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1
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Coffey NJ, Simon MC. Metabolic alterations in hereditary and sporadic renal cell carcinoma. Nat Rev Nephrol 2024; 20:233-250. [PMID: 38253811 PMCID: PMC11165401 DOI: 10.1038/s41581-023-00800-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/30/2023] [Indexed: 01/24/2024]
Abstract
Kidney cancer is the seventh leading cause of cancer in the world, and its incidence is on the rise. Renal cell carcinoma (RCC) is the most common form and is a heterogeneous disease comprising three major subtypes that vary in their histology, clinical course and driver mutations. These subtypes include clear cell RCC, papillary RCC and chromophobe RCC. Molecular analyses of hereditary and sporadic forms of RCC have revealed that this complex and deadly disease is characterized by metabolic pathway alterations in cancer cells that lead to deregulated oxygen and nutrient sensing, as well as impaired tricarboxylic acid cycle activity. These metabolic changes facilitate tumour growth and survival. Specifically, studies of the metabolic features of RCC have led to the discovery of oncometabolites - fumarate and succinate - that can promote tumorigenesis, moonlighting functions of enzymes, and substrate auxotrophy owing to the disruption of pathways that enable the production of arginine and cholesterol. These metabolic alterations within RCC can be exploited to identify new therapeutic targets and interventions, in combination with novel approaches that minimize the systemic toxicity of metabolic inhibitors and reduce the risk of drug resistance owing to metabolic plasticity.
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Affiliation(s)
- Nathan J Coffey
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - M Celeste Simon
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
- Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA.
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2
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Mu M, Zhang Q, Zhao C, Li X, Chen Z, Sun X, Yu J. 3-Bromopyruvate overcomes cetuximab resistance in human colorectal cancer cells by inducing autophagy-dependent ferroptosis. Cancer Gene Ther 2023; 30:1414-1425. [PMID: 37558749 PMCID: PMC10581902 DOI: 10.1038/s41417-023-00648-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 06/15/2023] [Accepted: 07/12/2023] [Indexed: 08/11/2023]
Abstract
Colorectal cancer (CRC) remains a leading cause of cancer-related death worldwide. Cetuximab, in combination with chemotherapy, is effective for treating patients with wild-type KRAS/BRAF metastatic CRC (mCRC). However, intrinsic or acquired drug resistance often limits the use of cetuximab. In this study, we investigated the potential of co-treatment with 3-Bromopyruvate (3-BP) and cetuximab to overcome cetuximab resistance in CRC, both in vitro and in vivo. Our results demonstrated that the co-treatment of 3-BP and cetuximab synergistically induced an antiproliferative effect in both CRC cell lines with intrinsic cetuximab resistance (DLD-1 (KRASG13D/-) and HT29 (BRAFV600E)) and in a cetuximab-resistant cell line derived from Caco-2 with acquired resistance (Caco-2-CR). Further analysis revealed that co-treatment induced ferroptosis, autophagy, and apoptosis. Mechanistically, co-treatment inhibited FOXO3a phosphorylation and degradation and activated the FOXO3a/AMPKα/pBeclin1 and FOXO3a/PUMA pathways, leading to the promotion of ferroptosis, autophagy, and apoptosis in DLD-1 (KRASG13D/-), HT29 (BRAFV600E), and Caco-2-CR cells. In conclusion, our findings suggest that co-treatment with 3-BP and cetuximab could be a promising strategy to overcome cetuximab resistance in human CRC.
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Affiliation(s)
- Mingchao Mu
- Department of General Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, Shaanxi, China
| | - Qin Zhang
- Department of Dermatology, Northwest Hospital, the Second Affiliated Hospital of Xi'an Jiaotong University, 710004, Xi'an, Shaanxi, China
| | - Chenye Zhao
- Department of General Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, Shaanxi, China
| | - Xiaopeng Li
- Department of General Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, Shaanxi, China
| | - Zilu Chen
- Department of General Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, Shaanxi, China
| | - Xuejun Sun
- Department of General Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, Shaanxi, China.
| | - Junhui Yu
- Department of General Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, Shaanxi, China.
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3
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Cunha A, Rocha AC, Barbosa F, Baião A, Silva P, Sarmento B, Queirós O. Glycolytic Inhibitors Potentiated the Activity of Paclitaxel and Their Nanoencapsulation Increased Their Delivery in a Lung Cancer Model. Pharmaceutics 2022; 14:pharmaceutics14102021. [PMID: 36297455 PMCID: PMC9611291 DOI: 10.3390/pharmaceutics14102021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 09/16/2022] [Accepted: 09/19/2022] [Indexed: 11/17/2022] Open
Abstract
Antiglycolytic agents inhibit cell metabolism and modify the tumor’s microenvironment, affecting chemotherapy resistance mechanisms. In this work, we studied the effect of the glycolytic inhibitors 3-bromopyruvate (3BP), dichloroacetate (DCA) and 2-deoxyglucose (2DG) on cancer cell properties and on the multidrug resistance phenotype, using lung cancer cells as a model. All compounds led to the loss of cell viability, with different effects on the cell metabolism, migration and proliferation, depending on the drug and cell line assayed. DCA was the most promising compound, presenting the highest inhibitory effect on cell metabolism and proliferation. DCA treatment led to decreased glucose consumption and ATP and lactate production in both A549 and NCI-H460 cell lines. Furthermore, the DCA pretreatment sensitized the cancer cells to Paclitaxel (PTX), a conventional chemotherapeutic drug, with a 2.7-fold and a 10-fold decrease in PTX IC50 values in A549 and NCI-H460 cell lines, respectively. To increase the intracellular concentration of DCA, thereby potentiating its effect, DCA-loaded poly(lactic-co-glycolic acid) nanoparticles were produced. At higher DCA concentrations, encapsulation was found to increase its toxicity. These results may help find a new treatment strategy through combined therapy, which could open doors to new treatment approaches.
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Affiliation(s)
- Andrea Cunha
- UNIPRO—Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences (IUCS), CESPU, 4585-116 Gandra, Portugal
| | - Ana Catarina Rocha
- UNIPRO—Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences (IUCS), CESPU, 4585-116 Gandra, Portugal
- DCM—Departamento de Ciências Médicas, Universidade de Aveiro, 3810-193 Aveiro, Portugal
| | - Flávia Barbosa
- UNIPRO—Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences (IUCS), CESPU, 4585-116 Gandra, Portugal
- DCM—Departamento de Ciências Médicas, Universidade de Aveiro, 3810-193 Aveiro, Portugal
| | - Ana Baião
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal
- INEB—Instituto de Engenharia Biomédica, Universidade do Porto, 4200-135 Porto, Portugal
- ICBAS—Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, 4050-313 Porto, Portugal
| | - Patrícia Silva
- UNIPRO—Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences (IUCS), CESPU, 4585-116 Gandra, Portugal
- TOXRUN—Toxicology Research Unit, University Institute of Health Sciences (IUCS), CESPU, 3810-193 Gandra, Portugal
| | - Bruno Sarmento
- UNIPRO—Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences (IUCS), CESPU, 4585-116 Gandra, Portugal
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal
- INEB—Instituto de Engenharia Biomédica, Universidade do Porto, 4200-135 Porto, Portugal
| | - Odília Queirós
- UNIPRO—Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences (IUCS), CESPU, 4585-116 Gandra, Portugal
- Correspondence:
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4
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Ciscato F, Ferrone L, Masgras I, Laquatra C, Rasola A. Hexokinase 2 in Cancer: A Prima Donna Playing Multiple Characters. Int J Mol Sci 2021; 22:ijms22094716. [PMID: 33946854 PMCID: PMC8125560 DOI: 10.3390/ijms22094716] [Citation(s) in RCA: 124] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 04/26/2021] [Accepted: 04/26/2021] [Indexed: 12/21/2022] Open
Abstract
Hexokinases are a family of ubiquitous exose-phosphorylating enzymes that prime glucose for intracellular utilization. Hexokinase 2 (HK2) is the most active isozyme of the family, mainly expressed in insulin-sensitive tissues. HK2 induction in most neoplastic cells contributes to their metabolic rewiring towards aerobic glycolysis, and its genetic ablation inhibits malignant growth in mouse models. HK2 can dock to mitochondria, where it performs additional functions in autophagy regulation and cell death inhibition that are independent of its enzymatic activity. The recent definition of HK2 localization to contact points between mitochondria and endoplasmic reticulum called Mitochondria Associated Membranes (MAMs) has unveiled a novel HK2 role in regulating intracellular Ca2+ fluxes. Here, we propose that HK2 localization in MAMs of tumor cells is key in sustaining neoplastic progression, as it acts as an intersection node between metabolic and survival pathways. Disrupting these functions by targeting HK2 subcellular localization can constitute a promising anti-tumor strategy.
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Affiliation(s)
- Francesco Ciscato
- Dipartimento di Scienze Biomediche, Università di Padova, 35131 Padova, Italy; (L.F.); (I.M.); (C.L.)
- Correspondence: (F.C.); (A.R.)
| | - Lavinia Ferrone
- Dipartimento di Scienze Biomediche, Università di Padova, 35131 Padova, Italy; (L.F.); (I.M.); (C.L.)
| | - Ionica Masgras
- Dipartimento di Scienze Biomediche, Università di Padova, 35131 Padova, Italy; (L.F.); (I.M.); (C.L.)
- Institute of Neuroscience, National Research Council, 56124 Pias, Italy
| | - Claudio Laquatra
- Dipartimento di Scienze Biomediche, Università di Padova, 35131 Padova, Italy; (L.F.); (I.M.); (C.L.)
| | - Andrea Rasola
- Dipartimento di Scienze Biomediche, Università di Padova, 35131 Padova, Italy; (L.F.); (I.M.); (C.L.)
- Correspondence: (F.C.); (A.R.)
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He S, Ma X, Zheng N, Wang G, Wang M, Xia W, Yu D. PRDM14 mediates chemosensitivity and glycolysis in drug‑resistant A549/cisplatin cells and their progenitor A549 human lung adenocarcinoma cells. Mol Med Rep 2020; 23:149. [PMID: 33355367 PMCID: PMC7789100 DOI: 10.3892/mmr.2020.11788] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 11/20/2020] [Indexed: 12/17/2022] Open
Abstract
Recent studies have reported that aberrant PR domain zinc finger protein 14 (PRDM14) expression is associated with the therapeutic sensitivity of cancer cells to drugs. However, its role in lung adenocarcinoma (LUAD) remains unclear. The present study aimed to determine the functions of knockdown or overexpression of PRDM14 in the chemosensitivity and glycolysis of LUAD cells. PRDM14 expression was analyzed in lung cancer tissues from patients resistant and sensitive to cisplatin (DDP), as well as in LUAD cell lines A549 and DDP-resistant A549 (A549/DDP) using reverse transcription quantitative-PCR and western blotting. Additionally, apoptosis was analyzed by flow cytometry, and flow cytometry and biochemical analysis was used to analyze glycolysis, indicated by glucose uptake and lactate release. The results of the present study demonstrated that PRDM14 expression was upregulated in patients with DDP-resistant LUAD and DDP-resistant cell lines. Overexpression of PRDM14 suppressed the sensitivity of A549 cells to DDP and silencing of PRDM14 using shRNA targeting PRDM14 promoted the sensitivity of A549/DDP cells to DDP, compared with that in the respective control groups. In mice with xenograft tumors, knockdown of PRDM14 using shRNA targeting PRDM14 inhibited the A549/DDP cell-derived tumor growth compared with scramble shRNA. The results of the glycolysis assays demonstrated that PRDM14 silencing inhibited glucose uptake, lactate release and glucose transporter 1 expression in A549/DDP cells compared with those in the control cells. PRDM14 overexpression relieved the inhibitory effects of 3-bromopyruvate, a potent glycolytic inhibitor for glycolysis, on glucose uptake and lactate release in A549 cells compared with those in the control cells. Therefore, the results of the present study suggested that PRDM14 may inhibit the chemosensitivity and promote glycolysis in human LUAD cells.
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Affiliation(s)
- Saifei He
- Department of Science and Research, The Seventh People's Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200137, P.R. China
| | - Xiaokun Ma
- Department of Nuclear Medicine, The Seventh People's Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200137, P.R. China
| | - Ni Zheng
- Department of Nuclear Medicine, The Seventh People's Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200137, P.R. China
| | - Guoyu Wang
- Department of Nuclear Medicine, The Seventh People's Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200137, P.R. China
| | - Menghan Wang
- Department of Nuclear Medicine, The Seventh People's Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200137, P.R. China
| | - Wei Xia
- Department of Nuclear Medicine, The Seventh People's Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200137, P.R. China
| | - Donghai Yu
- Department of Science and Education, The Municipal Health Commission, Shanghai 200125, P.R. China
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Guo Y, Liu X, Zhang Y, Qiu H, Ouyang F, He Y. 3-Bromopyruvate ameliorates pulmonary arterial hypertension by improving mitochondrial metabolism. Life Sci 2020; 256:118009. [PMID: 32603819 DOI: 10.1016/j.lfs.2020.118009] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Revised: 06/16/2020] [Accepted: 06/23/2020] [Indexed: 10/24/2022]
Abstract
AIMS Abnormal mitochondrial metabolism is an essential factor for excessive proliferation of pulmonary artery smooth muscle cells (PASMCs), which drives the pathological process of pulmonary arterial hypertension (PAH). 3-Bromopyruvate (3-BrPA) is an effective glycolytic inhibitor that improves mitochondrial metabolism, thereby repressing anomalous cell proliferation. MAIN METHODS An experimental PAH model was established by injection of monocrotaline (MCT) in male Sprague Dawley rats, following which rats were assigned to three groups: control, MCT, and 3-BrPA groups. Three days post injection of MCT, rats were treated with 3-BrPA or vehicle for 4 weeks. At the end of the study, hemodynamic data were measured to confirm PAH condition. Indicators of pulmonary arterial and right ventricular (RV) remodeling as well as the proliferative ability of PASMCs were assayed. Additionally, mitochondrial morphology and function, and antiglycolytic and antiproliferative pathways and genes were analyzed. KEY FINDINGS Treatment with 3-BrPA effectively improved pulmonary vascular remodeling and right ventricular function, inhibited PASMC proliferation, and preserved mitochondrial morphology and function. Besides, 3-BrPA treatment inhibited the PI3K/AKT/mTOR pathway and regulated the expression of antiproliferative genes in PASMCs. However, bloody ascites, bloating, and cirrhosis of organs were observed in some 3-BrPA treated rats. SIGNIFICANCE 3-BrPA acts as an important glycolytic inhibitor to improve energy metabolism and reverse the course of PAH. However, 3-BrPA is associated with side effects in MCT-induced rats, indicating that it should be caution in drug delivery dosage, and further studies are needed to evaluate this toxicological mechanism.
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Affiliation(s)
- Yuan Guo
- Department of Cardiovascular Medicine, The Affiliated Zhuzhou Hospital Xiangya Medical College, Central South University, Zhuzhou, Hunan 412000, China.
| | - Xiangyang Liu
- Department of Cardiovascular Medicine, The Affiliated Zhuzhou Hospital Xiangya Medical College, Central South University, Zhuzhou, Hunan 412000, China
| | - Yibo Zhang
- Department of Ultrasound, The Affiliated Zhuzhou Hospital Xiangya Medical College, Central South University, Zhuzhou, Hunan 412000, China
| | - Haihua Qiu
- Department of Cardiovascular Medicine, The Affiliated Zhuzhou Hospital Xiangya Medical College, Central South University, Zhuzhou, Hunan 412000, China
| | - Fan Ouyang
- Department of Cardiovascular Medicine, The Affiliated Zhuzhou Hospital Xiangya Medical College, Central South University, Zhuzhou, Hunan 412000, China
| | - Yi He
- Department of Cardiovascular Medicine, The Affiliated Zhuzhou Hospital Xiangya Medical College, Central South University, Zhuzhou, Hunan 412000, China
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Yadav S, Pandey SK, Goel Y, Temre MK, Singh SM. Antimetabolic Agent 3-Bromopyruvate Exerts Myelopotentiating Action in a Murine Host Bearing a Progressively Growing Ascitic Thymoma. Immunol Invest 2019; 49:425-442. [PMID: 31264492 DOI: 10.1080/08820139.2019.1627368] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Tumor growth and its chemotherapeutic regimens manifest myelosuppression, which is one of the possible causes underlying the limited success of immunotherapeutic anticancer strategies. Hence, approaches are being designed to develop safer therapeutic regimens that may have minimal damaging action on the process of myelopoiesis. 3-Bromopyruvate (3-BP) is a highly potent antimetabolic agent displaying a broad spectrum antineoplastic activity. However, 3-BP has not been investigated for its effect on the process of myelopoiesis in a tumor-bearing host. Hence, in this investigation, we studied the myelopoietic effect of in vivo administration of 3-BP to a murine host bearing a progressively growing ascitic thymoma designated as Dalton's lymphoma (DL). 3-BP administration to the DL-bearing mice resulted in a myelopotentiating action, reflected by an elevated count of bone marrow cells (BMC) accompanied by augmented proliferative ability and a declined induction of apoptosis. The BMC of 3-BP-administered mice displayed enhanced responsiveness to macrophage colony-stimulating factor for colony-forming ability of myeloid lineage along with an enhanced differentiation of F4/80+ bone marrow-derived macrophages (BMDM). BMDM differentiated from the BMC of 3-BP-administered DL-bearing mice showed an augmented response to lipopolysaccharide and interferon-γ for activation, displaying an augmented tumor cytotoxicity, expression of cytokines, reactive oxygen species, nitric oxide, CD11c, TLR-4, and HSP70. These features are indicative of the differentiation of M1 subtype of macrophages. Thus, this study demonstrates the myelopotentiating action of 3-BP, indicating its hematopoietic safety and potential for reinforcing the differentiation of macrophages in a tumor-bearing host.
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Affiliation(s)
- Saveg Yadav
- School of Biotechnology, Institute of Science, Banaras Hindu University, Varanasi, India
| | - Shrish Kumar Pandey
- School of Biotechnology, Institute of Science, Banaras Hindu University, Varanasi, India
| | - Yugal Goel
- School of Biotechnology, Institute of Science, Banaras Hindu University, Varanasi, India
| | - Mithlesh Kumar Temre
- School of Biotechnology, Institute of Science, Banaras Hindu University, Varanasi, India
| | - Sukh Mahendra Singh
- School of Biotechnology, Institute of Science, Banaras Hindu University, Varanasi, India
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Kumar A, Boradia VM, Thakare R, Singh AK, Gani Z, Das S, Patidar A, Dasgupta A, Chopra S, Raje M, Raje CI. Repurposing ethyl bromopyruvate as a broad-spectrum antibacterial. J Antimicrob Chemother 2019; 74:912-920. [PMID: 30689890 PMCID: PMC6419618 DOI: 10.1093/jac/dky555] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Revised: 11/20/2018] [Accepted: 12/04/2018] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND The emergence of drug-resistant bacteria is a major hurdle for effective treatment of infections caused by Mycobacterium tuberculosis and ESKAPE pathogens. In comparison with conventional drug discovery, drug repurposing offers an effective yet rapid approach to identifying novel antibiotics. METHODS Ethyl bromopyruvate was evaluated for its ability to inhibit M. tuberculosis and ESKAPE pathogens using growth inhibition assays. The selectivity index of ethyl bromopyruvate was determined, followed by time-kill kinetics against M. tuberculosis and Staphylococcus aureus. We first tested its ability to synergize with approved drugs and then tested its ability to decimate bacterial biofilm. Intracellular killing of M. tuberculosis was determined and in vivo potential was determined in a neutropenic murine model of S. aureus infection. RESULTS We identified ethyl bromopyruvate as an equipotent broad-spectrum antibacterial agent targeting drug-susceptible and -resistant M. tuberculosis and ESKAPE pathogens. Ethyl bromopyruvate exhibited concentration-dependent bactericidal activity. In M. tuberculosis, ethyl bromopyruvate inhibited GAPDH with a concomitant reduction in ATP levels and transferrin-mediated iron uptake. Apart from GAPDH, this compound inhibited pyruvate kinase, isocitrate lyase and malate synthase to varying extents. Ethyl bromopyruvate did not negatively interact with any drug and significantly reduced biofilm at a 64-fold lower concentration than vancomycin. When tested in an S. aureus neutropenic thigh infection model, ethyl bromopyruvate exhibited efficacy equal to that of vancomycin in reducing bacterial counts in thigh, and at 1/25th of the dosage. CONCLUSIONS Ethyl bromopyruvate exhibits all the characteristics required to be positioned as a potential broad-spectrum antibacterial agent.
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Affiliation(s)
- Ajay Kumar
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Phase X, Sector 67, SAS Nagar, Punjab, India
| | - Vishant Mahendra Boradia
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Phase X, Sector 67, SAS Nagar, Punjab, India
| | - Ritesh Thakare
- Division of Microbiology, Council of Scientific and Industrial Research-Central Drug Research Institute (CSIR-CDRI), Sitapur Road, Sector 10, Janakipuram Extension, Lucknow, Uttar Pradesh, India
| | - Alok Kumar Singh
- Division of Microbiology, Council of Scientific and Industrial Research-Central Drug Research Institute (CSIR-CDRI), Sitapur Road, Sector 10, Janakipuram Extension, Lucknow, Uttar Pradesh, India
| | - Zahid Gani
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Phase X, Sector 67, SAS Nagar, Punjab, India
| | - Swetarka Das
- Division of Microbiology, Council of Scientific and Industrial Research-Central Drug Research Institute (CSIR-CDRI), Sitapur Road, Sector 10, Janakipuram Extension, Lucknow, Uttar Pradesh, India
| | - Anil Patidar
- Council of Scientific and Industrial Research-Institute of Microbial Technology (CSIR-IMTECH), Sector 39A, Chandigarh, India
| | - Arunava Dasgupta
- Division of Microbiology, Council of Scientific and Industrial Research-Central Drug Research Institute (CSIR-CDRI), Sitapur Road, Sector 10, Janakipuram Extension, Lucknow, Uttar Pradesh, India
| | - Sidharth Chopra
- Division of Microbiology, Council of Scientific and Industrial Research-Central Drug Research Institute (CSIR-CDRI), Sitapur Road, Sector 10, Janakipuram Extension, Lucknow, Uttar Pradesh, India
| | - Manoj Raje
- Council of Scientific and Industrial Research-Institute of Microbial Technology (CSIR-IMTECH), Sector 39A, Chandigarh, India
| | - Chaaya Iyengar Raje
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Phase X, Sector 67, SAS Nagar, Punjab, India
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Tumor Energy Metabolism and Potential of 3-Bromopyruvate as an Inhibitor of Aerobic Glycolysis: Implications in Tumor Treatment. Cancers (Basel) 2019; 11:cancers11030317. [PMID: 30845728 PMCID: PMC6468516 DOI: 10.3390/cancers11030317] [Citation(s) in RCA: 117] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2019] [Revised: 02/28/2019] [Accepted: 03/01/2019] [Indexed: 12/24/2022] Open
Abstract
Tumor formation and growth depend on various biological metabolism processes that are distinctly different with normal tissues. Abnormal energy metabolism is one of the typical characteristics of tumors. It has been proven that most tumor cells highly rely on aerobic glycolysis to obtain energy rather than mitochondrial oxidative phosphorylation (OXPHOS) even in the presence of oxygen, a phenomenon called “Warburg effect”. Thus, inhibition of aerobic glycolysis becomes an attractive strategy to specifically kill tumor cells, while normal cells remain unaffected. In recent years, a small molecule alkylating agent, 3-bromopyruvate (3-BrPA), being an effective glycolytic inhibitor, has shown great potential as a promising antitumor drug. Not only it targets glycolysis process, but also inhibits mitochondrial OXPHOS in tumor cells. Excellent antitumor effects of 3-BrPA were observed in cultured cells and tumor-bearing animal models. In this review, we described the energy metabolic pathways of tumor cells, mechanism of action and cellular targets of 3-BrPA, antitumor effects, and the underlying mechanism of 3-BrPA alone or in combination with other antitumor drugs (e.g., cisplatin, doxorubicin, daunorubicin, 5-fluorouracil, etc.) in vitro and in vivo. In addition, few human case studies of 3-BrPA were also involved. Finally, the novel chemotherapeutic strategies of 3-BrPA, including wafer, liposomal nanoparticle, aerosol, and conjugate formulations, were also discussed for future clinical application.
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Visca P, Pisa F, Imperi F. The antimetabolite 3-bromopyruvate selectively inhibits Staphylococcus aureus. Int J Antimicrob Agents 2018; 53:449-455. [PMID: 30472291 DOI: 10.1016/j.ijantimicag.2018.11.008] [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: 09/21/2018] [Revised: 11/15/2018] [Accepted: 11/17/2018] [Indexed: 12/12/2022]
Abstract
Increased antibacterial resistance jeopardizes current therapeutic strategies to control infections, soliciting the development of novel antibacterial drugs with new mechanisms of action. This study reports the discovery of potent and selective antistaphylococcal activity of 3-bromopyruvate (3BP), an antimetabolite in preclinical development as an anticancer drug. 3BP showed bactericidal activity against Staphylococcus aureus, with active concentrations comparable with those reported to be effective against cancer cells. In contrast, no relevant activity was observed against other ESKAPE bacteria (Enterococcus faecium, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.). The antistaphylococcal activity of 3BP was confirmed using a panel of human and veterinary strains, including multi-drug-resistant isolates. 3BP showed highest antibacterial activity under conditions that increase its stability (acidic pH) or promote S. aureus fermentative metabolism (anaerobiosis), although 3BP was also able to kill metabolically inactive cells. 3BP showed synergism with gentamicin, and also disrupted preformed S. aureus biofilms at concentrations only slightly higher than those inhibiting planktonic cells. This study unravels novel antibacterial and antibiofilm activities for the anticancer drug 3BP, paving the way for further preclinical studies.
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Affiliation(s)
- Paolo Visca
- Department of Sciences, University 'Roma Tre', Rome, Italy
| | - Federica Pisa
- Department of Sciences, University 'Roma Tre', Rome, Italy; Department of Biology and Biotechnology Charles Darwin, Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Rome, Italy
| | - Francesco Imperi
- Department of Biology and Biotechnology Charles Darwin, Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Rome, Italy.
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Darabedian N, Chen TC, Molina H, Pratt MR, Schönthal AH. Bioorthogonal Profiling of a Cancer Cell Proteome Identifies a Large Set of 3-Bromopyruvate Targets beyond Glycolysis. ACS Chem Biol 2018; 13:3054-3058. [PMID: 30395437 DOI: 10.1021/acschembio.8b00743] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
3-Bromopyruvate (3BP) is a potential anticancer agent viewed as a glycolytic inhibitor that preferentially kills cancer cells through inhibition of glyceraldehyde 3-phosphate dehydrogenase (GAPDH), resulting in severe energy depletion. We previously identified four cysteine residues in GAPDH that are alkylated by 3BP, resulting in its inactivation. However, we also showed that addition of excess pyruvate, the final product of glycolysis, was unable to rescue cells from 3BP treatment. This result indicates that GAPDH may not be the only relevant target and is consistent with the chemical reactivity of 3BP that should result in the modification of cysteine residues in many different proteins. To directly test this hypothesis, we first synthesized a probe of 3BP activity bearing an alkyne functionality, termed AO3BP, and then demonstrated that this probe could modify a variety of proteins in living cells. Subsequent competition of AO3BP labeling with pretreatment by 3BP identified 62 statistically significant proteins of various functions as targets of 3BP, confirming that 3BP labeling is indeed widespread. We conclude that 3BP's cytotoxic impact on cancer cells does not only result from selective inhibition of glycolysis but rather from a more widespread effect on cellular proteins that could be driven by the pharmacokinetics of the 3BP. These pleiotropic consequences should be considered when thinking about the potential toxicity of this highly reactive compound.
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Affiliation(s)
| | | | - Henrik Molina
- Proteomics Resource Center, Rockefeller University, New York, New York 10065, United States
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12
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Yamada M, Kagaya M, Noguchi N, Ueki S, Hasunuma N, Osada SI, Manabe M. Topical 3-bromopyruvate is a novel targeted therapy for melanoma in a preclinical model. J Dermatol Sci 2018; 92:134-142. [DOI: 10.1016/j.jdermsci.2018.08.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Revised: 08/21/2018] [Accepted: 08/26/2018] [Indexed: 01/10/2023]
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13
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El Sayed SM. Enhancing anticancer effects, decreasing risks and solving practical problems facing 3-bromopyruvate in clinical oncology: 10 years of research experience. Int J Nanomedicine 2018; 13:4699-4709. [PMID: 30154655 PMCID: PMC6103555 DOI: 10.2147/ijn.s170564] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
3-Bromopyruvate (3BP) is a promising powerful general anticancer agent. Unfortunately, 3BP release faces many practical and biochemical problems in clinical human oncology, for example, 3BP induces burning venous sensation (during intravenous infusion) and rapid inactivation by thiol groups of glutathione and proteins. 3BP exhibits resistance in glutathione-rich tumors without being able to exert selective targeting. 3BP does not cross the blood–brain barrier and cannot treat nervous system tumors. Importantly, 3BP cannot persist in tumor tissues due to the phenomenon of enhanced permeability and retention effect. Here, the author presents the practical solutions for clinical problems facing 3BP use in clinical oncology, based on over 10 years of experience in 3BP research. Crude (unformulated 3BP that is purchased from chemical companies without being formulated in liposomes or other nanocarriers) should not be administered in clinical oncology. Instead, 3BP is better formulated with liposomes, polyethylene glycol (PEG), PEGylated liposomes (stealth liposomes) or perillyl alcohol that are used currently with many chemotherapeutics for treating clinical tumors in cancer patients. Formulating 3BP with targeted liposomes, for example, with folate, transferrin or other ligands, improves tumor targeting. Formulating 3BP with liposomes, PEG, stealth liposomes or perillyl alcohol may improve its pharmacokinetics, hide it from thiols in the circulation, protect it from serum proteins and enzymes, prevent burning sensation, prolong 3BP’s longevity and facilitate crossing the BBB. Formulating 3BP with stealth liposomes protects 3BP from the reticuloendothelial cells. Liposomal 3BP formulations may retain 3BP better inside the relatively large tumor capillary pores (abolish enhanced permeability and retention effect) sparing normal tissues, facilitate new delivery routes for 3BP (eg, topical and intranasal 3BP administration using perillyl alcohol) and improve cancer cytotoxicity. Formulating 3BP may be promising in overcoming many obstacles in clinical oncology.
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Affiliation(s)
- Salah Mohamed El Sayed
- Department of Clinical Biochemistry and Molecular Medicine, Taibah College of Medicine, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia, .,Department of Medical Biochemistry, Sohag Faculty of Medicine, Sohag University, Sohag, Egypt,
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14
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Lee WH, Loo CY, Ghadiri M, Leong CR, Young PM, Traini D. The potential to treat lung cancer via inhalation of repurposed drugs. Adv Drug Deliv Rev 2018; 133:107-130. [PMID: 30189271 DOI: 10.1016/j.addr.2018.08.012] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Revised: 08/27/2018] [Accepted: 08/31/2018] [Indexed: 01/10/2023]
Abstract
Lung cancer is a highly invasive and prevalent disease with ineffective first-line treatment and remains the leading cause of cancer death in men and women. Despite the improvements in diagnosis and therapy, the prognosis and outcome of lung cancer patients is still poor. This could be associated with the lack of effective first-line oncology drugs, formation of resistant tumors and non-optimal administration route. Therefore, the repurposing of existing drugs currently used for different indications and the introduction of a different method of drug administration could be investigated as an alternative to improve lung cancer therapy. This review describes the rationale and development of repositioning of drugs for lung cancer treatment with emphasis on inhalation. The review includes the current progress of repurposing non-cancer drugs, as well as current chemotherapeutics for lung malignancies via inhalation. Several potential non-cancer drugs such as statins, itraconazole and clarithromycin, that have demonstrated preclinical anti-cancer activity, are also presented. Furthermore, the potential challenges and limitations that might hamper the clinical translation of repurposed oncology drugs are described.
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Affiliation(s)
- Wing-Hin Lee
- Faculty of Pharmacy and Health Sciences, Royal College of Medicine Perak, Universiti Kuala Lumpur (RCMP UniKL), Ipoh, Perak, Malaysia; Respiratory Technology, Woolcock Institute of Medical Research, and Discipline of Pharmacology, Faculty of Medicine and Health, The University of Sydney, NSW 2037, Australia; Centre for Lung Cancer Research, 431 Glebe Point Road, 2037, Australia.
| | - Ching-Yee Loo
- Faculty of Pharmacy and Health Sciences, Royal College of Medicine Perak, Universiti Kuala Lumpur (RCMP UniKL), Ipoh, Perak, Malaysia; Respiratory Technology, Woolcock Institute of Medical Research, and Discipline of Pharmacology, Faculty of Medicine and Health, The University of Sydney, NSW 2037, Australia; Centre for Lung Cancer Research, 431 Glebe Point Road, 2037, Australia
| | - Maliheh Ghadiri
- Respiratory Technology, Woolcock Institute of Medical Research, and Discipline of Pharmacology, Faculty of Medicine and Health, The University of Sydney, NSW 2037, Australia; Centre for Lung Cancer Research, 431 Glebe Point Road, 2037, Australia
| | - Chean-Ring Leong
- Section of Bioengineering Technology, Universiti Kuala Lumpur (UniKL) MICET, Alor Gajah, Melaka, Malaysia
| | - Paul M Young
- Respiratory Technology, Woolcock Institute of Medical Research, and Discipline of Pharmacology, Faculty of Medicine and Health, The University of Sydney, NSW 2037, Australia; Centre for Lung Cancer Research, 431 Glebe Point Road, 2037, Australia
| | - Daniela Traini
- Respiratory Technology, Woolcock Institute of Medical Research, and Discipline of Pharmacology, Faculty of Medicine and Health, The University of Sydney, NSW 2037, Australia; Centre for Lung Cancer Research, 431 Glebe Point Road, 2037, Australia
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15
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Yadav S, Pandey SK, Kumar A, Kujur PK, Singh RP, Singh SM. Antitumor and chemosensitizing action of 3-bromopyruvate: Implication of deregulated metabolism. Chem Biol Interact 2017; 270:73-89. [DOI: 10.1016/j.cbi.2017.04.015] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Revised: 04/04/2017] [Accepted: 04/18/2017] [Indexed: 01/22/2023]
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16
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Chen TC, Yu J, Nouri Nigjeh E, Wang W, Myint PT, Zandi E, Hofman FM, Schönthal AH. A perillyl alcohol-conjugated analog of 3-bromopyruvate without cellular uptake dependency on monocarboxylate transporter 1 and with activity in 3-BP-resistant tumor cells. Cancer Lett 2017; 400:161-174. [PMID: 28450161 DOI: 10.1016/j.canlet.2017.04.015] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2016] [Revised: 03/07/2017] [Accepted: 04/17/2017] [Indexed: 02/08/2023]
Abstract
The anticancer agent 3-bromopyruvate (3-BP) is viewed as a glycolytic inhibitor that preferentially kills glycolytic cancer cells through energy depletion. However, its cytotoxic activity is dependent on cellular drug import through transmembrane monocarboxylate transporter 1 (MCT-1), which restricts its anticancer potential to MCT-1-positive tumor cells. We created and characterized an MCT-1-independent analog of 3-BP, called NEO218. NEO218 was synthesized by covalently conjugating 3-BP to perillyl alcohol (POH), a natural monoterpene. The responses of various tumor cell lines to treatment with either compound were characterized in the presence or absence of supplemental pyruvate or antioxidants N-acetyl-cysteine (NAC) and glutathione (GSH). Drug effects on glyceraldehyde 3-phosphate dehydrogenase (GAPDH) enzyme activity were investigated by mass spectrometric analysis. The development of 3-BP resistance was investigated in MCT-1-positive HCT116 colon carcinoma cells in vitro. Our results show that NEO218: (i) pyruvylated GAPDH on all 4 of its cysteine residues and shut down enzymatic activity; (ii) severely lowered cellular ATP content below life-sustaining levels, and (iii) triggered rapid necrosis. Intriguingly, supplemental antioxidants effectively prevented cytotoxic activity of NEO218 as well as 3-BP, but supplemental pyruvate powerfully protected cells only from 3-BP, not from NEO218. Unlike 3-BP, NEO218 exerted its potent cytotoxic activity irrespective of cellular MCT-1 status. Treatment of HCT116 cells with 3-BP resulted in prompt development of resistance, based on the emergence of MCT-1-negative cells. This was not the case with NEO218, and highly 3-BP-resistant cells remained exquisitely sensitive to NEO218. Thus, our study identifies a mechanism by which tumor cells develop rapid resistance to 3-BP, and presents NEO218 as a superior agent not subject to this cellular defense. Furthermore, our results offer alternative interpretations of previously published models on the role of supplemental antioxidants: Rather than quenching reactive oxygen species (ROS), supplemental NAC or GSH directly interact with 3-BP, thereby neutralizing the drug's cytotoxic potential before it can trigger ROS production. Altogether, our study introduces new aspects of the cytotoxic mechanism of 3-BP, and characterizes NEO218 as an analog able to overcome a key cellular defense mechanism towards this drug.
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Affiliation(s)
- Thomas C Chen
- Department of Neurosurgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
| | - Jiali Yu
- Department of Neurosurgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
| | - Eslam Nouri Nigjeh
- Research Center for Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
| | - Weijun Wang
- Department of Neurosurgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
| | - Phyo Thazin Myint
- Department of Molecular Microbiology & Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
| | - Ebrahim Zandi
- Department of Molecular Microbiology & Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
| | - Florence M Hofman
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
| | - Axel H Schönthal
- Department of Molecular Microbiology & Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
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17
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El Sayed SM, Baghdadi H, Zolaly M, Almaramhy HH, Ayat M, Donki JG. The promising anticancer drug 3-bromopyruvate is metabolized through glutathione conjugation which affects chemoresistance and clinical practice: An evidence-based view. Med Hypotheses 2017; 100:67-77. [DOI: 10.1016/j.mehy.2017.01.014] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2016] [Revised: 10/11/2016] [Accepted: 01/21/2017] [Indexed: 01/22/2023]
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18
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Paiardini A, Tramonti A, Schirch D, Guiducci G, di Salvo ML, Fiascarelli A, Giorgi A, Maras B, Cutruzzolà F, Contestabile R. Differential 3-bromopyruvate inhibition of cytosolic and mitochondrial human serine hydroxymethyltransferase isoforms, key enzymes in cancer metabolic reprogramming. BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS 2016; 1864:1506-17. [DOI: 10.1016/j.bbapap.2016.08.010] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Revised: 08/05/2016] [Accepted: 08/10/2016] [Indexed: 12/11/2022]
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Pan Q, Sun Y, Jin Q, Li Q, Wang Q, Liu H, Zhao S. Hepatotoxicity and nephrotoxicity of 3-bromopyruvate in mice. Acta Cir Bras 2016; 31:724-729. [DOI: 10.1590/s0102-865020160110000004] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2016] [Accepted: 10/10/2016] [Indexed: 11/22/2022] Open
Affiliation(s)
| | | | | | | | | | - Hao Liu
- Department of Pharmacy, China
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20
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Sobotka O, Endlicher R, Drahota Z, Kučera O, Rychtrmoc D, Raad M, Hakeem K, Červinková Z. Impaired mitochondrial functions contribute to 3-bromopyruvate toxicity in primary rat and mouse hepatocytes. J Bioenerg Biomembr 2016; 48:363-73. [PMID: 27530389 DOI: 10.1007/s10863-016-9674-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Accepted: 08/07/2016] [Indexed: 01/22/2023]
Abstract
A compound with promising anticancer properties, 3-bromopyruvate (3-BP) is a synthetic derivative of a pyruvate molecule; however, its toxicity in non-malignant cells has not yet been fully elucidated. Therefore, we elected to study the effects of 3-BP on primary hepatocytes in monolayer cultures, permeabilized hepatocytes and isolated mitochondria. After a 1-h treatment with 100 μM 3-BP cell viability of rat hepatocytes was decreased by 30 % as measured by the WST-1 test (p < 0.001); after 3-h exposure to ≥200 μM 3-BP lactate dehydrogenase leakage was increased (p < 0.001). Reactive oxygen species production was increased in the cell cultures after a 1-h treatment at concentrations ≥100 μmol/l (p < 0.01), and caspase 3 activity was increased after a 20-h incubation with 150 μM and 200 μM 3-BP (p < 0.001). This toxic effect of 3-BP was also proved using primary mouse hepatocytes. In isolated mitochondria, 3-BP induced a dose- and time-dependent decrease of mitochondrial membrane potential during a 10-min incubation both with Complex I substrates glutamate + malate or Complex II substrate succinate, although this decrease was more pronounced with the latter. We also measured the effect of 3-BP on respiration of isolated mitochondria. ADP-activated respiration was inhibited by 20 μM 3-BP within 10 min. Similar effects were also found in permeabilized hepatocytes of both species.
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Affiliation(s)
- Ondřej Sobotka
- Department of Physiology, Faculty of Medicine in Hradec Kralove, Charles University in Prague, Hradec Kralove, Czech Republic
| | - René Endlicher
- Department of Physiology, Faculty of Medicine in Hradec Kralove, Charles University in Prague, Hradec Kralove, Czech Republic
- Department of Anatomy, Faculty of Medicine in Hradec Kralove, Charles University in Prague, Hradec Kralove, Czech Republic
| | - Zdeněk Drahota
- Department of Physiology, Faculty of Medicine in Hradec Kralove, Charles University in Prague, Hradec Kralove, Czech Republic
- Institute of Physiology, The Czech Academy of Sciences, Prague, Czech Republic
| | - Otto Kučera
- Department of Physiology, Faculty of Medicine in Hradec Kralove, Charles University in Prague, Hradec Kralove, Czech Republic
| | - David Rychtrmoc
- Department of Physiology, Faculty of Medicine in Hradec Kralove, Charles University in Prague, Hradec Kralove, Czech Republic
| | - Marjan Raad
- Department of Physiology, Faculty of Medicine in Hradec Kralove, Charles University in Prague, Hradec Kralove, Czech Republic
| | - Khurum Hakeem
- Department of Physiology, Faculty of Medicine in Hradec Kralove, Charles University in Prague, Hradec Kralove, Czech Republic
| | - Zuzana Červinková
- Department of Physiology, Faculty of Medicine in Hradec Kralove, Charles University in Prague, Hradec Kralove, Czech Republic.
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The anticancer agent 3-bromopyruvate: a simple but powerful molecule taken from the lab to the bedside. J Bioenerg Biomembr 2016; 48:349-62. [PMID: 27457582 DOI: 10.1007/s10863-016-9670-z] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2016] [Accepted: 07/18/2016] [Indexed: 12/13/2022]
Abstract
At the beginning of the twenty-first century, 3-bromopyruvate (3BP), a simple alkylating chemical compound was presented to the scientific community as a potent anticancer agent, able to cause rapid toxicity to cancer cells without bystander effects on normal tissues. The altered metabolism of cancers, an essential hallmark for their progression, also became their Achilles heel by facilitating 3BP's selective entry and specific targeting. Treatment with 3BP has been administered in several cancer type models both in vitro and in vivo, either alone or in combination with other anticancer therapeutic approaches. These studies clearly demonstrate 3BP's broad action against multiple cancer types. Clinical trials using 3BP are needed to further support its anticancer efficacy against multiple cancer types thus making it available to more than 30 million patients living with cancer worldwide. This review discusses current knowledge about 3BP related to cancer and discusses also the possibility of its use in future clinical applications as it relates to safety and treatment issues.
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22
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Chinese Herbs Interfering with Cancer Reprogramming Metabolism. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2016; 2016:9282813. [PMID: 27242914 PMCID: PMC4875995 DOI: 10.1155/2016/9282813] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/06/2015] [Accepted: 02/03/2016] [Indexed: 12/11/2022]
Abstract
Emerging evidence promotes a reassessment of metabolic reprogramming regulation in cancer research. Although there exists a long history of Chinese herbs applied in cancer treatment, few reports have addressed the effects of Chinese herbal components on metabolic reprogramming, which is a central cancer hallmark involved in the slowing or prevention of chemoresistance in cancer cells. In this review, we have focused on four core elements altered by metabolic reprogramming in cancer cells. These include glucose transport, glycolysis, mitochondrial oxidative phosphorylation, and fatty acid synthesis. With this focus, we have summarized recent advances in metabolic reprogramming of cancer cells in response to specific Chinese herbal components. We propose that exploring Chinese herbal interference in cancer metabolic reprogramming might identify new therapeutic targets for cancer and more ways in which to approach metabolism-related diseases.
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Bodur C, Karakas B, Timucin AC, Tezil T, Basaga H. AMP-activated protein kinase couples 3-bromopyruvate-induced energy depletion to apoptosis via activation of FoxO3a and upregulation of proapoptotic Bcl-2 proteins. Mol Carcinog 2015; 55:1584-1597. [PMID: 26373689 DOI: 10.1002/mc.22411] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2015] [Revised: 08/21/2015] [Accepted: 08/31/2015] [Indexed: 01/15/2023]
Abstract
Most tumors primarily rely on glycolysis rather than mitochondrial respiration for ATP production. This phenomenon, also known as Warburg effect, renders tumors more sensitive to glycolytic disturbances compared to normal cells. 3-bromopyruvate is a potent inhibitor of glycolysis that shows promise as an anticancer drug candidate. Although investigations revealed that 3-BP triggers apoptosis through ATP depletion and subsequent AMPK activation, the underlying molecular mechanisms coupling AMPK to apoptosis are poorly understood. We showed that 3-BP leads to a rapid ATP depletion which was followed by growth inhibition and Bax-dependent apoptosis in HCT116 cells. Apoptosis was accompanied with activation of caspase-9 and -3 while pretreatment with a general caspase inhibitor attenuated cell death. AMPK, p38, JNK, and Akt were phosphorylated immediately upon treatment. Pharmacological inhibition and silencing of AMPK largely inhibited 3-BP-induced apoptosis and reversed phosphorylation of JNK. Transcriptional activity of FoxO3a was dramatically increased subsequent to AMPK-mediated phosphorylation of FoxO3a at Ser413. Cell death analysis of cells transiently transfected with wt or AMPK-phosphorylation-deficient FoxO3 expression plasmids verified the contributory role of AMPK-FoxO3a axis in 3-BP-induced apoptosis. In addition, expression of proapoptotic Bcl-2 proteins Bim and Bax were upregulated in an AMPK-dependent manner. Bim was transcriptionally activated in association with FoxO3a activity, while Bax upregulation was abolished in p53-null cells. Together, these data suggest that AMPK couples 3-BP-induced metabolic disruption to intrinsic apoptosis via modulation of FoxO3a-Bim axis and Bax expression. © 2015 Wiley Periodicals, Inc.
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Affiliation(s)
- Cagri Bodur
- Molecular Biology, Genetics, and Bioengineering Program, Sabanci University, Tuzla, Istanbul, Turkey.
| | - Bahriye Karakas
- Molecular Biology, Genetics, and Bioengineering Program, Sabanci University, Tuzla, Istanbul, Turkey
| | - Ahmet Can Timucin
- Molecular Biology, Genetics, and Bioengineering Program, Sabanci University, Tuzla, Istanbul, Turkey
| | - Tugsan Tezil
- Molecular Biology, Genetics, and Bioengineering Program, Sabanci University, Tuzla, Istanbul, Turkey
| | - Huveyda Basaga
- Molecular Biology, Genetics, and Bioengineering Program, Sabanci University, Tuzla, Istanbul, Turkey
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24
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Lee M, Yoon JH. Metabolic interplay between glycolysis and mitochondrial oxidation: The reverse Warburg effect and its therapeutic implication. World J Biol Chem 2015; 6:148-61. [PMID: 26322173 PMCID: PMC4549759 DOI: 10.4331/wjbc.v6.i3.148] [Citation(s) in RCA: 107] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2015] [Revised: 05/26/2015] [Accepted: 07/21/2015] [Indexed: 02/05/2023] Open
Abstract
Aerobic glycolysis, i.e., the Warburg effect, may contribute to the aggressive phenotype of hepatocellular carcinoma. However, increasing evidence highlights the limitations of the Warburg effect, such as high mitochondrial respiration and low glycolysis rates in cancer cells. To explain such contradictory phenomena with regard to the Warburg effect, a metabolic interplay between glycolytic and oxidative cells was proposed, i.e., the "reverse Warburg effect". Aerobic glycolysis may also occur in the stromal compartment that surrounds the tumor; thus, the stromal cells feed the cancer cells with lactate and this interaction prevents the creation of an acidic condition in the tumor microenvironment. This concept provides great heterogeneity in tumors, which makes the disease difficult to cure using a single agent. Understanding metabolic flexibility by lactate shuttles offers new perspectives to develop treatments that target the hypoxic tumor microenvironment and overcome the limitations of glycolytic inhibitors.
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25
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Cho JH, Jeon YJ, Park SM, Shin JC, Lee TH, Jung S, Park H, Ryu J, Chen H, Dong Z, Shim JH, Chae JI. Multifunctional effects of honokiol as an anti-inflammatory and anti-cancer drug in human oral squamous cancer cells and xenograft. Biomaterials 2015; 53:274-84. [DOI: 10.1016/j.biomaterials.2015.02.091] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2014] [Revised: 02/16/2015] [Accepted: 02/21/2015] [Indexed: 11/27/2022]
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Zhang Q, Pan J, Lubet RA, Komas SM, Kalyanaraman B, Wang Y, You M. Enhanced antitumor activity of 3-bromopyruvate in combination with rapamycin in vivo and in vitro. Cancer Prev Res (Phila) 2015; 8:318-26. [PMID: 25644152 DOI: 10.1158/1940-6207.capr-14-0142] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2014] [Accepted: 01/22/2015] [Indexed: 12/26/2022]
Abstract
3-Bromopyruvate (3-BrPA) is an alkylating agent and a well-known inhibitor of energy metabolism. Rapamycin is an inhibitor of the serine/threonine protein kinase mTOR. Both 3-BrPA and rapamycin show chemopreventive efficacy in mouse models of lung cancer. Aerosol delivery of therapeutic drugs for lung cancer has been reported to be an effective route of delivery with little systemic distribution in humans. In this study, 3-BrPA and rapamycin were evaluated in combination for their preventive effects against lung cancer in mice by aerosol treatment, revealing a synergistic ability as measured by tumor multiplicity and tumor load compared treatment with either single-agent alone. No evidence of liver toxicity was detected by monitoring serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) enzymes. To understand the mechanism in vitro experiments were performed using human non-small cell lung cancer (NSCLC) cell lines. 3-BrPA and rapamycin also synergistically inhibited cell proliferation. Rapamycin alone blocked the mTOR signaling pathway, whereas 3-BrPA did not potentiate this effect. Given the known role of 3-BrPA as an inhibitor of glycolysis, we investigated mitochondrial bioenergetics changes in vitro in 3-BrPA-treated NSCLC cells. 3-BrPA significantly decreased glycolytic activity, which may be due to adenosine triphosphate (ATP) depletion and decreased expression of GAPDH. Our results demonstrate that rapamycin enhanced the antitumor efficacy of 3-BrPA, and that dual inhibition of mTOR signaling and glycolysis may be an effective therapeutic strategy for lung cancer chemoprevention.
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Affiliation(s)
- Qi Zhang
- Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin. Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Jing Pan
- Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin. Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Ronald A Lubet
- Chemoprevention Branch, National Cancer Institute, Bethesda, Maryland
| | - Steven M Komas
- Department of Biophysics, Medical College of Wisconsin, Milwaukee, Wisconsin
| | | | - Yian Wang
- Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin. Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Ming You
- Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin. Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin.
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27
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Byrne FL, Poon IKH, Modesitt SC, Tomsig JL, Chow JDY, Healy ME, Baker WD, Atkins KA, Lancaster JM, Marchion DC, Moley KH, Ravichandran KS, Slack-Davis JK, Hoehn KL. Metabolic vulnerabilities in endometrial cancer. Cancer Res 2014; 74:5832-45. [PMID: 25205105 DOI: 10.1158/0008-5472.can-14-0254] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Women with metabolic disorders, including obesity and diabetes, have an increased risk of developing endometrial cancer. However, the metabolism of endometrial tumors themselves has been largely understudied. Comparing human endometrial tumors and cells with their nonmalignant counterparts, we found that upregulation of the glucose transporter GLUT6 was more closely associated with the cancer phenotype than other hallmark cancer genes, including hexokinase 2 and pyruvate kinase M2. Importantly, suppression of GLUT6 expression inhibited glycolysis and survival of endometrial cancer cells. Glycolysis and lipogenesis were also highly coupled with the cancer phenotype in patient samples and cells. To test whether targeting endometrial cancer metabolism could be exploited as a therapeutic strategy, we screened a panel of compounds known to target diverse metabolic pathways in endometrial cells. We identified that the glycolytic inhibitor, 3-bromopyruvate, is a powerful antagonist of lipogenesis through pyruvylation of CoA. We also provide evidence that 3-bromopyruvate promotes cell death via a necrotic mechanism that does not involve reactive oxygen species and that 3-bromopyruvate impaired the growth of endometrial cancer xenografts.
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Affiliation(s)
- Frances L Byrne
- Department of Pharmacology, University of Virginia, Charlottesville, Virginia. School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, Australia
| | - Ivan K H Poon
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia. Department of Biochemistry, La Trobe Institute for Molecular Science, La Trobe University, Victoria, Australia
| | - Susan C Modesitt
- Department of Obstetrics and Gynecology, University of Virginia, Charlottesville, Virginia
| | - Jose L Tomsig
- Department of Pharmacology, University of Virginia, Charlottesville, Virginia
| | - Jenny D Y Chow
- Department of Pharmacology, University of Virginia, Charlottesville, Virginia
| | - Marin E Healy
- Department of Pharmacology, University of Virginia, Charlottesville, Virginia
| | - William D Baker
- Department of Obstetrics and Gynecology, University of Virginia, Charlottesville, Virginia
| | - Kristen A Atkins
- Department of Pathology, University of Virginia, Charlottesville, Virginia
| | - Johnathan M Lancaster
- Departments of Women's Oncology and Experimental Therapeutics Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Douglas C Marchion
- Departments of Women's Oncology and Experimental Therapeutics Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Kelle H Moley
- Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri
| | - Kodi S Ravichandran
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia. Center for Cell Clearance, University of Virginia, Charlottesville, Virginia
| | - Jill K Slack-Davis
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia. Cancer Center, University of Virginia, Charlottesville, Virginia
| | - Kyle L Hoehn
- Department of Pharmacology, University of Virginia, Charlottesville, Virginia. School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, Australia. Cancer Center, University of Virginia, Charlottesville, Virginia. Department of Medicine, University of Virginia, Charlottesville, Virginia.
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Zhang Q, Pan J, Lubet RA, Wang Y, You M. Targeting the insulin-like growth factor-1 receptor by picropodophyllin for lung cancer chemoprevention. Mol Carcinog 2014; 54 Suppl 1:E129-37. [PMID: 25163779 DOI: 10.1002/mc.22206] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2014] [Accepted: 06/24/2014] [Indexed: 11/08/2022]
Abstract
Insulin-like growth factor-1 receptor (IGF-1R) is a transmembrane heterotetramer that is activated by Insulin-like growth factor 1 and is crucial for tumor transformation and survival of malignant cells. Importantly, IGF-1R overexpression has been reported in many different cancers, implicating this receptor as a potential target for anticancer therapy. Picropodophyllin (PPP) is a potent inhibitor of IGF-1R and has antitumor efficacy in several cancer types. However, the chemopreventive effect of PPP in lung tumorigenesis has not been investigated. In this study, we investigated the chemopreventive activity of PPP in a mouse lung tumor model. Benzo(a)pyrene was used to induce lung tumors, and PPP was given by nasal inhalation to female A/J mice. Lung tumorigenesis was assessed by tumor multiplicity and tumor load. PPP significantly decreased tumor multiplicity and tumor load. Tumor multiplicity and load were decreased by 52% and 78% respectively by 4 mg/ml aerosolized PPP. Pharmacokinetics analysis showed good bioavailability of PPP in lung and plasma. Treatment with PPP increased staining for cleaved caspase-3 and decreased Ki-67 in lung tumors, suggesting that the lung tumor inhibitory effects of PPP were partially through inhibition of proliferation and induction of apoptosis. In human lung cancer cell lines, PPP inhibited cell proliferation, and also inhibited phosphorylation of IGF-1R downstream targets, AKT and MAPK, ultimately resulting in increased apoptosis. PPP also reduced cell invasion in lung cancer cell lines. In view of our data, PPP merits further investigation as a promising chemopreventive agent for human lung cancer.
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Affiliation(s)
- Qi Zhang
- Medical College of Wisconsin Cancer Center and Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Jing Pan
- Medical College of Wisconsin Cancer Center and Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Ronald A Lubet
- Chemoprevention Branch, National Cancer Institute, Bethesda, Maryland
| | - Yian Wang
- Medical College of Wisconsin Cancer Center and Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Ming You
- Medical College of Wisconsin Cancer Center and Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin
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Wicks RT, Azadi J, Mangraviti A, Zhang I, Hwang L, Joshi A, Bow H, Hutt-Cabezas M, Martin KL, Rudek MA, Zhao M, Brem H, Tyler BM. Local delivery of cancer-cell glycolytic inhibitors in high-grade glioma. Neuro Oncol 2014; 17:70-80. [PMID: 25053853 DOI: 10.1093/neuonc/nou143] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND 3-bromopyruvate (3-BrPA) and dichloroacetate (DCA) are inhibitors of cancer-cell specific aerobic glycolysis. Their application in glioma is limited by 3-BrPA's inability to cross the blood-brain-barrier and DCA's dose-limiting toxicity. The safety and efficacy of intracranial delivery of these compounds were assessed. METHODS Cytotoxicity of 3-BrPA and DCA were analyzed in U87, 9L, and F98 glioma cell lines. 3-BrPA and DCA were incorporated into biodegradable pCPP:SA wafers, and the maximally tolerated dose was determined in F344 rats. Efficacies of the intracranial 3-BrPA wafer and DCA wafer were assessed in a rodent allograft model of high-grade glioma, both as a monotherapy and in combination with temozolomide (TMZ) and radiation therapy (XRT). RESULTS 3-BrPA and DCA were found to have similar IC50 values across the 3 glioma cell lines. 5% 3-BrPA wafer-treated animals had significantly increased survival compared with controls (P = .0027). The median survival of rats with the 50% DCA wafer increased significantly compared with both the oral DCA group (P = .050) and the controls (P = .02). Rats implanted on day 0 with a 5% 3-BrPA wafer in combination with TMZ had significantly increased survival over either therapy alone. No statistical difference in survival was noted when the wafers were added to the combination therapy of TMZ and XRT, but the 5% 3-BrPA wafer given on day 0 in combination with TMZ and XRT resulted in long-term survivorship of 30%. CONCLUSION Intracranial delivery of 3-BrPA and DCA polymer was safe and significantly increased survival in an animal model of glioma, a potential novel therapeutic approach. The combination of intracranial 3-BrPA and TMZ provided a synergistic effect.
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Affiliation(s)
- Robert T Wicks
- Department of Neurosurgery (R.T.W., J.A., A.M., I.Z., L.H., A.J., H.B., M.H.-C., K.L.M., H.B., B.M.T.); Departments of Oncology, Ophthalmology, and Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland (H.B.); Division of Chemical Therapeutics, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (M.A.R., M.Z.)
| | - Javad Azadi
- Department of Neurosurgery (R.T.W., J.A., A.M., I.Z., L.H., A.J., H.B., M.H.-C., K.L.M., H.B., B.M.T.); Departments of Oncology, Ophthalmology, and Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland (H.B.); Division of Chemical Therapeutics, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (M.A.R., M.Z.)
| | - Antonella Mangraviti
- Department of Neurosurgery (R.T.W., J.A., A.M., I.Z., L.H., A.J., H.B., M.H.-C., K.L.M., H.B., B.M.T.); Departments of Oncology, Ophthalmology, and Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland (H.B.); Division of Chemical Therapeutics, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (M.A.R., M.Z.)
| | - Irma Zhang
- Department of Neurosurgery (R.T.W., J.A., A.M., I.Z., L.H., A.J., H.B., M.H.-C., K.L.M., H.B., B.M.T.); Departments of Oncology, Ophthalmology, and Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland (H.B.); Division of Chemical Therapeutics, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (M.A.R., M.Z.)
| | - Lee Hwang
- Department of Neurosurgery (R.T.W., J.A., A.M., I.Z., L.H., A.J., H.B., M.H.-C., K.L.M., H.B., B.M.T.); Departments of Oncology, Ophthalmology, and Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland (H.B.); Division of Chemical Therapeutics, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (M.A.R., M.Z.)
| | - Avadhut Joshi
- Department of Neurosurgery (R.T.W., J.A., A.M., I.Z., L.H., A.J., H.B., M.H.-C., K.L.M., H.B., B.M.T.); Departments of Oncology, Ophthalmology, and Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland (H.B.); Division of Chemical Therapeutics, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (M.A.R., M.Z.)
| | - Hansen Bow
- Department of Neurosurgery (R.T.W., J.A., A.M., I.Z., L.H., A.J., H.B., M.H.-C., K.L.M., H.B., B.M.T.); Departments of Oncology, Ophthalmology, and Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland (H.B.); Division of Chemical Therapeutics, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (M.A.R., M.Z.)
| | - Marianne Hutt-Cabezas
- Department of Neurosurgery (R.T.W., J.A., A.M., I.Z., L.H., A.J., H.B., M.H.-C., K.L.M., H.B., B.M.T.); Departments of Oncology, Ophthalmology, and Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland (H.B.); Division of Chemical Therapeutics, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (M.A.R., M.Z.)
| | - Kristin L Martin
- Department of Neurosurgery (R.T.W., J.A., A.M., I.Z., L.H., A.J., H.B., M.H.-C., K.L.M., H.B., B.M.T.); Departments of Oncology, Ophthalmology, and Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland (H.B.); Division of Chemical Therapeutics, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (M.A.R., M.Z.)
| | - Michelle A Rudek
- Department of Neurosurgery (R.T.W., J.A., A.M., I.Z., L.H., A.J., H.B., M.H.-C., K.L.M., H.B., B.M.T.); Departments of Oncology, Ophthalmology, and Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland (H.B.); Division of Chemical Therapeutics, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (M.A.R., M.Z.)
| | - Ming Zhao
- Department of Neurosurgery (R.T.W., J.A., A.M., I.Z., L.H., A.J., H.B., M.H.-C., K.L.M., H.B., B.M.T.); Departments of Oncology, Ophthalmology, and Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland (H.B.); Division of Chemical Therapeutics, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (M.A.R., M.Z.)
| | - Henry Brem
- Department of Neurosurgery (R.T.W., J.A., A.M., I.Z., L.H., A.J., H.B., M.H.-C., K.L.M., H.B., B.M.T.); Departments of Oncology, Ophthalmology, and Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland (H.B.); Division of Chemical Therapeutics, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (M.A.R., M.Z.)
| | - Betty M Tyler
- Department of Neurosurgery (R.T.W., J.A., A.M., I.Z., L.H., A.J., H.B., M.H.-C., K.L.M., H.B., B.M.T.); Departments of Oncology, Ophthalmology, and Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland (H.B.); Division of Chemical Therapeutics, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (M.A.R., M.Z.)
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Galina A. Mitochondria: 3-bromopyruvate vs. mitochondria? A small molecule that attacks tumors by targeting their bioenergetic diversity. Int J Biochem Cell Biol 2014; 54:266-71. [PMID: 24842108 DOI: 10.1016/j.biocel.2014.05.013] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2013] [Revised: 04/03/2014] [Accepted: 05/10/2014] [Indexed: 01/11/2023]
Abstract
Enhanced glycolysis, the classic bioenergetic phenotype of cancer cells was described by Otto Warburg approximately 90 years ago. However, the Warburg hypothesis does not necessarily imply mitochondrial dysfunction. The alkyl-halogen, 3-bromopyruvate (3BP), would not be expected to have selective targets for cancer therapy due to its high potential reactivity toward many SH side groups. Contrary to predictions, 3BP interferes with glycolysis and oxidative phosphorylation in cancer cells without side effects in normal tissues. The mitochondrial hexokinase II has been claimed as the main target. This "Organelle in focus" article presents a historical view of the use of 3BP in biochemistry and its effects on ATP-producing pathways of cancer cells. I will discuss how the alkylated enzymes contribute to the cooperative collapse of mitochondria and apoptosis. Perspectives for targeting 3BP to bioenergetics enzymes for cancer treatment will be considered.
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Affiliation(s)
- Antonio Galina
- Instituto de Bioquímica Médica Leopoldo De Meis, Universidade Federal do Rio de Janeiro, Brazil.
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31
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3-Bromopyruvate: a novel antifungal agent against the human pathogen Cryptococcus neoformans. Biochem Biophys Res Commun 2013; 434:322-7. [PMID: 23541578 DOI: 10.1016/j.bbrc.2013.02.125] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2013] [Accepted: 02/26/2013] [Indexed: 01/01/2023]
Abstract
We have investigated the antifungal activity of the pyruvic acid analogue: 3-bromopyruvate (3-BP). Growth inhibition by 3-BP of 110 strains of yeast-like and filamentous fungi was tested by standard spot tests or microdilution method. The human pathogen Cryptococcus neoformans exhibited a low Minimal Inhibitory Concentration (MIC) of 0.12-0.15 mM 3-BP. The high toxicity of 3-BP toward C. neoformans correlated with high intracellular accumulation of 3-BP and also with low levels of intracellular ATP and glutathione. Weak cytotoxicity towards mammalian cells and lack of resistance conferred by the PDR (Pleiotropic Drug Resistance) network in the yeast Saccharomyces cerevisiae, are other properties of 3-BP that makes it a novel promising anticryptococcal drug.
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Dragnev K, You M, Wang Y, Lubet R. Lung cancer chemoprevention: difficulties, promise and potential agents? Expert Opin Investig Drugs 2012; 22:35-47. [PMID: 23167766 DOI: 10.1517/13543784.2013.731392] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
INTRODUCTION In a variety of cancers there is evidence that specific regimens can prevent or significantly delay the development of cancer. Thus, for breast cancer (ER+) use of SERMs or aromatase inhibitors can substantially decrease tumor incidence. For cervical cancer, HPV vaccination will inhibit long term cancer incidence. For colon cancer, the second greatest cancer killer, administration of aspirin and other NSAIDs decreases advanced colon adenomas in Phase II trials and epidemiologic data support their ability to prevent colon cancer. To date prevention trials in the area of lung cancer have shown minimal efficacy. AREAS COVERED The paper examines and discusses in greater detail certain promising agents which the authors have tested either preclinically and or in early phase clinical trials. These agents include RXR agonists, EGFr inhibitors, NSAIDs and Triterpenoids. Other agents including glucocorticoids, pioglitazone and iloprost are briefly mentioned. In addition, the paper presents various types of potential Phase II lung cancer prevention trials and describes their strengths and weaknesses. The potential use of various biomarkers as endpoints in trials e.g. histopathology, non-specific biomarkers (e.g., Ki67, cyclin D expression, apoptosis) and molecular biomarkers (e.g. specific phosphorylated proteins, gene expression etc.) is presented. Finally, we examine at least one approach, the use of aerosols, which may diminish the systemic toxicity associated with certain of these agents. EXPERT OPINION The manuscript presents: a) a number of promising agents which appear applicable to further Phase II prevention trials; b) approaches to defining potential preventive agents as well; c) approaches which might mitigate the side effects associated with potential agents most specifically the use of aerosols. Finally, we discuss biomarker studies both preclinical and clinical which might help support potential Phase II trials. The particular appeal to the preclinical studies is that they can be followed to a tumor endpoint. We hope that this will give the reader further background and allow one to appreciate the potential and some of the hurdles associated with lung cancer chemoprevention.
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The Warburg effect: insights from the past decade. Pharmacol Ther 2012; 137:318-30. [PMID: 23159371 DOI: 10.1016/j.pharmthera.2012.11.003] [Citation(s) in RCA: 162] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2012] [Accepted: 11/01/2012] [Indexed: 02/07/2023]
Abstract
Several decades ago, Otto Warburg discovered that cancer cells produce energy predominantly by glycolysis; a phenomenon now termed "Warburg effect". Warburg linked mitochondrial respiratory defects in cancer cells to aerobic glycolysis; this theory of his gradually lost its importance with the lack of conclusive evidence confirming the presence of mitochondrial defects in cancer cells. Scientists began to believe that this altered mechanism of energy production in cancer cells was more of an effect than the cause. More than 50 years later, the clinical use of FDG-PET imaging in the diagnosis and monitoring of cancers rekindled the interest of the scientific community in Warburg's hypothesis. In the last ten years considerable progress in the field has advanced our understanding of the Warburg effect. However, it still remains unclear if the Warburg effect plays a causal role in cancers or it is an epiphenomenon in tumorigenesis. In this review we aim to discuss the molecular mechanisms associated with the Warburg effect with emphasis on recent advances in the field including the role of epigenetic changes, miRNAs and post-translational modification of proteins. In addition, we also discuss emerging therapeutic strategies that target the dependence of cancer cells on altered energy processing through aerobic glycolysis.
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