, flubendazole was demonstrated to enhance the inhibitory effect of paclitaxel via HIF1α/PI3K/AKT signaling pathways. Collectively, our findings demonstrate the effectiveness of flubendazole in combination with paclitaxel for treating BC, providing an insight into exploiting more novel combination therapies for BC in the future.
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Affiliation(s)
- Yuxin Zhou
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China; (Y.Z.); (M.L.); (J.Y.); (L.W.); (Y.M.)
| | - Minru Liao
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China; (Y.Z.); (M.L.); (J.Y.); (L.W.); (Y.M.)
| | - Zixiang Li
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China;
| | - Jing Ye
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China; (Y.Z.); (M.L.); (J.Y.); (L.W.); (Y.M.)
| | - Lifeng Wu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China; (Y.Z.); (M.L.); (J.Y.); (L.W.); (Y.M.)
| | - Yi Mou
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China; (Y.Z.); (M.L.); (J.Y.); (L.W.); (Y.M.)
| | - Leilei Fu
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China;
| | - Yongqi Zhen
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China; (Y.Z.); (M.L.); (J.Y.); (L.W.); (Y.M.)
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6
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O'Meara CH, Jafri Z, Khachigian LM. Immune Checkpoint Inhibitors, Small-Molecule Immunotherapies and the Emerging Role of Neutrophil Extracellular Traps in Therapeutic Strategies for Head and Neck Cancer. Int J Mol Sci 2023; 24:11695. [PMID: 37511453 PMCID: PMC10380483 DOI: 10.3390/ijms241411695] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 07/13/2023] [Accepted: 07/17/2023] [Indexed: 07/30/2023] Open
Abstract
Immune checkpoint inhibitor (ICI) therapy has revolutionized the treatment of many cancer types, including head and neck cancers (HNC). When checkpoint and partner proteins bind, these send an "off" signal to T cells, which prevents the immune system from destroying tumor cells. However, in HNC, and indeed many other cancers, more people do not respond and/or suffer from toxic effects than those who do respond. Hence, newer, more effective approaches are needed. The challenge to durable therapy lies in a deeper understanding of the complex interactions between immune cells, tumor cells and the tumor microenvironment. This will help develop therapies that promote lasting tumorlysis by overcoming T-cell exhaustion. Here we explore the strengths and limitations of current ICI therapy in head and neck squamous cell carcinoma (HNSCC). We also review emerging small-molecule immunotherapies and the growing promise of neutrophil extracellular traps in controlling tumor progression and metastasis.
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Affiliation(s)
- Connor H O'Meara
- Department of Otorhinolaryngology, Head and Neck Surgery, Prince of Wales Hospital, Randwick, NSW 2031, Australia
| | - Zuhayr Jafri
- Vascular Biology and Translational Research, School of Biomedical Sciences, UNSW Faculty of Medicine and Health, University of New South Wales, Sydney, NSW 2052, Australia
| | - Levon M Khachigian
- Vascular Biology and Translational Research, School of Biomedical Sciences, UNSW Faculty of Medicine and Health, University of New South Wales, Sydney, NSW 2052, Australia
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7
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Wu Y, Xie M, Sun JH, Li CC, Dong GH, Zhang QS, Cui PL. Cellular senescence: a promising therapeutic target in colorectal cancer. Future Oncol 2022; 18:3463-3470. [PMID: 36069254 DOI: 10.2217/fon-2021-0661] [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: 11/21/2022] Open
Abstract
Colorectal cancer is one of the most malignant cancers worldwide, and efforts have been made to elucidate the mechanism of colorectal carcinogenesis. Cellular senescence is a physiological process in cell life, but it is also found in cancer initiation and progression. Lines of evidence show that senescence may influence the development and progression of colorectal carcinogenesis. Here, the authors review the characteristics of senescence and the recent findings of a relationship between senescence and colorectal cancer.
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Affiliation(s)
- Yue Wu
- International Medical Services (IMS), Beijing Tiantan Hospital of Capital Medical University, No. 119 South Fourth Ring West Road, Fengtai District, Beijing, 100070, China
| | - Min Xie
- International Medical Services (IMS), Beijing Tiantan Hospital of Capital Medical University, No. 119 South Fourth Ring West Road, Fengtai District, Beijing, 100070, China
| | - Jia-Huan Sun
- International Medical Services (IMS), Beijing Tiantan Hospital of Capital Medical University, No. 119 South Fourth Ring West Road, Fengtai District, Beijing, 100070, China
| | - Cong-Cong Li
- International Medical Services (IMS), Beijing Tiantan Hospital of Capital Medical University, No. 119 South Fourth Ring West Road, Fengtai District, Beijing, 100070, China
| | - Ge-Hong Dong
- Department of Pathology, Beijing Tiantan Hospital of Capital Medical University, No. 119 South Fourth Ring West Road, Fengtai District, Beijing, 100070, China
| | - Qin-Sheng Zhang
- Department of Gastroenterology, Henan Province Hospital of Traditional Chinese Medicine, Henan University of Chinese Medicine, No. 6 Dongfeng Road, Jinshui District, Zhengzhou, Henan, 450002, China
| | - Pei-Lin Cui
- International Medical Services (IMS), Beijing Tiantan Hospital of Capital Medical University, No. 119 South Fourth Ring West Road, Fengtai District, Beijing, 100070, China
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8
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Park D, Lee JH, Yoon SP. Anti-cancer effects of fenbendazole on 5-fluorouracil-resistant colorectal cancer cells. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY 2022; 26:377-387. [PMID: 36039738 PMCID: PMC9437363 DOI: 10.4196/kjpp.2022.26.5.377] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 06/07/2022] [Accepted: 06/20/2022] [Indexed: 12/24/2022]
Abstract
Benzimidazole anthelmintic agents have been recently repurposed to overcome cancers resistant to conventional therapies. To evaluate the anti-cancer effects of benzimidazole on resistant cells, various cell death pathways were investigated in 5-fluorouracil-resistant colorectal cancer cells. The viability of wild-type and 5-fluorouracil-resistant SNU-C5 colorectal cancer cells was assayed, followed by Western blotting. Flow cytometry assays for cell death and cell cycle was also performed to analyze the anti-cancer effects of benzimidazole. When compared with albendazole, fenbendazole showed higher susceptibility to 5-fluorouracil-resistant SNU-C5 cells and was used in subsequent experiments. Flow cytometry revealed that fenbendazole significantly induces apoptosis as well as cell cycle arrest at G2/M phase on both cells. When compared with wild-type SNU-C5 cells, 5-fluorouracil-resistant SNU-C5 cells showed reduced autophagy, increased ferroptosis and ferroptosis-augmented apoptosis, and less activation of caspase-8 and p53. These results suggest that fenbendazole may be a potential alternative treatment in 5-fluorouracil-resistant cancer cells, and the anticancer activity of fenbendazole does not require p53 in 5-fluorouracil-resistant SNU-C5 cells.
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Affiliation(s)
- Deokbae Park
- Department of Histology, College of Medicine, Jeju National University, Jeju 63243, Korea
| | - Jung-Hee Lee
- Department of Cellular and Molecular Medicine, Chosun University School of Medicine, Gwangju 61452, Korea
| | - Sang-Pil Yoon
- Department of Anatomy, College of Medicine, Jeju National University, Jeju 63243, Korea
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9
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Non-Canonical Programmed Cell Death in Colon Cancer. Cancers (Basel) 2022; 14:cancers14143309. [PMID: 35884370 PMCID: PMC9320762 DOI: 10.3390/cancers14143309] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 06/24/2022] [Accepted: 07/05/2022] [Indexed: 12/18/2022] Open
Abstract
Simple Summary Non-canonical PCD is an important player in colon cancer cell suicide. It influences colon cancer in many ways, such as through tumorigenesis, treatment, and prognosis. In this review, we present the mechanism, application, and prospect of different types of non-canonical PCD in colon cancer. Abstract Programmed cell death (PCD) is an evolutionarily conserved process of cell suicide that is regulated by various genes and the interaction of multiple signal pathways. Non-canonical programmed cell death (PCD) represents different signaling excluding apoptosis. Colon cancer is the third most incident and the fourth most mortal worldwide. Multiple factors such as alcohol, obesity, and genetic and epigenetic alternations contribute to the carcinogenesis of colon cancer. In recent years, emerging evidence has suggested that diverse types of non-canonical programmed cell death are involved in the initiation and development of colon cancer, including mitotic catastrophe, ferroptosis, pyroptosis, necroptosis, parthanatos, oxeiptosis, NETosis, PANoptosis, and entosis. In this review, we summarized the association of different types of non-canonical PCD with tumorigenesis, progression, prevention, treatments, and prognosis of colon cancer. In addition, the prospect of drug-resistant colon cancer therapy related to non-canonical PCD, and the interaction between different types of non-canonical PCD, was systemically reviewed.
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10
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Kim S, Leem J, Oh JS, Kim JS. Cytotoxicity of 9,10-Phenanthrenequinone Impairs Mitotic Progression and Spindle Assembly Independent of ROS Production in HeLa Cells. TOXICS 2022; 10:toxics10060327. [PMID: 35736935 PMCID: PMC9227850 DOI: 10.3390/toxics10060327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 06/10/2022] [Accepted: 06/14/2022] [Indexed: 11/16/2022]
Abstract
The polycyclic aromatic hydrocarbon quinone derivative 9,10-phenanthrenequinone (9,10-PQ) is one of the most abundant and toxic components found in diesel exhaust particles (DEPs). These DEPs are created during diesel fuel combustion and are considered the main source of urban air pollution. As 9,10-PQ can produce excessive reactive oxygen species (ROS) through redox cycling, it has been shown to exert potent cytotoxic effects against various cell types. However, the mechanisms underlying this cytotoxicity remain unclear. In this study, we showed that 9,10-PQ exerts cytotoxicity by impairing mitotic progression and spindle assembly in HeLa cells. Exposure to 9,10-PQ impaired spindle assembly and chromosome alignment, resulting in delayed mitotic entry and progression in HeLa cells. Furthermore, 9,10-PQ exposure decreased the CEP192 and p-Aurora A levels at the spindle poles. Notably, these mitotic defects induced by 9,10-PQ were not rescued by scavenging ROS, implying the ROS-independent activity of 9,10-PQ. Therefore, our results provide the first evidence that 9,10-PQ exerts its cytotoxicity through specific inhibition of mitotic progression and spindle assembly, independent of ROS.
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Affiliation(s)
- Seul Kim
- Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Korea;
| | - Jiyeon Leem
- Department of Integrative Biotechnology, College of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon 16419, Korea;
| | - Jeong Su Oh
- Department of Integrative Biotechnology, College of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon 16419, Korea;
- Correspondence: (J.S.O.); (J.-S.K.)
| | - Jae-Sung Kim
- Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Korea;
- Correspondence: (J.S.O.); (J.-S.K.)
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11
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Egorshina AY, Zamaraev AV, Kaminskyy VO, Radygina TV, Zhivotovsky B, Kopeina GS. Necroptosis as a Novel Facet of Mitotic Catastrophe. Int J Mol Sci 2022; 23:ijms23073733. [PMID: 35409093 PMCID: PMC8998610 DOI: 10.3390/ijms23073733] [Citation(s) in RCA: 12] [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: 01/25/2022] [Revised: 03/22/2022] [Accepted: 03/23/2022] [Indexed: 02/01/2023] Open
Abstract
Mitotic catastrophe is a defensive mechanism that promotes elimination of cells with aberrant mitosis by triggering the cell-death pathways and/or cellular senescence. Nowadays, it is known that apoptosis, autophagic cell death, and necrosis could be consequences of mitotic catastrophe. Here, we demonstrate the ability of a DNA-damaging agent, doxorubicin, at 600 nM concentration to stimulate mitotic catastrophe. We observe that the inhibition of caspase activity leads to accumulation of cells with mitotic catastrophe hallmarks in which RIP1-dependent necroptotic cell death is triggered. The suppression of autophagy by a chemical inhibitor or ATG13 knockout upregulates RIP1 phosphorylation and promotes necroptotic cell death. Thus, in certain conditions mitotic catastrophe, in addition to apoptosis and autophagy, can precede necroptosis.
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Affiliation(s)
- Aleksandra Yu. Egorshina
- Faculty of Medicine, MV Lomonosov Moscow State University, 119991 Moscow, Russia; (A.Y.E.); (A.V.Z.); (B.Z.)
| | - Alexey V. Zamaraev
- Faculty of Medicine, MV Lomonosov Moscow State University, 119991 Moscow, Russia; (A.Y.E.); (A.V.Z.); (B.Z.)
| | - Vitaliy O. Kaminskyy
- Division of Toxicology, Institute of Environmental Medicine, Karolinska Institute, P.O. Box 210, 171 77 Stockholm, Sweden;
| | - Tatiana V. Radygina
- Federal State Autonomous Institution “National Medical Research Center for Children’s Health” of the Ministry of Health of the Russian Federation, 119296 Moscow, Russia;
| | - Boris Zhivotovsky
- Faculty of Medicine, MV Lomonosov Moscow State University, 119991 Moscow, Russia; (A.Y.E.); (A.V.Z.); (B.Z.)
- Division of Toxicology, Institute of Environmental Medicine, Karolinska Institute, P.O. Box 210, 171 77 Stockholm, Sweden;
| | - Gelina S. Kopeina
- Faculty of Medicine, MV Lomonosov Moscow State University, 119991 Moscow, Russia; (A.Y.E.); (A.V.Z.); (B.Z.)
- Correspondence:
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12
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Fakhri S, Zachariah Moradi S, DeLiberto LK, Bishayee A. Cellular senescence signaling in cancer: A novel therapeutic target to combat human malignancies. Biochem Pharmacol 2022; 199:114989. [DOI: 10.1016/j.bcp.2022.114989] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 03/05/2022] [Accepted: 03/07/2022] [Indexed: 12/26/2022]
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13
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Chen C, Ding Y, Liu H, Sun M, Wang H, Wu D. Flubendazole Plays an Important Anti-Tumor Role in Different Types of Cancers. Int J Mol Sci 2022; 23:ijms23010519. [PMID: 35008943 PMCID: PMC8745596 DOI: 10.3390/ijms23010519] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 12/30/2021] [Accepted: 01/01/2022] [Indexed: 02/01/2023] Open
Abstract
Flubendazole, belonging to benzimidazole, is a broad-spectrum insect repellent and has been repurposed as a promising anticancer drug. In recent years, many studies have shown that flubendazole plays an anti-tumor role in different types of cancers, including breast cancer, melanoma, prostate cancer, colorectal cancer, and lung cancer. Although the anti-tumor mechanism of flubendazole has been studied, it has not been fully understood. In this review, we summarized the recent studies regarding the anti-tumor effects of flubendazole in different types of cancers and analyzed the related mechanisms, in order to provide the theoretical reference for further studies in the future.
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Affiliation(s)
- Chaoran Chen
- Institute of Nursing and Health, School of Nursing and Health, Henan University, Jinming Avenue, Kaifeng 475004, China; (C.C.); (Y.D.)
| | - Yueming Ding
- Institute of Nursing and Health, School of Nursing and Health, Henan University, Jinming Avenue, Kaifeng 475004, China; (C.C.); (Y.D.)
| | - Huiyang Liu
- Henan International Joint Laboratory of Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China;
| | - Mengyao Sun
- School of Clinical Medicine, Henan University, Kaifeng 475004, China;
| | - Honggang Wang
- Henan International Joint Laboratory of Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China;
- Correspondence: (H.W.); (D.W.)
| | - Dongdong Wu
- Henan International Joint Laboratory of Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China;
- School of Stomatology, Henan University, Kaifeng 475004, China
- Correspondence: (H.W.); (D.W.)
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14
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Khachigian LM. Emerging insights on functions of the anthelmintic flubendazole as a repurposed anticancer agent. Cancer Lett 2021; 522:57-62. [PMID: 34520820 DOI: 10.1016/j.canlet.2021.09.013] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 08/26/2021] [Accepted: 09/09/2021] [Indexed: 01/03/2023]
Abstract
While flubendazole has been used as a macrofilaricide in humans and animals for some 40 years, work in vitro and in preclinical models over the last decade has suggested its potential use as an anticancer agent. This article reviews recent studies in a range of tumor types indicating novel functions for flubendazole in its control of processes associated with tumor growth, spread and renewal including ferroptosis, autophagy, cancer stem-like cell killing and suppression of intratumoral myeloid-derived suppressor cell accumulation and programmed cell death protein 1. Flubendazole's potential use in clinical oncology will require further understanding of its mechanistic roles, range of inhibition of cancer types, capacity for adjunctive therapy and possible reformulation for enhanced solubility, bioavailability and potency.
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Affiliation(s)
- Levon M Khachigian
- Vascular Biology and Translational Research, School of Medical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, Australia.
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15
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Li YQ, Zheng Z, Liu QX, Lu X, Zhou D, Zhang J, Zheng H, Dai JG. Repositioning of Antiparasitic Drugs for Tumor Treatment. Front Oncol 2021; 11:670804. [PMID: 33996598 PMCID: PMC8117216 DOI: 10.3389/fonc.2021.670804] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 04/13/2021] [Indexed: 12/24/2022] Open
Abstract
Drug repositioning is a strategy for identifying new antitumor drugs; this strategy allows existing and approved clinical drugs to be innovatively repurposed to treat tumors. Based on the similarities between parasitic diseases and cancer, recent studies aimed to investigate the efficacy of existing antiparasitic drugs in cancer. In this review, we selected two antihelminthic drugs (macrolides and benzimidazoles) and two antiprotozoal drugs (artemisinin and its derivatives, and quinolines) and summarized the research progresses made to date on the role of these drugs in cancer. Overall, these drugs regulate tumor growth via multiple targets, pathways, and modes of action. These antiparasitic drugs are good candidates for comprehensive, in-depth analyses of tumor occurrence and development. In-depth studies may improve the current tumor diagnoses and treatment regimens. However, for clinical application, current investigations are still insufficient, warranting more comprehensive analyses.
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Affiliation(s)
- Yan-Qi Li
- Department of Thoracic Surgery, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Zhi Zheng
- Department of Thoracic Surgery, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Quan-Xing Liu
- Department of Thoracic Surgery, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Xiao Lu
- Department of Thoracic Surgery, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Dong Zhou
- Department of Thoracic Surgery, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Jiao Zhang
- Department of Thoracic Surgery, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Hong Zheng
- Department of Thoracic Surgery, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Ji-Gang Dai
- Department of Thoracic Surgery, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
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16
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Florio R, Carradori S, Veschi S, Brocco D, Di Genni T, Cirilli R, Casulli A, Cama A, De Lellis L. Screening of Benzimidazole-Based Anthelmintics and Their Enantiomers as Repurposed Drug Candidates in Cancer Therapy. Pharmaceuticals (Basel) 2021; 14:ph14040372. [PMID: 33920661 PMCID: PMC8072969 DOI: 10.3390/ph14040372] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 04/10/2021] [Accepted: 04/15/2021] [Indexed: 12/21/2022] Open
Abstract
Repurposing of approved non-antitumor drugs represents a promising and affordable strategy that may help to increase the repertoire of effective anticancer drugs. Benzimidazole-based anthelmintics are antiparasitic drugs commonly employed both in human and veterinary medicine. Benzimidazole compounds are being considered for drug repurposing due to antitumor activities displayed by some members of the family. In this study, we explored the effects of a large series of benzimidazole-based anthelmintics (and some enantiomerically pure forms of those containing a stereogenic center) on the viability of different tumor cell lines derived from paraganglioma, pancreatic and colorectal cancer. Flubendazole, parbendazole, oxibendazole, mebendazole, albendazole and fenbendazole showed the most consistent antiproliferative effects, displaying IC50 values in the low micromolar range, or even in the nanomolar range. In silico evaluation of their physicochemical, pharmacokinetics and medicinal chemistry properties also provided useful information related to the chemical structures and potential of these compounds. Furthermore, in view of the potential repurposing of these drugs in cancer therapy and considering that pharmaceutically active compounds may have different mechanisms of action, we performed an in silico target prediction to assess the polypharmacology of these benzimidazoles, which highlighted previously unknown cancer-relevant molecular targets.
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Affiliation(s)
- Rosalba Florio
- Department of Pharmacy, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (R.F.); (S.V.); (D.B.); (T.D.G.); (L.D.L.)
| | - Simone Carradori
- Department of Pharmacy, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (R.F.); (S.V.); (D.B.); (T.D.G.); (L.D.L.)
- Correspondence: (S.C.); (A.C.)
| | - Serena Veschi
- Department of Pharmacy, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (R.F.); (S.V.); (D.B.); (T.D.G.); (L.D.L.)
| | - Davide Brocco
- Department of Pharmacy, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (R.F.); (S.V.); (D.B.); (T.D.G.); (L.D.L.)
| | - Teresa Di Genni
- Department of Pharmacy, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (R.F.); (S.V.); (D.B.); (T.D.G.); (L.D.L.)
| | - Roberto Cirilli
- Centro Nazionale per il Controllo e la Valutazione dei Farmaci, Istituto Superiore di Sanità, 00161 Rome, Italy;
| | - Adriano Casulli
- WHO Collaborating Centre for the Epidemiology, Detection and Control of Cystic and Alveolar Echinococcosis (in Animals and Humans), Department of Infectious Diseases, Istituto Superiore di Sanità, 00161 Rome, Italy;
- European Union Reference Laboratory for Parasites, Department of Infectious Diseases, Istituto Superiore di Sanità, 00161 Rome, Italy
| | - Alessandro Cama
- Department of Pharmacy, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (R.F.); (S.V.); (D.B.); (T.D.G.); (L.D.L.)
- Center for Advanced Studies and Technology, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
- Correspondence: (S.C.); (A.C.)
| | - Laura De Lellis
- Department of Pharmacy, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (R.F.); (S.V.); (D.B.); (T.D.G.); (L.D.L.)
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17
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Dong T, Lu Z, Li J, Liu Y, Wen J. [Flubendazole Inhibits the Proliferation of A549 and H460 Cells and Promotes Autophagy]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2021; 23:306-313. [PMID: 32429634 PMCID: PMC7260388 DOI: 10.3779/j.issn.1009-3419.2020.104.17] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
背景与目的 氟苯达唑是一种苯并咪唑类驱虫药, 既往研究发现其对结肠癌、乳腺癌细胞增殖具有抑制作用。本研究旨在探讨氟苯达唑对非小细胞肺癌A549、H460细胞增殖的影响及机制。 方法 通过CCK-8(Cell Counting Kit-8)法检测不同浓度的氟苯达唑对A549、H460细胞活力的影响; Western blot法检测氟苯达唑处理后细胞自噬相关蛋白p62、LC3的表达水平; 自噬双标腺病毒(mRFP-GFP-LC3)转染细胞, 分析细胞内自噬流变化。 结果 氟苯达唑抑制A549、H460细胞增殖, 并呈剂量依赖关系(P < 0.001)。2 μmol/L氟苯达唑处理A549、H460细胞24 h、48 h后p62减少, LC3 II/I比值升高(P < 0.005)。mRFP-GFP-LC3转染细胞显示氟苯达唑处理组红色荧光增加, 提示自噬流增强。 结论 氟苯达唑可以抑制A549、H460细胞增殖并促进自噬。
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Affiliation(s)
- Tingjun Dong
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510280, China.,Tumor Diagnosis and Treatment Center, The Sixth Medical Center of PLA General Hospital, Beijing 100048, China
| | - Zejun Lu
- Tumor Diagnosis and Treatment Center, The Sixth Medical Center of PLA General Hospital, Beijing 100048, China
| | - Jingjiao Li
- Tumor Diagnosis and Treatment Center, The Sixth Medical Center of PLA General Hospital, Beijing 100048, China
| | - Yongzhen Liu
- Tumor Diagnosis and Treatment Center, The Sixth Medical Center of PLA General Hospital, Beijing 100048, China
| | - Juyi Wen
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510280, China.,Tumor Diagnosis and Treatment Center, The Sixth Medical Center of PLA General Hospital, Beijing 100048, China
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18
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Zhou X, Zou L, Chen W, Yang T, Luo J, Wu K, Shu F, Tan X, Yang Y, Cen S, Li C, Mao X. Flubendazole, FDA-approved anthelmintic, elicits valid antitumor effects by targeting P53 and promoting ferroptosis in castration-resistant prostate cancer. Pharmacol Res 2021; 164:105305. [PMID: 33197601 DOI: 10.1016/j.phrs.2020.105305] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 10/20/2020] [Accepted: 11/10/2020] [Indexed: 02/07/2023]
Abstract
On account of incurable castration-resistant prostate cancer (CRPC) inevitably developing after treating with androgen deprivation therapy, it is an urgent need to find new therapeutic strategies. Flubendazole is a well-known anti-malarial drug that is recently reported to be a potential anti-tumor agent in various types of human cancer cells. However, whether flubendazole could inhibit the castration-resistant prostate cancer has not been well charified. Thus, the aim of the present study was to characterize the precise mechanism of action of flubendazole on the CRPC. In this study, we investigated the potential effect of flubendazole on cell proliferation, cell cycle and cell death in CRPC cells (PC3 and DU145). We found that flubendazole inhibited cell proliferation, caused cell cycle arrest in G2/M phase and promoted cell death in vitro, and suppressed growth of CRPC tumor in xenograft models. In addition, we reported that flubendazole induced the expression of P53, which partly accounted for the G2/M phase arrest and led to inhibition of the transcription of SLC7A11, and then downregulated the GPX4, which is a major ferroptosis-related gene. Furthermore, flubendazole exhibited synergistic effect with 5-fluorouracil (5-Fu) in chemotherapy of CRPC. This study provides biological evidence that flubendazole is a novel P53 inducer which exerts anti-proliferation and pro-apoptosis effects in CRPC through hindering the cell cycle and activating the ferroptosis, and indicates that a novel utilization of flubendazole in neoadjuvant chemotherapy of CRPC.
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Affiliation(s)
- Xumin Zhou
- Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, PR China; Department of Pathogen Biology and Experimental Teaching Center of Preventive Medicine, Guangdong Provincial Key Laboratory of Tropical Disease, School of Public Health, Southern Medical University, Guangzhou 510515, PR China
| | - Libin Zou
- Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, PR China
| | - Wenbin Chen
- Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, PR China
| | - Taowei Yang
- Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, PR China
| | - Junqi Luo
- Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, PR China
| | - Kaihui Wu
- Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, PR China
| | - Fangpeng Shu
- Department of Urology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, PR China
| | - Xiao Tan
- Department of Urology, The First Affiliated Hospital, Southwest Medical University, Luzhou 646000, PR China
| | - Yu Yang
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen 518036, PR China
| | - Shengren Cen
- Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, PR China
| | - Chuanyin Li
- Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, PR China.
| | - Xiangming Mao
- Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, PR China.
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19
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Nath J, Paul R, Ghosh SK, Paul J, Singha B, Debnath N. Drug repurposing and relabeling for cancer therapy: Emerging benzimidazole antihelminthics with potent anticancer effects. Life Sci 2020; 258:118189. [DOI: 10.1016/j.lfs.2020.118189] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 07/25/2020] [Accepted: 07/30/2020] [Indexed: 02/08/2023]
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20
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Son DS, Lee ES, Adunyah SE. The Antitumor Potentials of Benzimidazole Anthelmintics as Repurposing Drugs. Immune Netw 2020; 20:e29. [PMID: 32895616 PMCID: PMC7458798 DOI: 10.4110/in.2020.20.e29] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 07/17/2020] [Accepted: 07/21/2020] [Indexed: 02/06/2023] Open
Abstract
The development of refractory tumor cells limits therapeutic efficacy in cancer by activating mechanisms that promote cellular proliferation, migration, invasion, metastasis, and survival. Benzimidazole anthelmintics have broad-spectrum action to remove parasites both in human and veterinary medicine. In addition to being antiparasitic agents, benzimidazole anthelmintics are known to exert anticancer activities, such as the disruption of microtubule polymerization, the induction of apoptosis, cell cycle (G2/M) arrest, anti-angiogenesis, and blockage of glucose transport. These antitumorigenic effects even extend to cancer cells resistant to approved therapies and when in combination with conventional therapeutics, enhance anticancer efficacy and hold promise as adjuvants. Above all, these anthelmintics may offer a broad, safe spectrum to treat cancer, as demonstrated by their long history of use as antiparasitic agents. The present review summarizes central literature regarding the anticancer effects of benzimidazole anthelmintics, including albendazole, parbendazole, fenbendazole, mebendazole, oxibendazole, oxfendazole, ricobendazole, and flubendazole in cancer cell lines, animal tumor models, and clinical trials. This review provides valuable information on how to improve the quality of life in patients with cancers by increasing the treatment options and decreasing side effects from conventional therapy.
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Affiliation(s)
- Deok-Soo Son
- Department of Biochemistry, Cancer Biology, Neurosciences and Pharmacology, School of Medicine, Meharry Medical College, Nashville, TN 37208, USA
| | - Eun-Sook Lee
- Department of Pharmaceutical Sciences, College of Pharmacy, Florida A&M University, Tallahassee, FL 32301, USA
| | - Samuel E Adunyah
- Department of Biochemistry, Cancer Biology, Neurosciences and Pharmacology, School of Medicine, Meharry Medical College, Nashville, TN 37208, USA
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21
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Vitovcova B, Skarkova V, Rudolf K, Rudolf E. Biology of Glioblastoma Multiforme-Exploration of Mitotic Catastrophe as a Potential Treatment Modality. Int J Mol Sci 2020; 21:ijms21155324. [PMID: 32727112 PMCID: PMC7432846 DOI: 10.3390/ijms21155324] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 07/22/2020] [Accepted: 07/25/2020] [Indexed: 12/23/2022] Open
Abstract
Glioblastoma multiforme (GBM) represents approximately 60% of all brain tumors in adults. This malignancy shows a high biological and genetic heterogeneity associated with exceptional aggressiveness, leading to a poor survival of patients. This review provides a summary of the basic biology of GBM cells with emphasis on cell cycle and cytoskeletal apparatus of these cells, in particular microtubules. Their involvement in the important oncosuppressive process called mitotic catastrophe will next be discussed along with select examples of microtubule-targeting agents, which are currently explored in this respect such as benzimidazole carbamate compounds. Select microtubule-targeting agents, in particular benzimidazole carbamates, induce G2/M cell cycle arrest and mitotic catastrophe in tumor cells including GBM, resulting in phenotypically variable cell fates such as mitotic death or mitotic slippage with subsequent cell demise or permanent arrest leading to senescence. Their effect is coupled with low toxicity in normal cells and not developed chemoresistance. Given the lack of efficient cytostatics or modern molecular target-specific compounds in the treatment of GBM, drugs inducing mitotic catastrophe might offer a new, efficient alternative to the existing clinical management of this at present incurable malignancy.
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22
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Laudisi F, Marônek M, Di Grazia A, Monteleone G, Stolfi C. Repositioning of Anthelmintic Drugs for the Treatment of Cancers of the Digestive System. Int J Mol Sci 2020; 21:ijms21144957. [PMID: 32668817 PMCID: PMC7404055 DOI: 10.3390/ijms21144957] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 07/10/2020] [Accepted: 07/12/2020] [Indexed: 12/20/2022] Open
Abstract
Tumors of the digestive system, when combined together, account for more new cases and deaths per year than tumors arising in any other system of the body and their incidence continues to increase. Despite major efforts aimed at discovering and validating novel and effective drugs against these malignancies, the process of developing such drugs remains lengthy and costly, with high attrition rates. Drug repositioning (also known as drug repurposing), that is, the process of finding new uses for approved drugs, has been gaining popularity in oncological drug development as it provides the opportunity to expedite promising anti-cancer agents into clinical trials. Among the drugs considered for repurposing in oncology, compounds belonging to some classes of anthelmintics—a group of agents acting against infections caused by parasitic worms (helminths) that colonize the mammalian intestine—have shown pronounced anti-tumor activities and attracted particular attention due to their ability to target key oncogenic signal transduction pathways. In this review, we summarize and discuss the available experimental and clinical evidence about the use of anthelmintic drugs for the treatment of cancers of the digestive system.
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Affiliation(s)
- Federica Laudisi
- Department of Systems Medicine, University of “Tor Vergata”, 00133 Rome, Italy; (F.L.); (A.D.G.); (G.M.)
| | - Martin Marônek
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, 811 08 Bratislava, Slovakia;
| | - Antonio Di Grazia
- Department of Systems Medicine, University of “Tor Vergata”, 00133 Rome, Italy; (F.L.); (A.D.G.); (G.M.)
| | - Giovanni Monteleone
- Department of Systems Medicine, University of “Tor Vergata”, 00133 Rome, Italy; (F.L.); (A.D.G.); (G.M.)
| | - Carmine Stolfi
- Department of Systems Medicine, University of “Tor Vergata”, 00133 Rome, Italy; (F.L.); (A.D.G.); (G.M.)
- Division of Clinical Biochemistry and Clinical Molecular Biology, University of Rome “Tor Vergata”, 00133 Rome, Italy
- Correspondence: ; Tel.: +39-06-72596163
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23
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Rudolf K, Rudolf E. An analysis of mitotic catastrophe induced cell responses in melanoma cells exposed to flubendazole. Toxicol In Vitro 2020; 68:104930. [PMID: 32652169 DOI: 10.1016/j.tiv.2020.104930] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 06/16/2020] [Accepted: 06/30/2020] [Indexed: 01/21/2023]
Abstract
Mitotic catastrophe induced by mictotubule-targeting drugs such as benzimidazole carbamates has been demonstrated to be an efficient mechanism for suppression of tumor cells growth and proliferation, with variable resulting endpoints. The present study was designed to explore some of these endpoints; i.e. the apoptosis as well as autophagy and their related signaling in several stabilized cell lines as well as human explant melanoma cells treated with flubendazole (FLU). FLU-induced mitotic catastrophe resulted in mitochondrial and caspase-dependent apoptosis, which occurred at various rates in all treated cells during 96 h of treatment. The process was characterized by enhanced transcriptional activity of TP53 and NF-κB as well as upregulated Noxa expression. Also, inactivation of Bcl-2, BclXL and Mcl-1 proteins by JNK mediated phosphorylation was observed. Although increased autophagic activity took place in treated cells too, no discernible functional linkage with ongoing cell death process was evidenced. Together these results advance our evidence over the effectiveness of FLU cytotoxicity-related killing of melanoma cells while calling for more extensive testing of melanoma samples as a prerequisite of further preclinical evaluation of FLU antineoplastic potential.
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Affiliation(s)
- K Rudolf
- Department of Medical Biology and Genetics, Charles University, Faculty of Medicine in Hradec Králové, Czech Republic
| | - E Rudolf
- Department of Medical Biology and Genetics, Charles University, Faculty of Medicine in Hradec Králové, Czech Republic.
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Zhen Y, Zhao R, Wang M, Jiang X, Gao F, Fu L, Zhang L, Zhou XL. Flubendazole elicits anti-cancer effects via targeting EVA1A-modulated autophagy and apoptosis in Triple-negative Breast Cancer. Am J Cancer Res 2020; 10:8080-8097. [PMID: 32724459 PMCID: PMC7381743 DOI: 10.7150/thno.43473] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2019] [Accepted: 06/18/2020] [Indexed: 02/07/2023] Open
Abstract
Background: Triple-negative breast cancer (TNBC) is one of the most prevalent neoplastic diseases worldwide, but efficacious treatments for this pathological condition are still challenging. The lack of an effective targeted therapy also leads to a poor prognosis for patients affected by TNBC. In the present study, we repurposed the distinctive inhibitory effects of flubendazole, a traditional anthelmintic drug, towards the putative modulation of proliferation and migration of TNBC in vitro and in vivo. Methods: According to a series of experimental approaches, including immunofluorescence (IF), immunoblotting (IB), siRNA and GFP-mRFP-LC3 plasmid transfection, respectively, we have found that flubendazole is capable of inducing autophagic cell death and apoptosis, thus exerting some anti-proliferative and anti-migration activity in TNBC cells. The therapeutic effects of flubendazole were evaluated by xenograft mouse models, followed by immunohistochemistry (IHC), IF and IB. Changes in the gene expression profiles of flubendazole-treated TNBC cells were analyzed by RNA sequencing (RNA-seq) and validated by IB. The potential binding mode of flubendazole and EVA1A was predicted by molecular docking and demonstrated by site-directed mutagenesis. Results: We have presently found that flubendazole exhibits a considerable anti-proliferative activity in vitro and in vivo. Mechanistically, the induction of autophagic cell death appears to be pivotal for flubendazole-mediated growth inhibition of TNBC cells, whereas blocking autophagy was able to improve the survival rate and migration ability of flubendazole-treated TNBC cells. Specifically, RNA-seq analysis showed that flubendazole treatment could promote the up-regulation of EVA1A. Flubendazole may regulate autophagy and apoptosis by targeting EVA1A, thus affecting the mechanisms of TNBC proliferation and migration. Furthermore, Thr113 may be the key amino acid residues for the binding of flubendazole to EVA1A. Conclusion: Our results provide novel insights towards the putative anti-cancer efficacy of flubendazole. Furthermore, here we show that flubendazole could serve as a potential therapeutic drug in TNBC. Altogether, this study highlights the possibility of this repurposed autophagic inducer for future cancer treatments.
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25
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Florio R, Veschi S, di Giacomo V, Pagotto S, Carradori S, Verginelli F, Cirilli R, Casulli A, Grassadonia A, Tinari N, Cataldi A, Amoroso R, Cama A, De Lellis L. The Benzimidazole-Based Anthelmintic Parbendazole: A Repurposed Drug Candidate That Synergizes with Gemcitabine in Pancreatic Cancer. Cancers (Basel) 2019; 11:cancers11122042. [PMID: 31861153 PMCID: PMC6966614 DOI: 10.3390/cancers11122042] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 12/09/2019] [Accepted: 12/14/2019] [Indexed: 12/24/2022] Open
Abstract
Pancreatic cancer (PC) is one of the most lethal, chemoresistant malignancies and it is of paramount importance to find more effective therapeutic agents. Repurposing of non-anticancer drugs may expand the repertoire of effective molecules. Studies on repurposing of benzimidazole-based anthelmintics in PC and on their interaction with agents approved for PC therapy are lacking. We analyzed the effects of four Food and Drug Administration (FDA)-approved benzimidazoles on AsPC-1 and Capan-2 pancreatic cancer cell line viability. Notably, parbendazole was the most potent benzimidazole affecting PC cell viability, with half maximal inhibitory concentration (IC50) values in the nanomolar range. The drug markedly inhibited proliferation, clonogenicity and migration of PC cell lines through mechanisms involving alteration of microtubule organization and formation of irregular mitotic spindles. Moreover, parbendazole interfered with cell cycle progression promoting G2/M arrest, followed by the emergence of enlarged, polyploid cells. These abnormalities, suggesting a mitotic catastrophe, culminated in PC cell apoptosis, are also associated with DNA damage in PC cell lines. Remarkably, combinations of parbendazole with gemcitabine, a drug employed as first-line treatment in PC, synergistically decreased PC cell viability. In conclusion, this is the first study providing evidence that parbendazole as a single agent, or in combination with gemcitabine, is a repurposing candidate in the currently dismal PC therapy.
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Affiliation(s)
- Rosalba Florio
- Department of Pharmacy, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (R.F.); (S.V.); (V.d.G.); (F.V.); (A.C.); (R.A.); (L.D.L.)
| | - Serena Veschi
- Department of Pharmacy, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (R.F.); (S.V.); (V.d.G.); (F.V.); (A.C.); (R.A.); (L.D.L.)
| | - Viviana di Giacomo
- Department of Pharmacy, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (R.F.); (S.V.); (V.d.G.); (F.V.); (A.C.); (R.A.); (L.D.L.)
| | - Sara Pagotto
- Department of Medical, Oral and Biotechnological Sciences, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (S.P.); (A.G.); (N.T.)
- Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
| | - Simone Carradori
- Department of Pharmacy, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (R.F.); (S.V.); (V.d.G.); (F.V.); (A.C.); (R.A.); (L.D.L.)
- Correspondence: (S.C.); (A.C.); Tel.: +39-0871-3554583 (S.C.); +39-0871-3554559 (A.C.)
| | - Fabio Verginelli
- Department of Pharmacy, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (R.F.); (S.V.); (V.d.G.); (F.V.); (A.C.); (R.A.); (L.D.L.)
- Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
| | - Roberto Cirilli
- Centro nazionale per il controllo e la valutazione dei farmaci, Istituto Superiore di Sanità, 00161 Rome, Italy;
| | - Adriano Casulli
- WHO Collaborating Centre for the Epidemiology, Detection and Control of Cystic and Alveolar Echinococcosis (in Animals and Humans), Istituto Superiore di Sanità (ISS), 00161 Rome, Italy;
- European Union Reference Laboratory for Parasites, Istituto Superiore di Sanità (ISS), 00161 Rome, Italy
| | - Antonino Grassadonia
- Department of Medical, Oral and Biotechnological Sciences, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (S.P.); (A.G.); (N.T.)
- Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
| | - Nicola Tinari
- Department of Medical, Oral and Biotechnological Sciences, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (S.P.); (A.G.); (N.T.)
- Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
| | - Amelia Cataldi
- Department of Pharmacy, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (R.F.); (S.V.); (V.d.G.); (F.V.); (A.C.); (R.A.); (L.D.L.)
| | - Rosa Amoroso
- Department of Pharmacy, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (R.F.); (S.V.); (V.d.G.); (F.V.); (A.C.); (R.A.); (L.D.L.)
| | - Alessandro Cama
- Department of Pharmacy, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (R.F.); (S.V.); (V.d.G.); (F.V.); (A.C.); (R.A.); (L.D.L.)
- Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
- Correspondence: (S.C.); (A.C.); Tel.: +39-0871-3554583 (S.C.); +39-0871-3554559 (A.C.)
| | - Laura De Lellis
- Department of Pharmacy, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (R.F.); (S.V.); (V.d.G.); (F.V.); (A.C.); (R.A.); (L.D.L.)
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Benzimidazoles Downregulate Mdm2 and MdmX and Activate p53 in MdmX Overexpressing Tumor Cells. Molecules 2019; 24:molecules24112152. [PMID: 31181622 PMCID: PMC6600429 DOI: 10.3390/molecules24112152] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Revised: 05/29/2019] [Accepted: 06/05/2019] [Indexed: 12/13/2022] Open
Abstract
Tumor suppressor p53 is mutated in about 50% of cancers. Most malignant melanomas carry wild-type p53, but p53 activity is often inhibited due to overexpression of its negative regulators Mdm2 or MdmX. We performed high throughput screening of 2448 compounds on A375 cells carrying p53 activity luciferase reporter construct to reveal compounds that promote p53 activity in melanoma. Albendazole and fenbendazole, two approved and commonly used benzimidazole anthelmintics, stimulated p53 activity and were selected for further studies. The protein levels of p53 and p21 increased upon the treatment with albendazole and fenbendazole, indicating activation of the p53–p21 pathway, while the levels of Mdm2 and MdmX decreased in melanoma and breast cancer cells overexpressing these proteins. We also observed a reduction of cell viability and changes of cellular morphology corresponding to mitotic catastrophe, i.e., G2/M cell cycle arrest of large multinucleated cells with disrupted microtubules. In summary, we established a new tool for testing the impact of small molecule compounds on the activity of p53 and used it to identify the action of benzimidazoles in melanoma cells. The drugs promoted the stability and transcriptional activity of wild-type p53 via downregulation of its negative regulators Mdm2 and MdmX in cells overexpressing these proteins. The results indicate the potential for repurposing the benzimidazole anthelmintics for the treatment of cancers overexpressing p53 negative regulators.
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Kubíček V, Skálová L, Skarka A, Králová V, Holubová J, Štěpánková J, Šubrt Z, Szotáková B. Carbonyl Reduction of Flubendazole in the Human Liver: Strict Stereospecificity, Sex Difference, Low Risk of Drug Interactions. Front Pharmacol 2019; 10:600. [PMID: 31191322 PMCID: PMC6546852 DOI: 10.3389/fphar.2019.00600] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Accepted: 05/10/2019] [Indexed: 12/15/2022] Open
Abstract
Flubendazole (FLU), an anthelmintic drug of benzimidazole type, is now considered a promising anti-cancer agent due to its tubulin binding ability and low system toxicity. The present study was aimed at determining more information about FLU reduction in human liver, because this information has been insufficient until now. Subcellular fractions from the liver of 12 human patients (6 male and 6 female patients) were used to study the stereospecificity, cellular localization, coenzyme preference, enzyme kinetics, and possible inter-individual or sex differences in FLU reduction. In addition, the risk of FLU interaction with other drugs was evaluated. Our study showed that FLU is predominantly reduced in cytosol, and the reduced nicotinamide adenine dinucleotide phosphate (NADPH) coenzyme is preferred. The strict stereospecificity of FLU carbonyl reduction was proven, and carbonyl reductase 1 was identified as the main enzyme of FLU reduction in the human liver. A higher reduction of FLU and a higher level of carbonyl reductase 1 protein were found in male patients than in female patients, but overall inter-individual variability was relatively low. Hepatic intrinsic clearance of FLU is very low, and FLU had no effect on doxorubicin carbonyl reduction in the liver and in cancer cells. All these results fill the gaps in the knowledge of FLU metabolism in human.
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Affiliation(s)
- Vladimír Kubíček
- Department of Biophysics and Physical Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czechia
| | - Lenka Skálová
- Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czechia
| | - Adam Skarka
- Department of Chemistry, Faculty of Science, University of Hradec Králové, Hradec Králové, Czechia
| | - Věra Králová
- Department of Biology, Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czechia
| | - Jana Holubová
- Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czechia
| | - Jana Štěpánková
- Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czechia
| | - Zdeněk Šubrt
- Department of Surgery, Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czechia.,Department of Surgery, University Hospital Hradec Králové, Hradec Králové, Czechia
| | - Barbora Szotáková
- Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czechia
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28
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Kuang WB, Huang RZ, Qin JL, Lu X, Qin QP, Zou BQ, Chen ZF, Liang H, Zhang Y. Design, synthesis and pharmacological evaluation of new 3-(1H-benzimidazol-2-yl)quinolin-2(1H)-one derivatives as potential antitumor agents. Eur J Med Chem 2018; 157:139-150. [PMID: 30092368 DOI: 10.1016/j.ejmech.2018.07.066] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Revised: 07/24/2018] [Accepted: 07/29/2018] [Indexed: 01/02/2023]
Abstract
A series of new 3-(1H-benzimidazol-2-yl)quinolin-2(1H)-one derivatives (5a1-5d6) were designed and synthesized as antitumor agents. In vitro antitumor assay results showed that some compounds exhibited moderate to high inhibitory activity against HepG2, SK-OV-3, NCI-H460 and BEL-7404 tumor cell lines, and most compounds exhibited much lower cytotoxicity against the HL-7702 normal cell line compared to 5-FU and cisplatin. In vivo antitumor assay results demonstrated that 5a3 exhibited effective inhibition on tumor growth in the NCI-H460 xenograft mouse model and that 5d3 displayed excellent antiproliferative activity in the BEL-7402 xenograft model. These results suggested that both 5a3 and 5d3 could be used as anticancer drug candidates. Mechanistic studies suggested that compounds 5a3 and 5d3 exerted their antitumor activity by up-regulation of Bax, intracellular Ca2+ release, ROS generation, downregulation of Bcl-2, activation of caspase-9 and caspase-3 and subsequent cleavage of PARP, inhibition of CDK activity and activation of the p53 protein.
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Affiliation(s)
- Wen-Bin Kuang
- School of Pharmacy, Guilin Medical University, Guilin 541004, China; State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, Guilin 541004, China
| | - Ri-Zhen Huang
- Department of Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China
| | - Jiao-Lan Qin
- State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, Guilin 541004, China
| | - Xing Lu
- State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, Guilin 541004, China
| | - Qi-Pin Qin
- State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, Guilin 541004, China
| | - Bi-Qun Zou
- State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, Guilin 541004, China; Department of Chemistry & Pharmaceutical Science, Guilin Normal College, Xinyi Road 15, Guangxi 541001, China
| | - Zhen-Feng Chen
- State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, Guilin 541004, China.
| | - Hong Liang
- State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, Guilin 541004, China.
| | - Ye Zhang
- School of Pharmacy, Guilin Medical University, Guilin 541004, China; State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, Guilin 541004, China; Department of Chemistry & Pharmaceutical Science, Guilin Normal College, Xinyi Road 15, Guangxi 541001, China.
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29
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Oh E, Kim YJ, An H, Sung D, Cho TM, Farrand L, Jang S, Seo JH, Kim JY. Flubendazole elicits anti-metastatic effects in triple-negative breast cancer via STAT3 inhibition. Int J Cancer 2018; 143:1978-1993. [PMID: 29744876 DOI: 10.1002/ijc.31585] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Revised: 03/23/2018] [Accepted: 04/12/2018] [Indexed: 12/16/2022]
Abstract
Tumor metastasis remains the cause of 90% of cancer-related deaths. Cancer stem cells (CSC) are thought to be responsible for the aggressive and metastatic nature of triple-negative breast cancers (TNBC), and new therapeutic strategies are being devised to target them. Flubendazole (FLU) is a widely used anthelmintic agent that also exhibits anticancer activity in several cancer types. The aim of this study was to characterize the mechanism of action of FLU on breast cancer stem cell (BCSC)-like properties and metastasis in TNBC. FLU treatment caused a significant induction of apoptosis, accompanied by G2/M phase accumulation, caspase-3/-7 activation and the dysregulation of STAT3 activation in TNBC cells. The latter phenomenon was associated with impairment of cancer stem-like traits, concomitant with a reduction in the CD24low /CD44high , CD24high /CD49fhigh subpopulation, ALDH1 activity and mammosphere formation. The BCSC-enriched populations exhibited enhanced metastasis with higher STAT3 activation, while FLU administration inhibited tumor growth, angiogenesis and lung and liver metastasis, coinciding with decreased MMP-2 and MMP-9 levels in circulating blood. FLU kills not only rapid proliferating tumor cells but also effectively eradicates BCSC-like cells in vitro and in vivo. Our findings warrant further investigation of FLU as a treatment for metastatic TNBC.
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Affiliation(s)
- Eunhye Oh
- Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul, 152-703, Republic of Korea.,Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul, 152-703, Republic of Korea
| | - Yoon-Jae Kim
- Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul, 152-703, Republic of Korea.,Department of Biomedical Research Center, Korea University Guro Hospital, Korea University, Seoul, 152-703, Republic of Korea
| | - Hyunsook An
- Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul, 152-703, Republic of Korea.,Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul, 152-703, Republic of Korea
| | - Daeil Sung
- Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul, 152-703, Republic of Korea.,Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul, 152-703, Republic of Korea
| | - Tae-Min Cho
- Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul, 152-703, Republic of Korea.,Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul, 152-703, Republic of Korea
| | - Lee Farrand
- Medvet Science, 65 Hardys Rd, Underdale, Adelaide, Australia
| | - Seojin Jang
- Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul, 152-703, Republic of Korea.,Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul, 152-703, Republic of Korea
| | - Jae Hong Seo
- Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul, 152-703, Republic of Korea.,Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul, 152-703, Republic of Korea
| | - Ji Young Kim
- Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul, 152-703, Republic of Korea.,Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul, 152-703, Republic of Korea
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Zhou X, Liu J, Zhang J, Wei Y, Li H. Flubendazole inhibits glioma proliferation by G2/M cell cycle arrest and pro-apoptosis. Cell Death Discov 2018. [PMID: 29531815 PMCID: PMC5841417 DOI: 10.1038/s41420-017-0017-2] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Flubendazole, FDA-approved anthelmintic, has been widely used in treating testinal parasites. In the recent years, Flubendazole has been reported to exert anticancer activities. On the other hand, little was known about the effects of Flubendazole on gliomas. Here we demonstrated a novel effect of flubendazole on glioma cells. We found that Flubendazole inhibited cell proliferation and promoted cell apoptosis of glioma cell lines in vitro, and suppressed tumor growth in xenograft models by intraperitoneal injection. However, Flubendazole might have no influence on cell migration. Mechanism study reaveled that Flubendazole caused cell cycle arrest in G2/M phase, which partly account for the suppressed proliferation. Consistently, Flubendazole induced P53 expression and reduced Cyclin B1 and p-cdc2 expression in glioma cells. In addition, Flubendazole promoted cell apoptosis by regulating the classical apoptosis protein BCL-2 expression. These observations suggest that Flubendazole exerts anti-proliferation and pro-apoptosis effects in Glioma through affecting the cell cycle and intrinsic apoptotic signaling, and indicate a novel utilization of Flubendazole in the treatment of Glioma.
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Affiliation(s)
- Xumin Zhou
- 1Department of Pathogen Biology and Experimental teaching center of Preventive Medicine, Guangdong Provincial Key Laboratory of Tropical Disease, School of Public Health, Southern Medical University, Guangzhou, 510515 China
| | - Jumei Liu
- 1Department of Pathogen Biology and Experimental teaching center of Preventive Medicine, Guangdong Provincial Key Laboratory of Tropical Disease, School of Public Health, Southern Medical University, Guangzhou, 510515 China
| | - Jinming Zhang
- 2Department of Respiration, Nanfang Hospital, Southern Medical University, Guangzhou, 510515 China
| | - Yong Wei
- 1Department of Pathogen Biology and Experimental teaching center of Preventive Medicine, Guangdong Provincial Key Laboratory of Tropical Disease, School of Public Health, Southern Medical University, Guangzhou, 510515 China
| | - Hua Li
- 1Department of Pathogen Biology and Experimental teaching center of Preventive Medicine, Guangdong Provincial Key Laboratory of Tropical Disease, School of Public Health, Southern Medical University, Guangzhou, 510515 China
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31
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Raisová Stuchlíková L, Králová V, Lněničková K, Zárybnický T, Matoušková P, Hanušová V, Ambrož M, Šubrt Z, Skálová L. The metabolism of flubendazole in human liver and cancer cell lines. Drug Test Anal 2018; 10:1139-1146. [PMID: 29426058 DOI: 10.1002/dta.2369] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Revised: 01/29/2018] [Accepted: 01/30/2018] [Indexed: 11/06/2022]
Abstract
Flubendazole (FLU), a benzimidazole anthelmintic drug widely used in veterinary medicine, has been approved for the treatment of gut-residing nematodes in humans. In addition, FLU is now considered a promising anti-cancer agent. Despite this, information about biotransformation of this compound in human is lacking. Moreover, there is no information regarding whether cancer cells are able to metabolize FLU in order to deactivate it. For these reasons, the present study was designed to identify all metabolites of Phase I and Phase II of FLU in human liver and in various cancer cells using ultra high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) analysis. Precision-cut human liver slices and 9 cell lines of different origin (breast, colon, oral cavity) were used as in vitro model systems. Our study showed that FLU with a reduced carbonyl group (FLUR) is the only FLU metabolite formed in the human liver. All human cancer cell lines were able to form FLUR. In addition, methylated FLUR was detected in breast cells MCF7 and intestinal SW480 cells. The accumulation of FLU and its reduction to FLUR markedly differed among cells. The extent of FLU reduction was in a good correlation with the detected expression level of carbonyl reductase 1. In most cases, FLU entered in a higher amount and was reduced to a lesser extent in proliferating (metastatic) cells than in differentiated (non-cancerous, non-metastatic) ones. These results support the promising potential of FLU in anti-cancer therapy.
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Affiliation(s)
- Lucie Raisová Stuchlíková
- Department of Biochemical Sciences, Faculty of Pharmacy, Charles University, Hradec Králové, Czech Republic
| | - Věra Králová
- Department of Biology, Faculty of Medicine, Charles University, Hradec Králové, Czech Republic
| | - Kateřina Lněničková
- Department of Biochemical Sciences, Faculty of Pharmacy, Charles University, Hradec Králové, Czech Republic
| | - Tomáš Zárybnický
- Department of Biochemical Sciences, Faculty of Pharmacy, Charles University, Hradec Králové, Czech Republic
| | - Petra Matoušková
- Department of Biochemical Sciences, Faculty of Pharmacy, Charles University, Hradec Králové, Czech Republic
| | - Veronika Hanušová
- Department of Biology, Faculty of Medicine, Charles University, Hradec Králové, Czech Republic
| | - Martin Ambrož
- Department of Biochemical Sciences, Faculty of Pharmacy, Charles University, Hradec Králové, Czech Republic
| | - Zdeněk Šubrt
- Department of Surgery, Faculty of Medicine, Charles University, Hradec Králové, Czech Republic
| | - Lenka Skálová
- Department of Biochemical Sciences, Faculty of Pharmacy, Charles University, Hradec Králové, Czech Republic
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32
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Kim YJ, Sung D, Oh E, Cho Y, Cho TM, Farrand L, Seo JH, Kim JY. Flubendazole overcomes trastuzumab resistance by targeting cancer stem-like properties and HER2 signaling in HER2-positive breast cancer. Cancer Lett 2018; 412:118-130. [DOI: 10.1016/j.canlet.2017.10.020] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Revised: 10/16/2017] [Accepted: 10/16/2017] [Indexed: 12/15/2022]
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33
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Kuang WB, Huang RZ, Fang YL, Liang GB, Yang CH, Ma XL, Zhang Y. Design, synthesis and pharmacological evaluation of novel 2-chloro-3-(1H-benzo[d]imidazol-2-yl)quinoline derivatives as antitumor agents: in vitro and in vivo antitumor activity, cell cycle arrest and apoptotic response. RSC Adv 2018; 8:24376-24385. [PMID: 35539175 PMCID: PMC9082043 DOI: 10.1039/c8ra04640a] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Accepted: 06/19/2018] [Indexed: 12/14/2022] Open
Abstract
A series of novel 2-chloro-3-(1H-benzo[d]imidazol-2-yl)quinoline derivatives were designed and synthesized as antitumor agents under the combination principle. The antitumor activity and mechanisms were then evaluated.
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Affiliation(s)
- Wen-Bin Kuang
- School of Pharmacy
- Guilin Medical University
- Guilin 541004
- PR China
- State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China)
| | - Ri-Zhen Huang
- Department of Pharmaceutical Engineering
- School of Chemistry and Chemical Engineering
- Southeast University
- Nanjing 211189
- PR China
| | - Yi-Lin Fang
- State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China)
- School of Chemistry and Pharmaceutical Sciences of Guangxi Normal University
- Guilin 541004
- PR China
| | - Gui-Bin Liang
- State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China)
- School of Chemistry and Pharmaceutical Sciences of Guangxi Normal University
- Guilin 541004
- PR China
| | - Chen-Hui Yang
- School of Pharmacy
- Guilin Medical University
- Guilin 541004
- PR China
| | - Xian-Li Ma
- School of Pharmacy
- Guilin Medical University
- Guilin 541004
- PR China
| | - Ye Zhang
- School of Pharmacy
- Guilin Medical University
- Guilin 541004
- PR China
- State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China)
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Synthesis and anticancer activity of novel water soluble benzimidazole carbamates. Eur J Med Chem 2018; 144:372-385. [DOI: 10.1016/j.ejmech.2017.11.037] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Revised: 11/06/2017] [Accepted: 11/17/2017] [Indexed: 02/07/2023]
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Čáňová K, Rozkydalová L, Vokurková D, Rudolf E. Flubendazole induces mitotic catastrophe and apoptosis in melanoma cells. Toxicol In Vitro 2017; 46:313-322. [PMID: 29107018 DOI: 10.1016/j.tiv.2017.10.025] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Revised: 10/20/2017] [Accepted: 10/25/2017] [Indexed: 01/04/2023]
Abstract
Flubendazole (FLU) is a widely used anthelmintic drug belonging to benzimidazole group. Recently, several studies have been published demonstrating its potential to inhibit growth of various tumor cells including those derived from colorectal cancer, breast cancer or leukemia via several mechanisms. In the present study we have investigated cytotoxic effects of FLU on malignant melanoma using A-375, BOWES and RPMI-7951 cell lines representing diverse melanoma molecular types. In all three cell lines, FLU inhibited cell growth and proliferation and disrupted microtubule structure and function which was accompanied by dramatic changes in cellular morphology. In addition, FLU-treated cells accumulated at the G2/M phase of cell cycle and displayed the features of mitotic catastrophe characterized by formation of giant cells with multiple nuclei, abnormal spindles and subsequent apoptotic demise. Although this endpoint was observed in all treated melanoma lines, our analyses showed different activated biochemical signaling in particular cells, thus suggesting a promising treatment potential of FLU in malignant melanoma warranting its further testing.
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Affiliation(s)
- K Čáňová
- Department of Medical Biology and Genetics, Charles University, Faculty of Medicine in Hradec Králové, Czech Republic
| | - L Rozkydalová
- Department of Pharmacology, Charles University, Faculty of Pharmacy in Hradec Králové, Czech Republic
| | - D Vokurková
- Department of Clinical Immunology and Allergology, University Hospital in Hradec Králové, Czech Republic
| | - E Rudolf
- Department of Medical Biology and Genetics, Charles University, Faculty of Medicine in Hradec Králové, Czech Republic.
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Čáňová K, Rozkydalová L, Rudolf E. Anthelmintic Flubendazole and Its Potential Use in Anticancer Therapy. ACTA MEDICA (HRADEC KRÁLOVÉ) 2017; 60:5-11. [DOI: 10.14712/18059694.2017.44] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Flubendazole is a widely used anthelmintic drug belonging to benzimidazole group. The molecular mechanism of action of flubendazole is based on its specific binding to tubulin, which results in disruption of microtubule structure and function, and in the interference with the microtubule-mediated transport of secretory vesicles in absorptive tissues of helminths. The microtubule-disrupting properties of benzimidazole derivatives raised recently interest in these compounds as possible anti-cancer agents. In this minireview flubendazole effects towards selected human malignant cells including myeloma, leukemia, neuroblastoma, breast cancer, colorectal cancer and melanoma are discussed along with basic data on its pharmacokinetics, metabolism and toxicity.
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