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Wolie ZT, Unwin S, Burke A, Won H, Wallis SC, Seaton RA, Gilchrist M, Roberts JA, Sime FB. Evaluation of the stability of tigecycline in elastomeric infusion devices used for outpatient parenteral antimicrobial therapy. JAC Antimicrob Resist 2025; 7:dlaf074. [PMID: 40365447 PMCID: PMC12070266 DOI: 10.1093/jacamr/dlaf074] [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: 12/20/2024] [Accepted: 04/26/2025] [Indexed: 05/15/2025] Open
Abstract
Background Tigecycline is increasingly being considered in outpatient parenteral antimicrobial therapy (OPAT) programmes given its spectrum of activity; however, stability data are lacking, necessitating further study. Objective To assess tigecycline stability in elastomeric infusers under OPAT conditions, following the UK Yellow Cover Document (YCD) stability testing guidelines. Methods Tigecycline was reconstituted with normal saline in Leventon Dosi-Fuser and Baxter-LV10 infusers at doses of 50, 100 and 200 mg in 240 mL. Additionally, a tigecycline intermittent infusion dose (50 mg/100 mL) was reconstituted in Baxter-SV100 infusers. The infusers were stored under refrigerated storage (2°C-8°C) for 7 days, followed by exposure at an in-use temperature of 32°C for 24 h, or at 25°C for 2 hours for the intermittent infusion. Stability was evaluated using a stability-indicating assay, pH measurement, subvisible particle count and visual inspection as per the YCD. Results After 7 days of refrigeration followed by 24 h exposure to 32°C, the mean ± SD percentage of tigecycline remaining was 97.9 ± 0.6, 97.3 ± 0.6 and 95.4 ± 0.8 for the Baxter LV10 devices, and 97.2 ± 0.3, 96.9 ± 0.5 and 95.8 ± 0.8 for Dosi-Fuser devices at the low, intermediate, and high dose levels, respectively. For intermittent infusion in Baxter-SV100 devices, the mean ± SD percentage remaining after 7 days of refrigerated storage followed by 2 h at 25°C was 99.7 ± 0.2. Conclusions Tigecycline meets the UK YCD criteria of ≤5% degradation limit, indicating its suitability for both intermittent and continuous 24-h infusion in OPAT programs.
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Affiliation(s)
- Zenaw T Wolie
- Faculty of Medicine, Centre for Clinical Research, The University of Queensland, Building 71/918 RBWH Herston, Brisbane, Queensland 4029, Australia
- Department of Pharmacy, College of medicine and health Sciences, Debre Markos University, Debre Markos, Ethiopia
| | - Sean Unwin
- Infection Management Services, Metro South Health, Princess Alexandra Hospital, Brisbane, Queensland, Australia
| | - Andrew Burke
- Faculty of Medicine, Centre for Clinical Research, The University of Queensland, Building 71/918 RBWH Herston, Brisbane, Queensland 4029, Australia
- Thoracic Medicine, The Prince Charles Hospital, Brisbane, Queensland 4032, Australia
| | - Hayoung Won
- Faculty of Medicine, Centre for Clinical Research, The University of Queensland, Building 71/918 RBWH Herston, Brisbane, Queensland 4029, Australia
| | - Steven C Wallis
- Faculty of Medicine, Centre for Clinical Research, The University of Queensland, Building 71/918 RBWH Herston, Brisbane, Queensland 4029, Australia
| | - R Andrew Seaton
- Department of Infectious Diseases, Queen Elizabeth University Hospital, Glasgow, UK
- OPAT Initiative, British Society for Antimicrobial Chemotherapy (BSAC), Birmingham, UK
| | - Mark Gilchrist
- OPAT Initiative, British Society for Antimicrobial Chemotherapy (BSAC), Birmingham, UK
- Department of Pharmacy/Infection, Imperial College Healthcare NHS Trust, London, UK
- Department of Infectious Diseases, Imperial College London, London, UK
| | - Jason A Roberts
- Faculty of Medicine, Centre for Clinical Research, The University of Queensland, Building 71/918 RBWH Herston, Brisbane, Queensland 4029, Australia
- Herston Infectious Diseases Institute (HeIDI), Metro North Health, Brisbane, Queensland, Australia
- Departments of Pharmacy and Intensive Care Medicine, Royal Brisbane and Women’s Hospital, Brisbane, Queensland 4029, Australia
- Division of Anaesthesiology Critical Care Emergency and Pain Medicine, Nîmes University Hospital, University of Montpellier, Nîmes 30029, France
| | - Fekade B Sime
- Faculty of Medicine, Centre for Clinical Research, The University of Queensland, Building 71/918 RBWH Herston, Brisbane, Queensland 4029, Australia
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Addanki S, Kim L, Stevens A. Understanding and Targeting Metabolic Vulnerabilities in Acute Myeloid Leukemia: An Updated Comprehensive Review. Cancers (Basel) 2025; 17:1355. [PMID: 40282531 PMCID: PMC12025543 DOI: 10.3390/cancers17081355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2025] [Revised: 04/05/2025] [Accepted: 04/15/2025] [Indexed: 04/29/2025] Open
Abstract
Acute Myeloid Leukemia (AML) is characterized by aggressive proliferation and metabolic reprogramming that support its survival and resistance to therapy. This review explores the metabolic distinctions between AML cells and normal hematopoietic stem cells (HSCs), emphasizing the role of altered mitochondrial function, oxidative phosphorylation (OXPHOS), and biosynthetic pathways in leukemic progression. AML cells exhibit distinct metabolic vulnerabilities, including increased mitochondrial biogenesis, reliance on glycolysis and amino acid metabolism, and unique signaling interactions that sustain leukemic stem cells (LSCs). These dependencies provide potential therapeutic targets, as metabolic inhibitors have demonstrated efficacy in disrupting AML cell survival while sparing normal hematopoietic cells. We examine current and emerging metabolic therapies, such as inhibitors targeting glycolysis, amino acid metabolism, and lipid biosynthesis, highlighting their potential in overcoming drug resistance. However, challenges remain in translating these strategies into clinical practice due to AML's heterogeneity and adaptability. Further research into AML's metabolic plasticity and precision medicine approaches is crucial for improving treatment outcomes. Understanding and exploiting AML's metabolic vulnerabilities could pave the way for novel, more effective therapeutic strategies.
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Affiliation(s)
- Sridevi Addanki
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
| | | | - Alexandra Stevens
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
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Kalita B, Martinez-Cebrian G, McEvoy J, Allensworth M, Knight M, Magli A, Perlingeiro RCR, Dyer MA, Stewart E, Dynlacht BD. PAX translocations remodel mitochondrial metabolism through altered leucine usage in rhabdomyosarcoma. Cell 2025:S0092-8674(25)00281-8. [PMID: 40185100 DOI: 10.1016/j.cell.2025.03.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 01/09/2025] [Accepted: 03/06/2025] [Indexed: 04/07/2025]
Abstract
Alveolar rhabdomyosarcoma (ARMS) patients harboring paired-box fusion proteins (PAX3/7-FOXO1) exhibit a greater incidence of tumor relapse, metastasis, and poor survival outcome, thereby underscoring the urgent need to develop effective therapies to treat this subtype of childhood cancer. To uncover mechanisms that contribute to tumor initiation, we develop a muscle progenitor model and use epigenomic approaches to unravel genome rewiring events mediated by PAX3/7 fusion proteins. Among the key targets of PAX3/7 fusion proteins, we identify a cohort of oncogenes, fibroblast growth factor (FGF) receptors, tRNA-modifying enzymes, and genes essential for mitochondrial metabolism and protein translation, which we successfully targeted in preclinical trials. We identify leucine usage as a key factor driving the growth of aggressive PAX-fusion tumors, as limiting its bioavailability impaired oxidative phosphorylation and mitochondrial metabolism, delaying tumor progression and improving survival in vivo. Our data provide a compelling list of actionable targets and suggest promising new strategies to treat this tumor.
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Affiliation(s)
- Bhargab Kalita
- Department of Pathology and Perlmutter Cancer Institute, New York University School of Medicine, New York, NY 10016, USA.
| | - Gerard Martinez-Cebrian
- Department of Pathology and Perlmutter Cancer Institute, New York University School of Medicine, New York, NY 10016, USA; Josep Carreras Leukaemia Research Institute, 08916 Badalona, Spain
| | - Justina McEvoy
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, MS 323, Memphis, TN 38105, USA
| | - Melody Allensworth
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, MS 323, Memphis, TN 38105, USA
| | - Michelle Knight
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, MS 323, Memphis, TN 38105, USA; Department of Oncology, St Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Alessandro Magli
- Department of Medicine, Lillehei Heart Institute, University of Minnesota, Minneapolis, MN 55455, USA; Stem Cell Institute, University of Minnesota, Minneapolis, MN 55455, USA; Genomic Medicine Unit, Sanofi, 225nd Avenue, Waltham, MA 02451, USA
| | - Rita C R Perlingeiro
- Department of Medicine, Lillehei Heart Institute, University of Minnesota, Minneapolis, MN 55455, USA
| | - Michael A Dyer
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, MS 323, Memphis, TN 38105, USA
| | - Elizabeth Stewart
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, MS 323, Memphis, TN 38105, USA; Department of Oncology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
| | - Brian David Dynlacht
- Department of Pathology and Perlmutter Cancer Institute, New York University School of Medicine, New York, NY 10016, USA.
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Wu H, Zhu X, Zhou H, Sha M, Ye J, Yu H. Mitochondrial Ribosomal Proteins and Cancer. MEDICINA (KAUNAS, LITHUANIA) 2025; 61:96. [PMID: 39859078 PMCID: PMC11766452 DOI: 10.3390/medicina61010096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 12/19/2024] [Accepted: 01/07/2025] [Indexed: 01/27/2025]
Abstract
Mitochondria play key roles in maintaining cell life and cell function, and their dysfunction can lead to cell damage. Mitochondrial ribosomal proteins (MRPs) are encoded by nuclear genes and are assembled within the mitochondria. MRPs are pivotal components of the mitochondrial ribosomes, which are responsible for translating 13 mitochondrial DNA-encoded proteins essential for the mitochondrial respiratory chain. Recent studies have underscored the importance of MRPs in cancer biology, revealing their altered expression patterns in various types of cancer and their potential as both prognostic biomarkers and therapeutic targets. Herein, we review the current knowledge regarding the multiple functions of MRPs in maintaining the structure of the mitochondrial ribosome and apoptosis, their implications for cancer susceptibility and progression, and the innovative strategies being developed to target MRPs and mitoribosome biogenesis in cancer therapy. This comprehensive overview aims to provide insights into the role of MRPs in cancer biology and highlight promising strategies for future precision oncology.
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Affiliation(s)
- Huiyi Wu
- Department of Pathology, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou 225300, China; (H.W.); (X.Z.); (H.Z.)
| | - Xiaowei Zhu
- Department of Pathology, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou 225300, China; (H.W.); (X.Z.); (H.Z.)
| | - Huilin Zhou
- Department of Pathology, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou 225300, China; (H.W.); (X.Z.); (H.Z.)
| | - Min Sha
- Translational Medicine Center, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou 225300, China; (M.S.); (J.Y.)
| | - Jun Ye
- Translational Medicine Center, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou 225300, China; (M.S.); (J.Y.)
| | - Hong Yu
- Department of Pathology, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou 225300, China; (H.W.); (X.Z.); (H.Z.)
- Translational Medicine Center, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou 225300, China; (M.S.); (J.Y.)
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5
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Capelletti MM, Montini O, Ruini E, Tettamanti S, Savino AM, Sarno J. Unlocking the Heterogeneity in Acute Leukaemia: Dissection of Clonal Architecture and Metabolic Properties for Clinical Interventions. Int J Mol Sci 2024; 26:45. [PMID: 39795903 PMCID: PMC11719665 DOI: 10.3390/ijms26010045] [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: 11/21/2024] [Revised: 12/17/2024] [Accepted: 12/19/2024] [Indexed: 01/13/2025] Open
Abstract
Genetic studies of haematological cancers have pointed out the heterogeneity of leukaemia in its different subpopulations, with distinct mutations and characteristics, impacting the treatment response. Next-generation sequencing (NGS) and genome-wide analyses, as well as single-cell technologies, have offered unprecedented insights into the clonal heterogeneity within the same tumour. A key component of this heterogeneity that remains unexplored is the intracellular metabolome, a dynamic network that determines cell functions, signalling, epigenome regulation, immunity and inflammation. Understanding the metabolic diversities among cancer cells and their surrounding environments is therefore essential in unravelling the complexities of leukaemia and improving therapeutic strategies. Here, we describe the currently available methodologies and approaches to addressing the dynamic heterogeneity of leukaemia progression. In the second section, we focus on metabolic leukaemic vulnerabilities in acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL). Lastly, we provide a comprehensive overview of the most interesting clinical trials designed to target these metabolic dependencies, highlighting their potential to advance therapeutic strategies in leukaemia treatment. The integration of multi-omics data for cancer identification with the metabolic states of tumour cells will enable a comprehensive "micro-to-macro" approach for the refinement of clinical practices and delivery of personalised therapies.
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Affiliation(s)
- Martina Maria Capelletti
- School of Medicine and Surgery, University of Milan-Bicocca, 20126 Milan, Italy; (M.M.C.); (O.M.); (E.R.); (A.M.S.)
- Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy
| | - Orsola Montini
- School of Medicine and Surgery, University of Milan-Bicocca, 20126 Milan, Italy; (M.M.C.); (O.M.); (E.R.); (A.M.S.)
- Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy
| | - Emilio Ruini
- School of Medicine and Surgery, University of Milan-Bicocca, 20126 Milan, Italy; (M.M.C.); (O.M.); (E.R.); (A.M.S.)
| | - Sarah Tettamanti
- Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy
| | - Angela Maria Savino
- School of Medicine and Surgery, University of Milan-Bicocca, 20126 Milan, Italy; (M.M.C.); (O.M.); (E.R.); (A.M.S.)
- Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy
| | - Jolanda Sarno
- School of Medicine and Surgery, University of Milan-Bicocca, 20126 Milan, Italy; (M.M.C.); (O.M.); (E.R.); (A.M.S.)
- Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy
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Al Khzem AH, Gomaa MS, Alturki MS, Tawfeeq N, Sarafroz M, Alonaizi SM, Al Faran A, Alrumaihi LA, Alansari FA, Alghamdi AA. Drug Repurposing for Cancer Treatment: A Comprehensive Review. Int J Mol Sci 2024; 25:12441. [PMID: 39596504 PMCID: PMC11595001 DOI: 10.3390/ijms252212441] [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: 10/28/2024] [Revised: 11/12/2024] [Accepted: 11/17/2024] [Indexed: 11/28/2024] Open
Abstract
Cancer ranks among the primary contributors to global mortality. In 2022, the global incidence of new cancer cases reached about 20 million, while the number of cancer-related fatalities reached 9.7 million. In Saudi Arabia, there were 13,399 deaths caused by cancer and 28,113 newly diagnosed cases of cancer. Drug repurposing is a drug discovery strategy that has gained special attention and implementation to enhance the process of drug development due to its time- and money-saving effect. It involves repositioning existing medications to new clinical applications. Cancer treatment is a therapeutic area where drug repurposing has shown the most prominent impact. This review presents a compilation of medications that have been repurposed for the treatment of various types of cancers. It describes the initial therapeutic and pharmacological classes of the repurposed drugs and their new applications and mechanisms of action in cancer treatment. The review reports on drugs from various pharmacological classes that have been successfully repurposed for cancer treatment, including approved ones and those in clinical trials and preclinical development. It stratifies drugs based on their anticancer repurpose as multi-type, type-specific, and mechanism-directed, and according to their pharmacological classes. The review also reflects on the future potential that drug repurposing has in the clinical development of novel anticancer therapies.
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Affiliation(s)
- Abdulaziz H. Al Khzem
- Department of Pharmaceutical Chemistry, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Eastern Province, Saudi Arabia; (M.S.A.); (N.T.); (M.S.)
| | - Mohamed S. Gomaa
- Department of Pharmaceutical Chemistry, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Eastern Province, Saudi Arabia; (M.S.A.); (N.T.); (M.S.)
| | - Mansour S. Alturki
- Department of Pharmaceutical Chemistry, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Eastern Province, Saudi Arabia; (M.S.A.); (N.T.); (M.S.)
| | - Nada Tawfeeq
- Department of Pharmaceutical Chemistry, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Eastern Province, Saudi Arabia; (M.S.A.); (N.T.); (M.S.)
| | - Mohammad Sarafroz
- Department of Pharmaceutical Chemistry, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Eastern Province, Saudi Arabia; (M.S.A.); (N.T.); (M.S.)
| | - Shareefa M. Alonaizi
- College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Eastern Province, Saudi Arabia; (S.M.A.); (A.A.F.); (L.A.A.); (F.A.A.); (A.A.A.)
| | - Alhassan Al Faran
- College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Eastern Province, Saudi Arabia; (S.M.A.); (A.A.F.); (L.A.A.); (F.A.A.); (A.A.A.)
| | - Laela Ahmed Alrumaihi
- College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Eastern Province, Saudi Arabia; (S.M.A.); (A.A.F.); (L.A.A.); (F.A.A.); (A.A.A.)
| | - Fatimah Ahmed Alansari
- College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Eastern Province, Saudi Arabia; (S.M.A.); (A.A.F.); (L.A.A.); (F.A.A.); (A.A.A.)
| | - Abdullah Abbas Alghamdi
- College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Eastern Province, Saudi Arabia; (S.M.A.); (A.A.F.); (L.A.A.); (F.A.A.); (A.A.A.)
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7
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Berner MJ, Wall SW, Echeverria GV. Deregulation of mitochondrial gene expression in cancer: mechanisms and therapeutic opportunities. Br J Cancer 2024; 131:1415-1424. [PMID: 39143326 PMCID: PMC11519338 DOI: 10.1038/s41416-024-02817-1] [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: 05/22/2024] [Revised: 07/30/2024] [Accepted: 08/01/2024] [Indexed: 08/16/2024] Open
Abstract
"Reprogramming of energy metabolism" was first considered an emerging hallmark of cancer in 2011 by Hanahan & Weinberg and is now considered a core hallmark of cancer. Mitochondria are the hubs of metabolism, crucial for energetic functions and cellular homeostasis. The mitochondrion's bacterial origin and preservation of their own genome, which encodes proteins and RNAs essential to their function, make them unique organelles. Successful generation of mitochondrial gene products requires coordinated functioning of the mitochondrial 'central dogma,' encompassing all steps necessary for mtDNA to yield mitochondrial proteins. Each of these processes has several levels of regulation, including mtDNA accessibility and protection through mtDNA packaging and epigenetic modifications, mtDNA copy number through mitochondrial replication, mitochondrial transcription through mitochondrial transcription factors, and mitochondrial translation through mitoribosome formation. Deregulation of these mitochondrial processes in the context of cancers has only recently been appreciated, with most studies being correlative in nature. Nonetheless, numerous significant associations of the mitochondrial central dogma with pro-tumor phenotypes have been documented. Several studies have even provided mechanistic insights and further demonstrated successful pharmacologic targeting strategies. Based on the emergent importance of mitochondria for cancer biology and therapeutics, it is becoming increasingly important that we gain an understanding of the underpinning mechanisms so they can be successfully therapeutically targeted. It is expected that this mechanistic understanding will result in mitochondria-targeting approaches that balance anticancer potency with normal cell toxicity. This review will focus on current evidence for the dysregulation of mitochondrial gene expression in cancers, as well as therapeutic opportunities on the horizon.
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Affiliation(s)
- Mariah J Berner
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA
- Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
- Department of Radiation Oncology, Baylor College of Medicine, Houston, TX, USA
| | - Steven W Wall
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA
- Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
- Department of Radiation Oncology, Baylor College of Medicine, Houston, TX, USA
| | - Gloria V Echeverria
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA.
- Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA.
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
- Department of Radiation Oncology, Baylor College of Medicine, Houston, TX, USA.
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Liu L, Shao M, Huang Y, Qian P, Huang H. Unraveling the roles and mechanisms of mitochondrial translation in normal and malignant hematopoiesis. J Hematol Oncol 2024; 17:95. [PMID: 39396039 PMCID: PMC11470598 DOI: 10.1186/s13045-024-01615-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 09/30/2024] [Indexed: 10/14/2024] Open
Abstract
Due to spatial and genomic independence, mitochondria possess a translational mechanism distinct from that of cytoplasmic translation. Several regulators participate in the modulation of mitochondrial translation. Mitochondrial translation is coordinated with cytoplasmic translation through stress responses. Importantly, the inhibition of mitochondrial translation leads to the inhibition of cytoplasmic translation and metabolic disruption. Therefore, defects in mitochondrial translation are closely related to the functions of hematopoietic cells and various immune cells. Finally, the inhibition of mitochondrial translation is a potential therapeutic target for treating multiple hematologic malignancies. Collectively, more in-depth insights into mitochondrial translation not only facilitate our understanding of its functions in hematopoiesis, but also provide a basis for the discovery of new treatments for hematological malignancies and the modulation of immune cell function.
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Affiliation(s)
- Lianxuan Liu
- Bone Marrow Transplantation Center of the First Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, 310058, China
- Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China
- Institute of Hematology Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, 310058, China
| | - Mi Shao
- Bone Marrow Transplantation Center of the First Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, 310058, China
- Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China
- Institute of Hematology Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, 310058, China
| | - Yue Huang
- Bone Marrow Transplantation Center of the First Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, 310058, China
- Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China
- Institute of Hematology Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, 310058, China
| | - Pengxu Qian
- Bone Marrow Transplantation Center of the First Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, 310058, China.
- Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China.
- Institute of Hematology Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, 310058, China.
| | - He Huang
- Bone Marrow Transplantation Center of the First Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, 310058, China.
- Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China.
- Institute of Hematology Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, 310058, China.
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Kalita B, Martinez-Cebrian G, McEvoy J, Allensworth M, Knight M, Magli A, Perlingeiro RCR, Dyer MA, Stewart E, Dynlacht BD. PAX fusion proteins deregulate gene networks controlling mitochondrial translation in pediatric rhabdomyosarcoma. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.07.31.606039. [PMID: 39211084 PMCID: PMC11360909 DOI: 10.1101/2024.07.31.606039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Alveolar rhabdomyosarcoma (ARMS) patients harboring PAX3-FOXO1 and PAX7-FOXO1 fusion proteins exhibit a greater incidence of tumor relapse, metastasis, and poor survival outcome, thereby underscoring the urgent need to develop effective therapies to treat this subtype of childhood cancer. To uncover mechanisms that contribute to tumor initiation, we developed a novel muscle progenitor model and used epigenomic approaches to unravel genome re-wiring events mediated by PAX3/7 fusion proteins. Importantly, these regulatory mechanisms are conserved across established ARMS cell lines, primary tumors, and orthotopic-patient derived xenografts. Among the key targets of PAX3- and PAX7-fusion proteins, we identified a cohort of oncogenes, FGF receptors, and genes essential for mitochondrial metabolism and protein translation, which we successfully targeted in preclinical trials. Our data suggest an explanation for the relative paucity of recurring mutations in this tumor, provide a compelling list of actionable targets, and suggest promising new strategies to treat this tumor.
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10
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Khalaf A, de Beauchamp L, Kalkman E, Rattigan K, Himonas E, Jones J, James D, Shokry ESA, Scott MT, Dunn K, Tardito S, Copland M, Sumpton D, Shanks E, Helgason GV. Nutrient-sensitizing drug repurposing screen identifies lomerizine as a mitochondrial metabolism inhibitor of chronic myeloid leukemia. Sci Transl Med 2024; 16:eadi5336. [PMID: 38865484 DOI: 10.1126/scitranslmed.adi5336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Accepted: 05/15/2024] [Indexed: 06/14/2024]
Abstract
In chronic myeloid leukemia (CML), the persistence of leukemic stem cells (LSCs) after treatment with tyrosine kinase inhibitors (TKIs), such as imatinib, can lead to disease relapse. It is known that therapy-resistant LSCs rely on oxidative phosphorylation (OXPHOS) for their survival and that targeting mitochondrial respiration sensitizes CML LSCs to imatinib treatment. However, current OXPHOS inhibitors have demonstrated limited efficacy or have shown adverse effects in clinical trials, highlighting that identification of clinically safe oxidative pathway inhibitors is warranted. We performed a high-throughput drug repurposing screen designed to identify mitochondrial metabolism inhibitors in myeloid leukemia cells. This identified lomerizine, a US Food and Drug Administration (FDA)-approved voltage-gated Ca2+ channel blocker now used for the treatment of migraines, as one of the top hits. Transcriptome analysis revealed increased expression of voltage-gated CACNA1D and receptor-activated TRPC6 Ca2+ channels in CML LSCs (CD34+CD38-) compared with normal counterparts. This correlated with increased endoplasmic reticulum (ER) mass and increased ER and mitochondrial Ca2+ content in CML stem/progenitor cells. We demonstrate that lomerizine-mediated inhibition of Ca2+ uptake leads to ER and mitochondrial Ca2+ depletion, with similar effects seen after CACNA1D and TRPC6 knockdown. Through stable isotope-assisted metabolomics and functional assays, we observe that lomerizine treatment inhibits mitochondrial isocitrate dehydrogenase activity and mitochondrial oxidative metabolism and selectively sensitizes CML LSCs to imatinib treatment. In addition, combination treatment with imatinib and lomerizine reduced CML tumor burden, targeted CML LSCs, and extended survival in xenotransplantation model of human CML, suggesting this as a potential therapeutic strategy to prevent disease relapse in patients.
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MESH Headings
- Drug Repositioning
- Humans
- Mitochondria/metabolism
- Mitochondria/drug effects
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism
- Animals
- Cell Line, Tumor
- Endoplasmic Reticulum/metabolism
- Endoplasmic Reticulum/drug effects
- Piperazines/pharmacology
- Piperazines/therapeutic use
- Mice
- Neoplastic Stem Cells/drug effects
- Neoplastic Stem Cells/metabolism
- Neoplastic Stem Cells/pathology
- Calcium/metabolism
- Oxidative Phosphorylation/drug effects
- Imatinib Mesylate/pharmacology
- Imatinib Mesylate/therapeutic use
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Affiliation(s)
- Ahmed Khalaf
- Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, UK
| | - Lucie de Beauchamp
- Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, UK
| | - Eric Kalkman
- Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, UK
| | - Kevin Rattigan
- Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, UK
| | - Ekaterini Himonas
- Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, UK
| | - Joe Jones
- Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, UK
| | - Daniel James
- Cancer Research UK Scotland Institute, Glasgow, G61 1BD, UK
| | | | - Mary T Scott
- Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, UK
| | - Karen Dunn
- Paul O'Gorman Leukaemia Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G12 0ZD, UK
| | - Saverio Tardito
- Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, UK
- Cancer Research UK Scotland Institute, Glasgow, G61 1BD, UK
| | - Mhairi Copland
- Paul O'Gorman Leukaemia Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G12 0ZD, UK
| | - David Sumpton
- Cancer Research UK Scotland Institute, Glasgow, G61 1BD, UK
| | - Emma Shanks
- Cancer Research UK Scotland Institute, Glasgow, G61 1BD, UK
| | - G Vignir Helgason
- Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, UK
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11
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Xiang X, Dai Z, Luo B, Zhao N, Liu S, Sui J, Huang J, Zhou Y, Gu J, Zhang J, Yang T, Bao R, Luo Y. Rational Design of a Novel Class of Human ClpP Agonists through a Ring-Opening Strategy with Enhanced Antileukemia Activity. J Med Chem 2024; 67:6769-6792. [PMID: 38620134 DOI: 10.1021/acs.jmedchem.4c00338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/17/2024]
Abstract
The activation of Homo sapiens Casein lysing protease P (HsClpP) by a chemical or genetic strategy has been proved to be a new potential therapy in acute myeloid leukemia (AML). However, limited efficacy has been achieved with classic agonist imipridone ONC201. Here, a novel class of HsClpP agonists is designed and synthesized using a ring-opening strategy based on the lead compound 1 reported in our previous study. Among these novel scaffold agonists, compound 7k exhibited remarkably enhanced proteolytic activity of HsClpP (EC50 = 0.79 ± 0.03 μM) and antitumor activity in vitro (IC50 = 0.038 ± 0.003 μM). Moreover, the intraperitoneal administration of compound 7k markedly suppressed tumor growth in Mv4-11 xenograft models, achieving a tumor growth inhibition rate of 88%. Concurrently, 7k displayed advantageous pharmacokinetic properties in vivo. This study underscores the promise of compound 7k as a significant HsClpP agonist and an antileukemia drug candidate, warranting further exploration for AML treatment.
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Affiliation(s)
- Xinrong Xiang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Zhengyi Dai
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Baozhu Luo
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Ninglin Zhao
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Song Liu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jing Sui
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jiasheng Huang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yuanzheng Zhou
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jinlong Gu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jiangnan Zhang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Tao Yang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
- Laboratory of Human Diseases and Immunotherapies, West China Hospital and Institute of Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Rui Bao
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Youfu Luo
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
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12
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Bailly C, Degand C, Laine W, Sauzeau V, Kluza J. Implication of Rac1 GTPase in molecular and cellular mitochondrial functions. Life Sci 2024; 342:122510. [PMID: 38387701 DOI: 10.1016/j.lfs.2024.122510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 02/07/2024] [Accepted: 02/16/2024] [Indexed: 02/24/2024]
Abstract
Rac1 is a member of the Rho GTPase family which plays major roles in cell mobility, polarity and migration, as a fundamental regulator of actin cytoskeleton. Signal transduction by Rac1 occurs through interaction with multiple effector proteins, and its activity is regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). The small protein is mainly anchored to the inner side of the plasma membrane but it can be found in endocellular compartments, notably endosomes and cell nuclei. The protein localizes also into mitochondria where it contributes to the regulation of mitochondrial dynamics, including both mitobiogenesis and mitophagy, in addition to signaling processes via different protein partners, such as the proapoptotic protein Bcl-2 and chaperone sigma-1 receptor (σ-1R). The mitochondrial form of Rac1 (mtRac1) has been understudied thus far, but it is as essential as the nuclear or plasma membrane forms, via its implication in regulation of oxidative stress and DNA damages. Rac1 is subject to diverse post-translational modifications, notably to a geranylgeranylation which contributes importantly to its mitochondrial import and its anchorage to mitochondrial membranes. In addition, Rac1 contributes to the mitochondrial translocation of other proteins, such as p53. The mitochondrial localization and functions of Rac1 are discussed here, notably in the context of human diseases such as cancers. Inhibitors of Rac1 have been identified (NSC-23766, EHT-1864) and some are being developed for the treatment of cancer (MBQ-167) or central nervous system diseases (JK-50561). Their effects on mtRac1 warrant further investigations. An overview of mtRac1 is provided here.
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Affiliation(s)
- Christian Bailly
- University of Lille, CNRS, Inserm, CHU Lille, UMR9020 - UMR1277 - Canther - Cancer Heterogeneity, Plasticity and Resistance to Therapies, 59000 Lille, France; University of Lille, Faculty of Pharmacy, Institut de Chimie Pharmaceutique Albert Lespagnol (ICPAL), 3 rue du Professeur Laguesse, 59000 Lille, France; OncoWitan, Consulting Scientific Office, Lille (Wasquehal) 59290, France.
| | - Claire Degand
- University of Lille, CNRS, Inserm, CHU Lille, UMR9020 - UMR1277 - Canther - Cancer Heterogeneity, Plasticity and Resistance to Therapies, 59000 Lille, France
| | - William Laine
- University of Lille, CNRS, Inserm, CHU Lille, UMR9020 - UMR1277 - Canther - Cancer Heterogeneity, Plasticity and Resistance to Therapies, 59000 Lille, France
| | - Vincent Sauzeau
- Université de Nantes, CHU Nantes, CNRS, INSERM, Institut du thorax, Nantes, France
| | - Jérôme Kluza
- University of Lille, CNRS, Inserm, CHU Lille, UMR9020 - UMR1277 - Canther - Cancer Heterogeneity, Plasticity and Resistance to Therapies, 59000 Lille, France
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13
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Jang Y, Koh JS, Park JH, Choi S, Duong PTT, Heo BY, Lee SW, Kim JY, Lee MW, Kim SH, Song IC. Enhanced Expression of Glycolytic Enzymes and Succinate Dehydrogenase Complex Flavoprotein Subunit A by Mesothelin Promotes Glycolysis and Mitochondrial Respiration in Myeloblasts of Acute Myeloid Leukemia. Int J Mol Sci 2024; 25:2140. [PMID: 38396817 PMCID: PMC10888725 DOI: 10.3390/ijms25042140] [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: 11/29/2023] [Revised: 02/01/2024] [Accepted: 02/07/2024] [Indexed: 02/25/2024] Open
Abstract
Acute myeloid leukemia (AML) is an aggressive malignancy characterized by rapid growth and uncontrolled proliferation of undifferentiated myeloid cells. Metabolic reprogramming is commonly observed in the bone marrow of AML patients, as leukemia cells require increased ATP supply to support disease progression. In this study, we examined the potential role of mesothelin as a metabolic modulator in myeloid cells in AML. Mesothelin is a well-known marker of solid tumors that promotes cancer cell proliferation and survival. We initially analyzed alterations in mesothelin expression in the myeloblast subpopulations, defined as SSC-Alow/CD45dim, obtained from the bone marrow of AML patients using flow cytometry. Our results showed overexpression of mesothelin in 34.8% of AML patients. Subsequently, metabolic changes in leukemia cells were evaluated by comparing the oxygen consumption rates (OCR) of bone marrow samples derived from adult AML patients. Notably, a higher OCR was observed in the mesothelin-positive compared to the mesothelin-low and non-expressing groups. Treatment with recombinant human mesothelin protein enhanced OCR and increased the mRNA expression of glycolytic enzymes and mitochondrial complex II in KG1α AML cells. Notably, siRNA targeting mesothelin in KG1α cells led to the reduction of glycolysis-related gene expression but had no effect on the mitochondrial complex gene. The collective results demonstrate that mesothelin induces metabolic changes in leukemia cells, facilitating the acquisition of a rapid supply of ATP for proliferation in AML. Therefore, the targeting of mesothelin presents a potentially promising approach to mitigating the progression of AML through the inhibition of glycolysis and mitochondrial respiration in myeloid cells.
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Affiliation(s)
- Yunseon Jang
- Translational Immunology Institute, School of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
| | - Jeong Suk Koh
- Department of Internal Medicine, Chungnam National University Hospital, Daejeon 35015, Republic of Korea
| | - Jung-Hyun Park
- Translational Immunology Institute, School of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
| | - Suyoung Choi
- Brain Korea 21 FOUR Project for Medical Science, School of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
- Department of Medical Science, School of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
| | - Pham Thi Thuy Duong
- Brain Korea 21 FOUR Project for Medical Science, School of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
- Department of Medical Science, School of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
| | - Bu Yeon Heo
- Brain Korea 21 FOUR Project for Medical Science, School of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
- Department of Medical Science, School of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
| | - Sang Woo Lee
- Department of Medical Science, School of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
| | - Jung Yeon Kim
- Research Institute for Medical Science, School of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
| | - Myung-Won Lee
- Department of Internal Medicine, Chungnam National University Hospital, Daejeon 35015, Republic of Korea
| | - Seok-Hwan Kim
- Research Institute for Medical Science, School of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
- Department of Surgery, Chungnam National University Hospital, Daejeon 35015, Republic of Korea
| | - Ik-Chan Song
- Translational Immunology Institute, School of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
- Department of Internal Medicine, Chungnam National University Hospital, Daejeon 35015, Republic of Korea
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14
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Mazloumi Z, Rafat A, Dizaji Asl K, Karimipour M, Shanehbandi D, Talebi M, Montazer M, Movassaghpour AA, Dehnad A, Farahzadi R, Nozad Charoudeh H. Telomerase and mitochondria inhibition promote apoptosis and TET2 and ANMT3a expression in triple negative breast cancer cell lines. BIOIMPACTS : BI 2023; 14:27640. [PMID: 39104619 PMCID: PMC11298022 DOI: 10.34172/bi.2023.27640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 09/15/2023] [Accepted: 09/17/2023] [Indexed: 08/07/2024]
Abstract
Introduction High metastasis, resistance to common treatments, and high mortality rate, has made triple-negative breast cancer (TNBC) to be the most invasive type of breast cancer. High telomerase activity and mitochondrial biogenesis are involved in breast cancer tumorigenesis. The catalytic subunit of telomerase, telomerase reverse transcriptase (hTERT), plays a role in telomere lengthening and extra-biological functions such as gene expression, mitochondria function, and apoptosis. In this study, it has been aimed to evaluate intrinsic-, extrinsic-apoptosis and DNMT3a and TET2 expression following the inhibition of telomerase and mitochondria respiration in TNBC cell lines. Methods TNBC cells were treated with IC50 levels of BIBR1532, tigecycline, and also their combination. Then, telomere length, and DNMT3a, TET2, and hTERT expression were evaluated. Finally, apoptosis rate, apoptosis-related proteins, and genes were analyzed. Results The present results showed that IC50 level of telomerase and inhibition of mitochondria respiration induced apoptosis but did not leave any significant effect on telomere length. The results also indicated that telomerase inhibition induced extrinsic-apoptosis in MDA-MB-231 and caused intrinsic- apoptosis in MDA-MB-468 cells. Furthermore, it was found that the expression of p53 decreased and was ineffective in cell apoptosis. The expressions of DNMT3a and TET2 increased in cells. In addition, combination treatment was better than BIBR1532 and tigecycline alone. Conclusion The inhibition of telomerase and mitochondria respiration caused intrinsic- and extrinsic- apoptosis and increased DNMT3a and TET2 expression and it could be utilized in breast cancer treatment.
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Affiliation(s)
- Zeinab Mazloumi
- Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Rafat
- Anatomical Sciences Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Khadijeh Dizaji Asl
- Department of Histopathology and Anatomy, Faculty of Medical Sciences, Tabriz Medical Sciences, Islamic Azad University, Tabriz, Iran
| | - Mohammad Karimipour
- Department of Anatomical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Dariush Shanehbandi
- Immunology Research Center, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Talebi
- Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Majid Montazer
- Department of Cardiovascular Surgery, Imam Reza Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Alireza Dehnad
- Department of Bacterial Disease Research, Razi Vaccine, and Serum Research Institute, AREEO, Tabriz, Iran
| | - Raheleh Farahzadi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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15
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Hossenipour Khodaei S, Sabetnam S, Nozad Charoudeh H, Dizaji Asl K, Rafat A, Mazloumi Z. The effect of mitochondria inhibition on natural killer cells cytotoxicity in triple-negative breast cancer cells. Eur J Pharmacol 2023; 960:176106. [PMID: 37839666 DOI: 10.1016/j.ejphar.2023.176106] [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: 05/21/2023] [Revised: 09/29/2023] [Accepted: 10/04/2023] [Indexed: 10/17/2023]
Abstract
Triple-Negative Breast Cancer (TNBC), the most common invasive breast cancer, depicts cancer poor response to conventional therapies. The clinical management of TNBC is a challenging issue. Natural killer (NK) cell therapy in the field of cancer treatment is rapidly growing however, regarding the immunogenicity of breast cancer cells, this type of therapy has shown limited efficacy. Recently, targeting tumor biomarkers has revolutionized the field of cancer therapy. Mitochondria affects apoptosis and innate immunity. Therefore, in this study, mitochondria were inhibited with Tigecycline in stimulating the cytotoxicity of NK cells against TNBC cell lines. MDA-MB-468 and MDA-MB-231 were cultured and treated with IC50 (the half-maximal inhibitory concentration) level of Tigecycline for 48 h and afterward co-cultured with peripheral blood NK cells for 5 h. Lastly, the inhibitory effects of mitochondria on the cytotoxicity of NK cells and apoptosis of TNBC cells were evaluated. Moreover, the expression of apoptotic-related genes was studied. The results showed that mitochondria inhibition increased NK cells cytotoxicity against TNBC cells. Moreover, NK cell/mitochondria inhibition in a combinative form improved apoptosis in TNBC cells by the upregulation of Bad and Bid expression. In conclusion, Tigecycline inhibited mitochondria and sensitized TNBC cells to NK cell therapy. Therefore, mitochondria inhibition could help NK cells function properly.
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Affiliation(s)
- Sepide Hossenipour Khodaei
- Department of Dentistry, Eastern Mediterranean University (EMU) Famagusta, North Cyprus Mersin 10, Turkey
| | - Shahbaz Sabetnam
- Department of Anatomy, Faculty of Medicine, University of Kyrenia, Mersin 10, Kyrenia, Turkey; Department of Histopathology and Anatomy, Faculty of Medicine Sciences, Tabriz Medical Sciences, Islamic Azad Tabriz University, Tabriz, Iran
| | | | - Khadijeh Dizaji Asl
- Department of Histopathology and Anatomy, Faculty of Medicine Sciences, Tabriz Medical Sciences, Islamic Azad Tabriz University, Tabriz, Iran
| | - Ali Rafat
- Anatomical Sciences Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Zeinab Mazloumi
- Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
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16
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Bakhtiyari M, Liaghat M, Aziziyan F, Shapourian H, Yahyazadeh S, Alipour M, Shahveh S, Maleki-Sheikhabadi F, Halimi H, Forghaniesfidvajani R, Zalpoor H, Nabi-Afjadi M, Pornour M. The role of bone marrow microenvironment (BMM) cells in acute myeloid leukemia (AML) progression: immune checkpoints, metabolic checkpoints, and signaling pathways. Cell Commun Signal 2023; 21:252. [PMID: 37735675 PMCID: PMC10512514 DOI: 10.1186/s12964-023-01282-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Accepted: 08/17/2023] [Indexed: 09/23/2023] Open
Abstract
Acute myeloid leukemia (AML) comprises a multifarious and heterogeneous array of illnesses characterized by the anomalous proliferation of myeloid cells in the bone marrow microenvironment (BMM). The BMM plays a pivotal role in promoting AML progression, angiogenesis, and metastasis. The immune checkpoints (ICs) and metabolic processes are the key players in this process. In this review, we delineate the metabolic and immune checkpoint characteristics of the AML BMM, with a focus on the roles of BMM cells e.g. tumor-associated macrophages, natural killer cells, dendritic cells, metabolic profiles and related signaling pathways. We also discuss the signaling pathways stimulated in AML cells by BMM factors that lead to AML progression. We then delve into the roles of immune checkpoints in AML angiogenesis, metastasis, and cell proliferation, including co-stimulatory and inhibitory ICs. Lastly, we discuss the potential therapeutic approaches and future directions for AML treatment, emphasizing the potential of targeting metabolic and immune checkpoints in AML BMM as prognostic and therapeutic targets. In conclusion, the modulation of these processes through the use of directed drugs opens up new promising avenues in combating AML. Thereby, a comprehensive elucidation of the significance of these AML BMM cells' metabolic and immune checkpoints and signaling pathways on leukemic cells can be undertaken in the future investigations. Additionally, these checkpoints and cells should be considered plausible multi-targeted therapies for AML in combination with other conventional treatments in AML. Video Abstract.
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Affiliation(s)
- Maryam Bakhtiyari
- Department of Medical Laboratory Sciences, Faculty of Allied Medicine, Qazvin University of Medical Sciences, Qazvin, Iran
- Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran
| | - Mahsa Liaghat
- Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran
- Department of Medical Laboratory Sciences, Faculty of Medical Sciences, Kazerun Branch, Islamic Azad University, Kazerun, Iran
| | - Fatemeh Aziziyan
- Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran
- Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Hooriyeh Shapourian
- Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Sheida Yahyazadeh
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Maedeh Alipour
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Shaghayegh Shahveh
- American Association of Naturopath Physician (AANP), Washington, DC, USA
| | - Fahimeh Maleki-Sheikhabadi
- Department of Hematology and Blood Banking, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Hossein Halimi
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Razieh Forghaniesfidvajani
- Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran
| | - Hamidreza Zalpoor
- Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran.
- Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Mohsen Nabi-Afjadi
- Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.
| | - Majid Pornour
- Department of Biochemistry and Molecular Biology, University of Maryland, Baltimore, MD, USA.
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, Maryland, USA.
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17
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Rattigan KM, Zarou MM, Helgason GV. Metabolism in stem cell-driven leukemia: parallels between hematopoiesis and immunity. Blood 2023; 141:2553-2565. [PMID: 36634302 PMCID: PMC10646800 DOI: 10.1182/blood.2022018258] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 12/21/2022] [Accepted: 01/03/2023] [Indexed: 01/14/2023] Open
Abstract
Our understanding of cancer metabolism spans from its role in cellular energetics and supplying the building blocks necessary for proliferation, to maintaining cellular redox and regulating the cellular epigenome and transcriptome. Cancer metabolism, once thought to be solely driven by upregulated glycolysis, is now known to comprise multiple pathways with great plasticity in response to extrinsic challenges. Furthermore, cancer cells can modify their surrounding niche during disease initiation, maintenance, and metastasis, thereby contributing to therapy resistance. Leukemia is a paradigm model of stem cell-driven cancer. In this study, we review how leukemia remodels the niche and rewires its metabolism, with particular attention paid to therapy-resistant stem cells. Specifically, we aim to give a global, nonexhaustive overview of key metabolic pathways. By contrasting the metabolic rewiring required by myeloid-leukemic stem cells with that required for hematopoiesis and immune cell function, we highlight the metabolic features they share. This is a critical consideration when contemplating anticancer metabolic inhibitor options, especially in the context of anticancer immune therapies. Finally, we examine pathways that have not been studied in leukemia but are critical in solid cancers in the context of metastasis and interaction with new niches. These studies also offer detailed mechanisms that are yet to be investigated in leukemia. Given that cancer (and normal) cells can meet their energy requirements by not only upregulating metabolic pathways but also utilizing systemically available substrates, we aim to inform how interlinked these metabolic pathways are, both within leukemic cells and between cancer cells and their niche.
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Affiliation(s)
- Kevin M. Rattigan
- Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Martha M. Zarou
- Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
| | - G. Vignir Helgason
- Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
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18
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Kumbhar P, Kole K, Yadav T, Bhavar A, Waghmare P, Bhokare R, Manjappa A, Jha NK, Chellappan DK, Shinde S, Singh SK, Dua K, Salawi A, Disouza J, Patravale V. Drug repurposing: An emerging strategy in alleviating skin cancer. Eur J Pharmacol 2022; 926:175031. [PMID: 35580707 DOI: 10.1016/j.ejphar.2022.175031] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 04/22/2022] [Accepted: 05/11/2022] [Indexed: 12/24/2022]
Abstract
Skin cancer is one of the most common forms of cancer. Several million people are estimated to have affected with this condition worldwide. Skin cancer generally includes melanoma and non-melanoma with the former being the most dangerous. Chemotherapy has been one of the key therapeutic strategies employed in the treatment of skin cancer, especially in advanced stages of the disease. It could be also used as an adjuvant with other treatment modalities depending on the type of skin cancer. However, there are several shortfalls associated with the use of chemotherapy such as non-selectivity, tumour resistance, life-threatening toxicities, and the exorbitant cost of medicines. Furthermore, new drug discovery is a lengthy and costly process with minimal likelihood of success. Thus, drug repurposing (DR) has emerged as a new avenue where the drug approved formerly for the treatment of one disease can be used for the treatment of another disease like cancer. This approach is greatly beneficial over the de novo approach in terms of time and cost. Moreover, there is minimal risk of failure of repurposed therapeutics in clinical trials. There are a considerable number of studies that have reported on drugs repurposed for the treatment of skin cancer. Thus, the present manuscript offers a comprehensive overview of drugs that have been investigated as repurposing candidates for the efficient treatment of skin cancers mainly melanoma and its oncogenic subtypes, and non-melanoma. The prospects of repurposing phytochemicals against skin cancer are also discussed. Furthermore, repurposed drug delivery via topical route and repurposed drugs in clinical trials are briefed. Based on the findings from the reported studies discussed in this manuscript, drug repurposing emerges to be a promising approach and thus is expected to offer efficient treatment at a reasonable cost in devitalizing skin cancer.
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Affiliation(s)
- Popat Kumbhar
- Tatyasaheb Kore College of Pharmacy, Warananagar, Tal: Panhala, Dist: Kolhapur Maharashtra, 416113, India
| | - Kapil Kole
- Tatyasaheb Kore College of Pharmacy, Warananagar, Tal: Panhala, Dist: Kolhapur Maharashtra, 416113, India
| | - Tejashree Yadav
- Tatyasaheb Kore College of Pharmacy, Warananagar, Tal: Panhala, Dist: Kolhapur Maharashtra, 416113, India
| | - Ashwini Bhavar
- Tatyasaheb Kore College of Pharmacy, Warananagar, Tal: Panhala, Dist: Kolhapur Maharashtra, 416113, India
| | - Pramod Waghmare
- Tatyasaheb Kore College of Pharmacy, Warananagar, Tal: Panhala, Dist: Kolhapur Maharashtra, 416113, India
| | - Rajdeep Bhokare
- Tatyasaheb Kore College of Pharmacy, Warananagar, Tal: Panhala, Dist: Kolhapur Maharashtra, 416113, India
| | - Arehalli Manjappa
- Tatyasaheb Kore College of Pharmacy, Warananagar, Tal: Panhala, Dist: Kolhapur Maharashtra, 416113, India
| | - Niraj Kumar Jha
- Department of Biotechnology, School of Engineering & Technology (SET), Sharda University, Greater Noida, 201310, Uttar Pradesh, India; Department of Biotechnology, School of Applied and Life Sciences (SALS), Uttaranchal University, Dehradun 248007, India
| | - Dinesh Kumar Chellappan
- Department of Life Sciences, School of Pharmacy, International Medical University, Bukit Jalil, 57000, Kuala Lumpur, Malaysia
| | - Sunita Shinde
- Tatyasaheb Kore College of Pharmacy, Warananagar, Tal: Panhala, Dist: Kolhapur Maharashtra, 416113, India
| | - Sachin Kumar Singh
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, 144411, India; Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, NSW, 2007, Australia
| | - Kamal Dua
- Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, NSW, 2007, Australia; Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, NSW, 2007, Australia; Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, 248007, India
| | - Ahmad Salawi
- Department of Pharmaceutics, College of Pharmacy, Jazan University, Jazan, 45142, Saudi Arabia
| | - John Disouza
- Tatyasaheb Kore College of Pharmacy, Warananagar, Tal: Panhala, Dist: Kolhapur Maharashtra, 416113, India.
| | - Vandana Patravale
- Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Matunga, Mumbai, Maharashtra, 400019, India.
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In situ green analytical methods for the rapid and sensitive determination of a newly launched orphan anticancer drug; Tigecycline in infusion bags: comparative study. BENI-SUEF UNIVERSITY JOURNAL OF BASIC AND APPLIED SCIENCES 2022. [DOI: 10.1186/s43088-022-00250-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Tigecycline (TIG), an antimicrobial agent indicated for complex bacterial infections, is now approved by FDA as an orphan chemotherapeutic agent for the treatment of acute myeloid leukemia due to its inhibitory effects on pathways of activating, signaling and abnormal mitochondrial function in cancer cells. TIG is mainly administered as intravenous infusion through centralized unit of oncology centers. This necessitates the continuous analytical quality control of the prepared solution in order to identify and quantify TIG for safe intravenous administration to patients. Moreover, the clinical staff exposure risk to toxic drugs during daily handling must be considered. Such concerns require a fast, cost-effective and green analytical procedure for sensitive determination of TIG directly in infusion bags. In this work, we propose a simple, rapid and green capillary zone electrophoretic (CZE) method for the sensitive assay of TIG directly in infusion bags, in addition to three simple and green spectrophotometric methods.
Results
TIG solutions corresponding to clinical ranges were detected in 5%glucose. Validation of all the proposed methods was according to ICH guidelines. Greenness assessment was performed depending on Green Analytical Procedure Index (GAPI) and the Eco-scale approach which showed that the proposed methods are better eco-friendly methods than reported ones. It also revealed the superiority of our proposed methods in terms of simplicity and sensitivity for TIG determination in infusion bags. Quantification limits obtained were significantly lower than the administered range of TIG in infusion bags and lower than its maximum serum concentration (Cmax). This promotes the application of the proposed methods for the pharmacokinetics and bioavailability studies of TIG in various biological fluids.
Conclusions
This work reports, for the first time, CZE method for the direct and rapid determination of TIG and its separation from other components in intravenous infusion solution. The developed CZE method has several advantages over current chromatographic methods such as higher efficiency of separation within short analysis time, consumption of fewer quantities of chemicals and offering better resolution than HPLC. Moreover, three green spectrophotometric methods are also proposed for TIG determination that offer many advantages such as accuracy, precision, simplicity, specificity and facility of quantification and separation of the selected drug in infusion bags and pharmaceutical preparations without any techniques for extraction.
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20
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Leukemic Stem Cells as a Target for Eliminating Acute Myeloid Leukemia: Gaps in Translational Research. Crit Rev Oncol Hematol 2022; 175:103710. [DOI: 10.1016/j.critrevonc.2022.103710] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 04/29/2022] [Accepted: 05/11/2022] [Indexed: 12/26/2022] Open
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21
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Miranda M, Bonekamp NA, Kühl I. Starting the engine of the powerhouse: mitochondrial transcription and beyond. Biol Chem 2022; 403:779-805. [PMID: 35355496 DOI: 10.1515/hsz-2021-0416] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 03/09/2022] [Indexed: 12/25/2022]
Abstract
Mitochondria are central hubs for cellular metabolism, coordinating a variety of metabolic reactions crucial for human health. Mitochondria provide most of the cellular energy via their oxidative phosphorylation (OXPHOS) system, which requires the coordinated expression of genes encoded by both the nuclear (nDNA) and mitochondrial genomes (mtDNA). Transcription of mtDNA is not only essential for the biogenesis of the OXPHOS system, but also generates RNA primers necessary to initiate mtDNA replication. Like the prokaryotic system, mitochondria have no membrane-based compartmentalization to separate the different steps of mtDNA maintenance and expression and depend entirely on nDNA-encoded factors imported into the organelle. Our understanding of mitochondrial transcription in mammalian cells has largely progressed, but the mechanisms regulating mtDNA gene expression are still poorly understood despite their profound importance for human disease. Here, we review mechanisms of mitochondrial gene expression with a focus on the recent findings in the field of mammalian mtDNA transcription and disease phenotypes caused by defects in proteins involved in this process.
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Affiliation(s)
- Maria Miranda
- Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, Cologne, D-50931, Germany
| | - Nina A Bonekamp
- Department of Neuroanatomy, Mannheim Center for Translational Neurosciences (MCTN), Medical Faculty Mannheim, Heidelberg University, Mannheim, D-68167, Germany
| | - Inge Kühl
- Department of Cell Biology, Institute of Integrative Biology of the Cell (I2BC), UMR9198, CEA, CNRS, Université Paris-Saclay, Gif-sur-Yvette, F-91190, France
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22
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Mesbahi Y, Trahair TN, Lock RB, Connerty P. Exploring the Metabolic Landscape of AML: From Haematopoietic Stem Cells to Myeloblasts and Leukaemic Stem Cells. Front Oncol 2022; 12:807266. [PMID: 35223487 PMCID: PMC8867093 DOI: 10.3389/fonc.2022.807266] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Accepted: 01/18/2022] [Indexed: 12/13/2022] Open
Abstract
Despite intensive chemotherapy regimens, up to 60% of adults with acute myeloid leukaemia (AML) will relapse and eventually succumb to their disease. Recent studies suggest that leukaemic stem cells (LSCs) drive AML relapse by residing in the bone marrow niche and adapting their metabolic profile. Metabolic adaptation and LSC plasticity are novel hallmarks of leukemogenesis that provide important biological processes required for tumour initiation, progression and therapeutic responses. These findings highlight the importance of targeting metabolic pathways in leukaemia biology which might serve as the Achilles' heel for the treatment of AML relapse. In this review, we highlight the metabolic differences between normal haematopoietic cells, bulk AML cells and LSCs. Specifically, we focus on four major metabolic pathways dysregulated in AML; (i) glycolysis; (ii) mitochondrial metabolism; (iii) amino acid metabolism; and (iv) lipid metabolism. We then outline established and emerging drug interventions that exploit metabolic dependencies of leukaemic cells in the treatment of AML. The metabolic signature of AML cells alters during different biological conditions such as chemotherapy and quiescence. Therefore, targeting the metabolic vulnerabilities of these cells might selectively eradicate them and improve the overall survival of patients with AML.
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Affiliation(s)
- Yashar Mesbahi
- Children's Cancer Institute, Lowy Cancer Centre, University of New South Wales (UNSW) Sydney, Kensington, NSW, Australia.,School of Women's and Children's Health, University of New South Wales (UNSW) Sydney, Kensington, NSW, Australia.,University of New South Wales Centre for Childhood Cancer Research, University of New South Wales (UNSW) Sydney, Kensington, NSW, Australia
| | - Toby N Trahair
- Children's Cancer Institute, Lowy Cancer Centre, University of New South Wales (UNSW) Sydney, Kensington, NSW, Australia.,School of Women's and Children's Health, University of New South Wales (UNSW) Sydney, Kensington, NSW, Australia.,Kids Cancer Centre, Sydney Children's Hospital, Randwick, NSW, Australia
| | - Richard B Lock
- Children's Cancer Institute, Lowy Cancer Centre, University of New South Wales (UNSW) Sydney, Kensington, NSW, Australia.,School of Women's and Children's Health, University of New South Wales (UNSW) Sydney, Kensington, NSW, Australia.,University of New South Wales Centre for Childhood Cancer Research, University of New South Wales (UNSW) Sydney, Kensington, NSW, Australia
| | - Patrick Connerty
- Children's Cancer Institute, Lowy Cancer Centre, University of New South Wales (UNSW) Sydney, Kensington, NSW, Australia.,School of Women's and Children's Health, University of New South Wales (UNSW) Sydney, Kensington, NSW, Australia.,University of New South Wales Centre for Childhood Cancer Research, University of New South Wales (UNSW) Sydney, Kensington, NSW, Australia
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23
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Hayat U, Elliott GT, Olszanski AJ, Altieri DC. Feasibility and safety of targeting mitochondria for cancer therapy – preclinical characterization of gamitrinib, a first-in-class, mitochondriaL-targeted small molecule Hsp90 inhibitor. Cancer Biol Ther 2022; 23:117-126. [PMID: 35129069 PMCID: PMC8820820 DOI: 10.1080/15384047.2022.2029132] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Mitochondria are key tumor drivers, but their suitability as a therapeutic target is unknown. Here, we report on the preclinical characterization of Gamitrinib (GA mitochondrial matrix inhibitor), a first-in-class anticancer agent that couples the Heat Shock Protein-90 (Hsp90) inhibitor 17-allylamino-geldanamycin (17-AAG) to the mitochondrial-targeting moiety, triphenylphosphonium. Formulated as a stable (≥24 weeks at −20°C) injectable suspension produced by microfluidization (<200 nm particle size), Gamitrinib (>99.5% purity) is heavily bound to plasma proteins (>99%), has intrinsic clearance from liver microsomes of 3.30 mL/min/g and minimally penetrates a Caco-2 intestinal monolayer. Compared to 17-AAG, Gamitrinib has slower clearance (85.6 ± 5.8 mL/min/kg), longer t1/2 (12.2 ± 1.55 h), mean AUC0-t of 783.1 ± 71.3 h∙ng/mL, and unique metabolism without generation of 17-AG. Concentrations of Gamitrinib that trigger tumor cell killing (IC50 ~1-4 µM) do not affect cytochrome P450 isoforms CYP1A2, CYP2A6, CYP2B6, CYP2C8 or ion channel conductance (Nav1.5, Kv4.3/KChIP2, Cav1.2, Kv1.5, KCNQ1/mink, HCN4, Kir2). Twice weekly IV administration of Gamitrinib to Sprague-Dawley rats or beagle dogs for up to 36 d is feasible. At dose levels of up to 5 (rats)- and 12 (dogs)-fold higher than therapeutically effective doses in mice (10 mg/kg), Gamitrinib treatment is unremarkable in dogs with no alterations in clinical-chemistry parameters, heart function, or tissue histology, and causes occasional inflammation at the infusion site and mild elevation of serum urea nitrogen in rats (≥10 mg/kg/dose). Therefore, targeting mitochondria for cancer therapy is feasible and well tolerated. A publicly funded, first-in-human phase I clinical trial of Gamitrinib in patients with advanced cancer is ongoing (ClinicalTrials.gov NCT04827810)
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Affiliation(s)
- Umar Hayat
- Pharmaceutical Advisors, LLC, Princeton, USA
| | | | - Anthony J. Olszanski
- Phase 1 Developmental Therapeutics Program, Department of Hematology/Oncology Fox Chase Cancer Center, Philadelphia
| | - Dario C. Altieri
- Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, USA
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24
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Mennuni M, Filograna R, Felser A, Bonekamp NA, Giavalisco P, Lytovchenko O, Larsson N. Metabolic resistance to the inhibition of mitochondrial transcription revealed by CRISPR-Cas9 screen. EMBO Rep 2022; 23:e53054. [PMID: 34779571 PMCID: PMC8728608 DOI: 10.15252/embr.202153054] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 10/12/2021] [Accepted: 10/19/2021] [Indexed: 12/20/2022] Open
Abstract
Cancer cells depend on mitochondria to sustain their increased metabolic need and mitochondria therefore constitute possible targets for cancer treatment. We recently developed small-molecule inhibitors of mitochondrial transcription (IMTs) that selectively impair mitochondrial gene expression. IMTs have potent antitumor properties in vitro and in vivo, without affecting normal tissues. Because therapy-induced resistance is a major constraint to successful cancer therapy, we investigated mechanisms conferring resistance to IMTs. We employed a CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats)-(CRISP-associated protein 9) whole-genome screen to determine pathways conferring resistance to acute IMT1 treatment. Loss of genes belonging to von Hippel-Lindau (VHL) and mammalian target of rapamycin complex 1 (mTORC1) pathways caused resistance to acute IMT1 treatment and the relevance of these pathways was confirmed by chemical modulation. We also generated cells resistant to chronic IMT treatment to understand responses to persistent mitochondrial gene expression impairment. We report that IMT1-acquired resistance occurs through a compensatory increase of mitochondrial DNA (mtDNA) expression and cellular metabolites. We found that mitochondrial transcription factor A (TFAM) downregulation and inhibition of mitochondrial translation impaired survival of resistant cells. The identified susceptibility and resistance mechanisms to IMTs may be relevant for different types of mitochondria-targeted therapies.
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Affiliation(s)
- Mara Mennuni
- Department of Medical Biochemistry and BiophysicsKarolinska InstitutetStockholmSweden
| | - Roberta Filograna
- Department of Medical Biochemistry and BiophysicsKarolinska InstitutetStockholmSweden
| | - Andrea Felser
- Department of Medical Biochemistry and BiophysicsKarolinska InstitutetStockholmSweden
- University Institute of Clinical ChemistryBern University HospitalBernSwitzerland
| | - Nina A Bonekamp
- Mitochondrial Biology GroupMax Planck Institute for Biology of AgeingCologneGermany
- Department of NeuroanatomyMannheim Center for Translational Neuroscience (MCTN)Medical Faculty MannheimHeidelberg UniversityMannheimGermany
| | - Patrick Giavalisco
- Metabolomics Core FacilityMax Planck Institute for Biology of AgeingCologneGermany
| | - Oleksandr Lytovchenko
- Department of Medical Biochemistry and BiophysicsKarolinska InstitutetStockholmSweden
| | - Nils‐Göran Larsson
- Department of Medical Biochemistry and BiophysicsKarolinska InstitutetStockholmSweden
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25
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de Beauchamp L, Himonas E, Helgason GV. Mitochondrial metabolism as a potential therapeutic target in myeloid leukaemia. Leukemia 2022; 36:1-12. [PMID: 34561557 PMCID: PMC8727299 DOI: 10.1038/s41375-021-01416-w] [Citation(s) in RCA: 76] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 09/06/2021] [Accepted: 09/07/2021] [Indexed: 02/07/2023]
Abstract
While the understanding of the genomic aberrations that underpin chronic and acute myeloid leukaemia (CML and AML) has allowed the development of therapies for these diseases, limitations remain. These become apparent when looking at the frequency of treatment resistance leading to disease relapse in leukaemia patients. Key questions regarding the fundamental biology of the leukaemic cells, such as their metabolic dependencies, are still unresolved. Even though a majority of leukaemic cells are killed during initial treatment, persistent leukaemic stem cells (LSCs) and therapy-resistant cells are still not eradicated with current treatments, due to various mechanisms that may contribute to therapy resistance, including cellular metabolic adaptations. In fact, recent studies have shown that LSCs and treatment-resistant cells are dependent on mitochondrial metabolism, hence rendering them sensitive to inhibition of mitochondrial oxidative phosphorylation (OXPHOS). As a result, rewired energy metabolism in leukaemic cells is now considered an attractive therapeutic target and the significance of this process is increasingly being recognised in various haematological malignancies. Therefore, identifying and targeting aberrant metabolism in drug-resistant leukaemic cells is an imperative and a relevant strategy for the development of new therapeutic options in leukaemia. In this review, we present a detailed overview of the most recent studies that present experimental evidence on how leukaemic cells can metabolically rewire, more specifically the importance of OXPHOS in LSCs and treatment-resistant cells, and the current drugs available to target this process. We highlight that uncovering specific energy metabolism dependencies will guide the identification of new and more targeted therapeutic strategies for myeloid leukaemia.
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Affiliation(s)
- Lucie de Beauchamp
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Ekaterini Himonas
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - G Vignir Helgason
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
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26
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Vendramin R, Katopodi V, Cinque S, Konnova A, Knezevic Z, Adnane S, Verheyden Y, Karras P, Demesmaeker E, Bosisio FM, Kucera L, Rozman J, Gladwyn-Ng I, Rizzotto L, Dassi E, Millevoi S, Bechter O, Marine JC, Leucci E. Activation of the integrated stress response confers vulnerability to mitoribosome-targeting antibiotics in melanoma. J Exp Med 2021; 218:e20210571. [PMID: 34287642 PMCID: PMC8424468 DOI: 10.1084/jem.20210571] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 05/10/2021] [Accepted: 06/16/2021] [Indexed: 12/15/2022] Open
Abstract
The ability to adapt to environmental stress, including therapeutic insult, contributes to tumor evolution and drug resistance. In suboptimal conditions, the integrated stress response (ISR) promotes survival by dampening cytosolic translation. We show that ISR-dependent survival also relies on a concomitant up-regulation of mitochondrial protein synthesis, a vulnerability that can be exploited using mitoribosome-targeting antibiotics. Accordingly, such agents sensitized to MAPK inhibition, thus preventing the development of resistance in BRAFV600E melanoma models. Additionally, this treatment compromised the growth of melanomas that exhibited elevated ISR activity and resistance to both immunotherapy and targeted therapy. In keeping with this, pharmacological inactivation of ISR, or silencing of ATF4, rescued the antitumoral response to the tetracyclines. Moreover, a melanoma patient exposed to doxycycline experienced complete and long-lasting response of a treatment-resistant lesion. Our study indicates that the repurposing of mitoribosome-targeting antibiotics offers a rational salvage strategy for targeted therapy in BRAF mutant melanoma and a therapeutic option for NRAS-driven and immunotherapy-resistant tumors.
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Affiliation(s)
- Roberto Vendramin
- Laboratory for RNA Cancer Biology, Department of Oncology, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Vicky Katopodi
- Laboratory for RNA Cancer Biology, Department of Oncology, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Sonia Cinque
- Laboratory for RNA Cancer Biology, Department of Oncology, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Angelina Konnova
- Laboratory for RNA Cancer Biology, Department of Oncology, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Zorica Knezevic
- Laboratory for RNA Cancer Biology, Department of Oncology, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Sara Adnane
- Laboratory for RNA Cancer Biology, Department of Oncology, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Yvessa Verheyden
- Laboratory for RNA Cancer Biology, Department of Oncology, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Panagiotis Karras
- Laboratory for Molecular Cancer Biology, Center for Cancer Biology, Vlaams Instituut voor Biotechnologie, Leuven, Belgium
- Department of Oncology, Laboratory for Molecular Cancer Biology, Katholieke Universiteit Leuven, Belgium
| | - Ewout Demesmaeker
- Laboratory for RNA Cancer Biology, Department of Oncology, Katholieke Universiteit Leuven, Leuven, Belgium
| | | | - Lukas Kucera
- Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, Vestec, Czech Republic
| | - Jan Rozman
- Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, Vestec, Czech Republic
| | | | - Lara Rizzotto
- Trace, Leuven Cancer Institute, Katholieke Universiteit Leuven, Belgium
| | - Erik Dassi
- Laboratory of RNA Regulatory Networks, Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy
| | - Stefania Millevoi
- Cancer Research Centre of Toulouse, Institut national de la santé et de la recherche médicale Joint Research Unit 1037, Toulouse, France
- Université Toulouse III Paul Sabatier, Toulouse, France
- Laboratoire d’Excellence “TOUCAN,” Toulouse, France
| | - Oliver Bechter
- Department of General Medical Oncology, Leuven Cancer Institute, Universitair Ziekenhuis Leuven, Leuven, Belgium
| | - Jean-Christophe Marine
- Laboratory for Molecular Cancer Biology, Center for Cancer Biology, Vlaams Instituut voor Biotechnologie, Leuven, Belgium
- Department of Oncology, Laboratory for Molecular Cancer Biology, Katholieke Universiteit Leuven, Belgium
| | - Eleonora Leucci
- Laboratory for RNA Cancer Biology, Department of Oncology, Katholieke Universiteit Leuven, Leuven, Belgium
- Trace, Leuven Cancer Institute, Katholieke Universiteit Leuven, Belgium
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27
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Mitochondrial Metabolism in Carcinogenesis and Cancer Therapy. Cancers (Basel) 2021; 13:cancers13133311. [PMID: 34282749 PMCID: PMC8269082 DOI: 10.3390/cancers13133311] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 06/25/2021] [Accepted: 06/28/2021] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Reprogramming metabolism is a hallmark of cancer. Warburg’s effect, defined as increased aerobic glycolysis at the expense of mitochondrial respiration in cancer cells, opened new avenues of research in the field of cancer. Later findings, however, have revealed that mitochondria remain functional and that they actively contribute to metabolic plasticity of cancer cells. Understanding the mechanisms by which mitochondrial metabolism controls tumor initiation and progression is necessary to better characterize the onset of carcinogenesis. These studies may ultimately lead to the design of novel anti-cancer strategies targeting mitochondrial functions. Abstract Carcinogenesis is a multi-step process that refers to transformation of a normal cell into a tumoral neoplastic cell. The mechanisms that promote tumor initiation, promotion and progression are varied, complex and remain to be understood. Studies have highlighted the involvement of oncogenic mutations, genomic instability and epigenetic alterations as well as metabolic reprogramming, in different processes of oncogenesis. However, the underlying mechanisms still have to be clarified. Mitochondria are central organelles at the crossroad of various energetic metabolisms. In addition to their pivotal roles in bioenergetic metabolism, they control redox homeostasis, biosynthesis of macromolecules and apoptotic signals, all of which are linked to carcinogenesis. In the present review, we discuss how mitochondria contribute to the initiation of carcinogenesis through gene mutations and production of oncometabolites, and how they promote tumor progression through the control of metabolic reprogramming and mitochondrial dynamics. Finally, we present mitochondrial metabolism as a promising target for the development of novel therapeutic strategies.
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28
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Panina SB, Pei J, Kirienko NV. Mitochondrial metabolism as a target for acute myeloid leukemia treatment. Cancer Metab 2021; 9:17. [PMID: 33883040 PMCID: PMC8058979 DOI: 10.1186/s40170-021-00253-w] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 03/30/2021] [Indexed: 02/06/2023] Open
Abstract
Acute myeloid leukemias (AML) are a group of aggressive hematologic malignancies resulting from acquired genetic mutations in hematopoietic stem cells that affect patients of all ages. Despite decades of research, standard chemotherapy still remains ineffective for some AML subtypes and is often inappropriate for older patients or those with comorbidities. Recently, a number of studies have identified unique mitochondrial alterations that lead to metabolic vulnerabilities in AML cells that may present viable treatment targets. These include mtDNA, dependency on oxidative phosphorylation, mitochondrial metabolism, and pro-survival signaling, as well as reactive oxygen species generation and mitochondrial dynamics. Moreover, some mitochondria-targeting chemotherapeutics and their combinations with other compounds have been FDA-approved for AML treatment. Here, we review recent studies that illuminate the effects of drugs and synergistic drug combinations that target diverse biomolecules and metabolic pathways related to mitochondria and their promise in experimental studies, clinical trials, and existing chemotherapeutic regimens.
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Affiliation(s)
| | - Jingqi Pei
- Department of BioSciences, Rice University, Houston, TX, USA
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Jones CL, Inguva A, Jordan CT. Targeting Energy Metabolism in Cancer Stem Cells: Progress and Challenges in Leukemia and Solid Tumors. Cell Stem Cell 2021; 28:378-393. [PMID: 33667359 PMCID: PMC7951949 DOI: 10.1016/j.stem.2021.02.013] [Citation(s) in RCA: 82] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Malignant stem cells have long been considered a key therapeutic target in leukemia. Therapeutic strategies designed to target the fundamental biology of leukemia stem cells while sparing normal hematopoietic cells may provide better outcomes for leukemia patients. One process in leukemia stem cell biology that has intriguing therapeutic potential is energy metabolism. In this article we discuss the metabolic properties of leukemia stem cells and how targeting energy metabolism may provide more effective therapeutic regimens for leukemia patients. In addition, we highlight the similarities and differences in energy metabolism between leukemia stem cells and malignant stem cells from solid tumors.
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Affiliation(s)
- Courtney L Jones
- Princess Margaret Cancer Centre, 101 College St. Toronto, ON M5G 1L7, Canada
| | - Anagha Inguva
- Division of Hematology, University of Colorado, 12700 East 19th Ave., Aurora, CO 80045, USA
| | - Craig T Jordan
- Division of Hematology, University of Colorado, 12700 East 19th Ave., Aurora, CO 80045, USA.
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30
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Kispal B, Walker SAN. Monte Carlo simulation evaluation of tigecycline dosing for bacteria with raised minimum inhibitory concentrations in non-critically ill adults. Eur J Clin Pharmacol 2020; 77:197-205. [PMID: 32975650 DOI: 10.1007/s00228-020-02998-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 09/14/2020] [Indexed: 12/23/2022]
Abstract
PURPOSE Tigecycline is one of few antibiotics active against multidrug-resistant bacteria; however, the assessment of dosing strategies to optimize its activity is needed. The purpose was to use Monte Carlo Simulation (MCS) to determine if safe tigecycline dosing options attaining breakpoints for pharmacokinetic/pharmacodynamic (PK-PD) targets in non-critically ill adults could be identified. METHODS Publications that evaluated tigecycline dosing regimens and provided mean PK variables of interest (minimum 2 of: elimination rate constant or half-life and volume of distribution or clearance), with SDs, were included. Weighted mean (±SDs) for each PK parameter were determined. Food and Drug Administration minimum inhibitory concentration (MIC) tigecycline breakpoints for susceptible (MIC ≤ 2 μg/mL), intermediate (MIC 4 μg/mL), and resistant (MIC ≥ 8 μg/mL) Enterobacteriaceae were used. MCS probability distributions for PK-PD target attainment of AUC for total tigecycline plasma concentration from 0 to 24 h following an intravenous dose (AUCtotal, 0-24h) to MIC ratios of ≥ 18, 7, and 4.5 were generated, with success defined as ≥ 80% probability of target attainment at a given MIC. RESULTS Ten studies (n = 442) were eligible. Tigecycline 150 mg IV q12h for ward patients with resistant bacteria up to a MIC of 0.48, 1, and 2 μg/mL for an AUCtotal, 0-24h/MIC target attainment of 18, 7, and 4.5, respectively, may be appropriate. CONCLUSION Bacterial infections with tigecycline MICs ≥ 0.48-2 μg/mL, depending on AUCtotal, 0-24h/MIC target, may require treatment with alternate antibiotics due to target attainment failure.
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Affiliation(s)
- Brianna Kispal
- Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College St, Toronto, Ontario, M5S 3M2, Canada
- Department of Pharmacy, Kingston General Hospital, 76 Stuart St, Kingston, Ontario, K7L 2V7, Canada
| | - Sandra A N Walker
- Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College St, Toronto, Ontario, M5S 3M2, Canada.
- Department of Pharmacy Bayview Campus, Sunnybrook Health Sciences Center (SHSC), 2075 Bayview Avenue, Toronto, Ontario, M4N 3M5, Canada.
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Wojcicki AV, Kasowski MM, Sakamoto KM, Lacayo N. Metabolomics in acute myeloid leukemia. Mol Genet Metab 2020; 130:230-238. [PMID: 32457018 DOI: 10.1016/j.ymgme.2020.05.005] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 05/12/2020] [Accepted: 05/13/2020] [Indexed: 12/16/2022]
Abstract
Acute myeloid leukemia (AML) is a complex, heterogenous hematological malignancy caused by mutations in myeloid differentiation and proliferation. Response to therapy and long-term outcomes vary widely based on chromosomal and molecular aberrations. Many platforms have been used to characterize and stratify AML. Metabolomics, the global profiling of small molecules in a biological sample, has emerged in the last decade as an important tool for studying the metabolic dependency of cancer cells. Metabolic reprogramming is not only an important manifestation of AML but clinically relevant for diagnosis, risk stratification and targeted drug development. In this review, we discuss notable metabolic studies of the last decade and their application to novel therapies.
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Affiliation(s)
- Anna V Wojcicki
- Division of Hematology/Oncology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA
| | - Maya M Kasowski
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
| | - Kathleen M Sakamoto
- Division of Hematology/Oncology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
| | - Norman Lacayo
- Division of Hematology/Oncology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
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32
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Deshpande D, Magombedze G, Srivastava S, Bendet P, Lee PS, Cirrincione KN, Martin KR, Dheda K, Gumbo T. Once-a-week tigecycline for the treatment of drug-resistant TB. J Antimicrob Chemother 2020; 74:1607-1617. [PMID: 30820554 DOI: 10.1093/jac/dkz061] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Revised: 01/17/2019] [Accepted: 01/22/2019] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND MDR-TB and XDR-TB have poor outcomes. OBJECTIVES To examine the efficacy of tigecycline monotherapy in the hollow fibre system model of TB. METHODS We performed pharmacokinetic/pharmacodynamic studies using tigecycline human-like concentration-time profiles in the hollow fibre system model of TB in five separate experiments using Mycobacterium tuberculosis in log-phase growth or as semi-dormant or intracellular bacilli, as monotherapy. We also compared efficacy with the isoniazid/rifampicin/pyrazinamide combination (standard therapy). We then applied extinction mathematics, morphisms and Latin hypercube sampling to identify duration of therapy with tigecycline monotherapy. RESULTS The median tigecycline MIC for 30 M. tuberculosis clinical and laboratory isolates (67% MDR/XDR) was 2 mg/L. Tigecycline monotherapy was highly effective in killing M. tuberculosis in log-phase-growth and semi-dormant and intracellular M. tuberculosis. Once-a-week dosing had the same efficacy as daily therapy for the same cumulative dose; thus, tigecycline efficacy was linked to the AUC0-24/MIC ratio. Tigecycline replacement by daily minocycline after 4 weeks of therapy was effective in sterilizing bacilli. The AUC0-24/MIC ratio associated with optimal kill was 42.3. Tigecycline monotherapy had a maximum sterilizing effect (day 0 minus day 28) of 3.06 ± 0.20 log10 cfu/mL (r2 = 0.92) compared with 3.92 ± 0.45 log10 cfu/mL (r2 = 0.80) with optimized standard therapy. In our modelling, at a tigecycline monotherapy duration of 12 months, the proportion of patients with XDR-TB who reached bacterial population extinction was 64.51%. CONCLUSIONS Tigecycline could cure patients with XDR-TB or MDR-TB who have failed recommended therapy. Once-a-week tigecycline could also replace second-line injectables in MDR-TB regimens.
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Affiliation(s)
- Devyani Deshpande
- Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, USA
| | - Gesham Magombedze
- Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, USA
| | - Shashikant Srivastava
- Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, USA
| | - Paula Bendet
- Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, USA
| | - Pooi S Lee
- Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, USA
| | - Kayle N Cirrincione
- Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, USA
| | - Katherine R Martin
- Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, USA
| | - Keertan Dheda
- Lung Infection and Immunity Unit, Department of Medicine, Division of Pulmonology and UCT Lung Institute, Department of Medicine, University of Cape Town, Observatory, South Africa
| | - Tawanda Gumbo
- Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, USA.,Lung Infection and Immunity Unit, Department of Medicine, Division of Pulmonology and UCT Lung Institute, Department of Medicine, University of Cape Town, Observatory, South Africa
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33
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Valli D, Gruszka AM, Alcalay M. Has Drug Repurposing Fulfilled its Promise in Acute Myeloid Leukaemia? J Clin Med 2020; 9:E1892. [PMID: 32560371 PMCID: PMC7356362 DOI: 10.3390/jcm9061892] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 06/11/2020] [Accepted: 06/15/2020] [Indexed: 12/16/2022] Open
Abstract
Drug repurposing is a method of drug discovery that consists of finding a new therapeutic context for an old drug. Compound identification arises from screening of large libraries of active compounds, through interrogating databases of cell line gene expression response upon treatment or by merging several types of information concerning disease-drug relationships. Although, there is a general consensus on the potential and advantages of this drug discovery modality, at the practical level to-date no non-anti-cancer repurposed compounds have been introduced into standard acute myeloid leukaemia (AML) management, albeit that preclinical validation yielded several candidates. The review presents the state-of-the-art drug repurposing approach in AML and poses the question of what has to be done in order to take a full advantage of it, both at the stage of screening design and later when progressing from the preclinical to the clinical phases of drug development. We argue that improvements are needed to model and read-out systems as well as to screening technologies, but also to more funding and trust in drug repurposing strategies.
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Affiliation(s)
- Debora Valli
- Department of Experimental Oncology, Istituto Europeo di Oncologia IRCCS, Via Adamello 16, 20 139 Milan, Italy; (D.V.); (M.A.)
| | - Alicja M. Gruszka
- Department of Experimental Oncology, Istituto Europeo di Oncologia IRCCS, Via Adamello 16, 20 139 Milan, Italy; (D.V.); (M.A.)
| | - Myriam Alcalay
- Department of Experimental Oncology, Istituto Europeo di Oncologia IRCCS, Via Adamello 16, 20 139 Milan, Italy; (D.V.); (M.A.)
- Department of Oncology and Hemato-Oncology, University of Milan, Via Festa del Perdono 7, 20 122 Milan, Italy
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Yang J, Dong Z, Ren A, Fu G, Zhang K, Li C, Wang X, Cui H. Antibiotic tigecycline inhibits cell proliferation, migration and invasion via down-regulating CCNE2 in pancreatic ductal adenocarcinoma. J Cell Mol Med 2020; 24:4245-4260. [PMID: 32141702 PMCID: PMC7171345 DOI: 10.1111/jcmm.15086] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Revised: 10/17/2019] [Accepted: 01/15/2020] [Indexed: 12/17/2022] Open
Abstract
Recently, many researches have reported that antibiotic tigecycline has significant effect on cancer treatment. However, biomedical functions and molecular mechanisms of tigecycline in human pancreatic ductal adenocarcinoma (PDAC) remain unclear. In the current study, we tried to assess the effect of tigecycline in PDAC cells. AsPC‐1 and HPAC cells were treated with indicated concentrations of tigecycline for indicated time, and then, MTT, BrdU and soft agar assay were used to test cell proliferation. The effect of tigecycline on cell cycle and cellular apoptosis was tested by cytometry. Migration and invasion were detected by wound healing assay and transwell migration/invasion assay. Expressions of cell cycle‐related and migration/invasion‐related protein were determined by using Western blot. The results revealed that tigecycline observably suppressed cell proliferation by inducing cell cycle arrest at G0/G1 phase and blocked cell migration/invasion via holding back the epithelial‐mesenchymal transition (EMT) process in PDAC. In addition, tigecycline also remarkably blocked tumorigenecity in vivo. Furthermore, the effects of tigecycline alone or combined with gemcitabine in vitro or on PDAC xenografts were also performed. The results showed that tigecycline enhanced the chemosensitivity of PDAC cells to gemcitabine. Interestingly, we found CCNE2 expression was declined distinctly after tigecycline treatment. Then, CCNE2 was overexpressed to rescue tigecycline‐induced effect. The results showed that CCNE2 overexpression significantly rescued tigecycline‐inhibited cell proliferation and migration/invasion. Collectively, we showed that tigecycline inhibits cell proliferation, migration and invasion via down‐regulating CCNE2, and tigecycline might be used as a potential drug for PDAC treatment alone or combined with gemcitabine.
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Affiliation(s)
- Jie Yang
- State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, Southwest University, Beibei, Chongqing, China.,Cancer Center, Medical Research Institute, Southwest University, Beibei, Chongqing, China.,Engineering Research Center for Cancer Biomedical and Translational Medicine, Southwest University, Beibei, Chongqing, China.,Chongqing Engineering and Technology Research Center for Silk Biomaterials and Regenerative Medicine, Southwest University, Beibei, Chongqing, China
| | - Zhen Dong
- State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, Southwest University, Beibei, Chongqing, China.,Cancer Center, Medical Research Institute, Southwest University, Beibei, Chongqing, China.,Engineering Research Center for Cancer Biomedical and Translational Medicine, Southwest University, Beibei, Chongqing, China.,Chongqing Engineering and Technology Research Center for Silk Biomaterials and Regenerative Medicine, Southwest University, Beibei, Chongqing, China
| | - Aishu Ren
- College of Stomatology, Chongqing Medical University, Chongqing, China
| | - Gang Fu
- College of Stomatology, Chongqing Medical University, Chongqing, China
| | - Kui Zhang
- State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, Southwest University, Beibei, Chongqing, China.,Cancer Center, Medical Research Institute, Southwest University, Beibei, Chongqing, China.,Engineering Research Center for Cancer Biomedical and Translational Medicine, Southwest University, Beibei, Chongqing, China.,Chongqing Engineering and Technology Research Center for Silk Biomaterials and Regenerative Medicine, Southwest University, Beibei, Chongqing, China
| | - Changhong Li
- State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, Southwest University, Beibei, Chongqing, China.,Cancer Center, Medical Research Institute, Southwest University, Beibei, Chongqing, China.,Engineering Research Center for Cancer Biomedical and Translational Medicine, Southwest University, Beibei, Chongqing, China.,Chongqing Engineering and Technology Research Center for Silk Biomaterials and Regenerative Medicine, Southwest University, Beibei, Chongqing, China
| | - Xiangwei Wang
- Department of Urology, Carson International Cancer Center, Shenzhen University General Hospital & Shenzhen University Clinical Medical Academy Center, Shenzhen University, Shenzhen, China
| | - Hongjuan Cui
- State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, Southwest University, Beibei, Chongqing, China.,Cancer Center, Medical Research Institute, Southwest University, Beibei, Chongqing, China.,Engineering Research Center for Cancer Biomedical and Translational Medicine, Southwest University, Beibei, Chongqing, China.,Chongqing Engineering and Technology Research Center for Silk Biomaterials and Regenerative Medicine, Southwest University, Beibei, Chongqing, China
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35
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Wojcicki AV, Kadapakkam M, Frymoyer A, Lacayo N, Chae HD, Sakamoto KM. Repurposing Drugs for Acute Myeloid Leukemia: A Worthy Cause or a Futile Pursuit? Cancers (Basel) 2020; 12:cancers12020441. [PMID: 32069925 PMCID: PMC7072462 DOI: 10.3390/cancers12020441] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2020] [Revised: 02/05/2020] [Accepted: 02/10/2020] [Indexed: 12/20/2022] Open
Abstract
Acute myeloid leukemia (AML) is a clinically and genetically heterogenous malignancy of myeloid progenitor cells that affects patients of all ages. Despite decades of research and improvement in overall outcomes, standard therapy remains ineffective for certain subtypes of AML. Current treatment is intensive and leads to a number of secondary effects with varying results by patient population. Due to the high cost of discovery and an unmet need for new targeted therapies that are well tolerated, alternative drug development strategies have become increasingly attractive. Repurposing existing drugs is one approach to identify new therapies with fewer financial and regulatory hurdles. In this review, we provide an overview of previously U.S. Food and Drug Administration (FDA) approved non-chemotherapy drugs under investigation for the treatment of AML.
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Affiliation(s)
- Anna V. Wojcicki
- Division of Hematology/Oncology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA; (A.V.W.); (M.K.); (N.L.); (H.-D.C.)
| | - Meena Kadapakkam
- Division of Hematology/Oncology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA; (A.V.W.); (M.K.); (N.L.); (H.-D.C.)
| | - Adam Frymoyer
- Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA;
| | - Norman Lacayo
- Division of Hematology/Oncology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA; (A.V.W.); (M.K.); (N.L.); (H.-D.C.)
| | - Hee-Don Chae
- Division of Hematology/Oncology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA; (A.V.W.); (M.K.); (N.L.); (H.-D.C.)
| | - Kathleen M. Sakamoto
- Division of Hematology/Oncology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA; (A.V.W.); (M.K.); (N.L.); (H.-D.C.)
- Correspondence: ; Tel.: +650-725-7126
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Sillar JR, Germon ZP, De Iuliis GN, Dun MD. The Role of Reactive Oxygen Species in Acute Myeloid Leukaemia. Int J Mol Sci 2019; 20:ijms20236003. [PMID: 31795243 PMCID: PMC6929020 DOI: 10.3390/ijms20236003] [Citation(s) in RCA: 88] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 11/27/2019] [Accepted: 11/27/2019] [Indexed: 12/26/2022] Open
Abstract
Acute myeloid leukaemia (AML) is an aggressive haematological malignancy with a poor overall survival. Reactive oxygen species (ROS) have been shown to be elevated in a wide range of cancers including AML. Whilst previously thought to be mere by-products of cellular metabolism, it is now clear that ROS modulate the function of signalling proteins through oxidation of critical cysteine residues. In this way, ROS have been shown to regulate normal haematopoiesis as well as promote leukaemogenesis in AML. In addition, ROS promote genomic instability by damaging DNA, which promotes chemotherapy resistance. The source of ROS in AML appears to be derived from members of the “NOX family” of NADPH oxidases. Most studies link NOX-derived ROS to activating mutations in the Fms-like tyrosine kinase 3 (FLT3) and Ras-related C3 botulinum toxin substrate (Ras). Targeting ROS through either ROS induction or ROS inhibition provides a novel therapeutic target in AML. In this review, we summarise the role of ROS in normal haematopoiesis and in AML. We also explore the current treatments that modulate ROS levels in AML and discuss emerging drug targets based on pre-clinical work.
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Affiliation(s)
- Jonathan R. Sillar
- Haematology Department, Calvary Mater Hospital, Newcastle, NSW 2298, Australia
- Cancer Signalling Research Group, School of Biomedical Sciences & Pharmacy, Faculty of Health & Medicine, University of Newcastle, Callaghan, NSW 2308, Australia;
- Priority Research Centre for Cancer Research, Innovation & Translation, Faculty of Health & Medicine, Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
- Correspondence: (J.R.S.); (M.D.D.); Tel.: +612-4921-5693 (M.D.D.)
| | - Zacary P. Germon
- Cancer Signalling Research Group, School of Biomedical Sciences & Pharmacy, Faculty of Health & Medicine, University of Newcastle, Callaghan, NSW 2308, Australia;
- Priority Research Centre for Cancer Research, Innovation & Translation, Faculty of Health & Medicine, Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
| | - Geoffry N. De Iuliis
- Priority Research Centre for Reproductive Sciences, Faculty of Science, University of Newcastle, Callaghan, NSW 2308, Australia;
| | - Matthew D. Dun
- Cancer Signalling Research Group, School of Biomedical Sciences & Pharmacy, Faculty of Health & Medicine, University of Newcastle, Callaghan, NSW 2308, Australia;
- Priority Research Centre for Cancer Research, Innovation & Translation, Faculty of Health & Medicine, Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
- Correspondence: (J.R.S.); (M.D.D.); Tel.: +612-4921-5693 (M.D.D.)
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Kreitz J, Schönfeld C, Seibert M, Stolp V, Alshamleh I, Oellerich T, Steffen B, Schwalbe H, Schnütgen F, Kurrle N, Serve H. Metabolic Plasticity of Acute Myeloid Leukemia. Cells 2019; 8:E805. [PMID: 31370337 PMCID: PMC6721808 DOI: 10.3390/cells8080805] [Citation(s) in RCA: 106] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Revised: 07/26/2019] [Accepted: 07/28/2019] [Indexed: 02/07/2023] Open
Abstract
Acute myeloid leukemia (AML) is one of the most common and life-threatening leukemias. A highly diverse and flexible metabolism contributes to the aggressiveness of the disease that is still difficult to treat. By using different sources of nutrients for energy and biomass supply, AML cells gain metabolic plasticity and rapidly outcompete normal hematopoietic cells. This review aims to decipher the diverse metabolic strategies and the underlying oncogenic and environmental changes that sustain continuous growth, mediate redox homeostasis and induce drug resistance in AML. We revisit Warburg's hypothesis and illustrate the role of glucose as a provider of cellular building blocks rather than as a supplier of the tricarboxylic acid (TCA) cycle for energy production. We discuss how the diversity of fuels for the TCA cycle, including glutamine and fatty acids, contributes to the metabolic plasticity of the disease and highlight the roles of amino acids and lipids in AML metabolism. Furthermore, we point out the potential of the different metabolic effectors to be used as novel therapeutic targets.
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Affiliation(s)
- Johanna Kreitz
- Department of Medicine 2, Hematology/Oncology, Goethe University, 60590 Frankfurt am Main, Germany
- German Cancer Consortium (DKTK) and DKFZ, 69120 Heidelberg, Germany
| | - Christine Schönfeld
- Department of Medicine 2, Hematology/Oncology, Goethe University, 60590 Frankfurt am Main, Germany
- German Cancer Consortium (DKTK) and DKFZ, 69120 Heidelberg, Germany
| | - Marcel Seibert
- Department of Medicine 2, Hematology/Oncology, Goethe University, 60590 Frankfurt am Main, Germany
- German Cancer Consortium (DKTK) and DKFZ, 69120 Heidelberg, Germany
| | - Verena Stolp
- Department of Medicine 2, Hematology/Oncology, Goethe University, 60590 Frankfurt am Main, Germany
- German Cancer Consortium (DKTK) and DKFZ, 69120 Heidelberg, Germany
| | - Islam Alshamleh
- Center for Biomolecular Magnetic Resonance, Institute of Organic Chemistry and Chemical Biology, Goethe-University, 60438 Frankfurt am Main, Germany
| | - Thomas Oellerich
- Department of Medicine 2, Hematology/Oncology, Goethe University, 60590 Frankfurt am Main, Germany
- German Cancer Consortium (DKTK) and DKFZ, 69120 Heidelberg, Germany
- Frankfurt Cancer Institute (FCI), 60590 Frankfurt am Main, Germany
| | - Björn Steffen
- Department of Medicine 2, Hematology/Oncology, Goethe University, 60590 Frankfurt am Main, Germany
- German Cancer Consortium (DKTK) and DKFZ, 69120 Heidelberg, Germany
- Frankfurt Cancer Institute (FCI), 60590 Frankfurt am Main, Germany
| | - Harald Schwalbe
- German Cancer Consortium (DKTK) and DKFZ, 69120 Heidelberg, Germany
- Center for Biomolecular Magnetic Resonance, Institute of Organic Chemistry and Chemical Biology, Goethe-University, 60438 Frankfurt am Main, Germany
| | - Frank Schnütgen
- Department of Medicine 2, Hematology/Oncology, Goethe University, 60590 Frankfurt am Main, Germany
- German Cancer Consortium (DKTK) and DKFZ, 69120 Heidelberg, Germany
- Frankfurt Cancer Institute (FCI), 60590 Frankfurt am Main, Germany
| | - Nina Kurrle
- Department of Medicine 2, Hematology/Oncology, Goethe University, 60590 Frankfurt am Main, Germany.
- German Cancer Consortium (DKTK) and DKFZ, 69120 Heidelberg, Germany.
- Frankfurt Cancer Institute (FCI), 60590 Frankfurt am Main, Germany.
| | - Hubert Serve
- Department of Medicine 2, Hematology/Oncology, Goethe University, 60590 Frankfurt am Main, Germany.
- German Cancer Consortium (DKTK) and DKFZ, 69120 Heidelberg, Germany.
- Frankfurt Cancer Institute (FCI), 60590 Frankfurt am Main, Germany.
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38
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Dong Z, Abbas MN, Kausar S, Yang J, Li L, Tan L, Cui H. Biological Functions and Molecular Mechanisms of Antibiotic Tigecycline in the Treatment of Cancers. Int J Mol Sci 2019; 20:ijms20143577. [PMID: 31336613 PMCID: PMC6678986 DOI: 10.3390/ijms20143577] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Revised: 07/17/2019] [Accepted: 07/19/2019] [Indexed: 12/14/2022] Open
Abstract
As an FDA-approved drug, glycylcycline tigecycline has been used to treat complicated microbial infections. However, recent studies in multiple hematologic and malignant solid tumors reveal that tigecycline treatment induces cell cycle arrest, apoptosis, autophagy and oxidative stress. In addition, tigecycline also inhibits mitochondrial oxidative phosphorylation, cell proliferation, migration, invasion and angiogenesis. Importantly, combinations of tigecycline with chemotherapeutic or targeted drugs such as venetoclax, doxorubicin, vincristine, paclitaxel, cisplatin, and imatinib, have shown to be promising strategies for cancer treatment. Mechanism of action studies reveal that tigecycline leads to the inhibition of mitochondrial translation possibly through interacting with mitochondrial ribosome. Meanwhile, this drug also interferes with several other cell pathways/targets including MYC, HIFs, PI3K/AKT or AMPK-mediated mTOR, cytoplasmic p21 CIP1/Waf1, and Wnt/β-catenin signaling. These evidences indicate that antibiotic tigecycline is a promising drug for cancer treatment alone or in combination with other anticancer drugs. This review summarizes the biological function of tigecycline in the treatment of tumors and comprehensively discusses its mode of action.
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Affiliation(s)
- Zhen Dong
- State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, Southwest University, Beibei, Chongqing 400716, China
- Cancer Center, Medical Research Institute, Southwest University, Beibei, Chongqing 400716, China
- Engineering Research Center for Cancer Biomedical and Translational Medicine, Southwest University, Beibei, Chongqing 400716, China
- Chongqing Engineering and Technology Research Center for Silk Biomaterials and Regenerative Medicine, Southwest University, Beibei, Chongqing 400716, China
| | - Muhammad Nadeem Abbas
- State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, Southwest University, Beibei, Chongqing 400716, China
- Cancer Center, Medical Research Institute, Southwest University, Beibei, Chongqing 400716, China
- Engineering Research Center for Cancer Biomedical and Translational Medicine, Southwest University, Beibei, Chongqing 400716, China
- Chongqing Engineering and Technology Research Center for Silk Biomaterials and Regenerative Medicine, Southwest University, Beibei, Chongqing 400716, China
| | - Saima Kausar
- State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, Southwest University, Beibei, Chongqing 400716, China
- Cancer Center, Medical Research Institute, Southwest University, Beibei, Chongqing 400716, China
- Engineering Research Center for Cancer Biomedical and Translational Medicine, Southwest University, Beibei, Chongqing 400716, China
- Chongqing Engineering and Technology Research Center for Silk Biomaterials and Regenerative Medicine, Southwest University, Beibei, Chongqing 400716, China
| | - Jie Yang
- State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, Southwest University, Beibei, Chongqing 400716, China
- Cancer Center, Medical Research Institute, Southwest University, Beibei, Chongqing 400716, China
- Engineering Research Center for Cancer Biomedical and Translational Medicine, Southwest University, Beibei, Chongqing 400716, China
- Chongqing Engineering and Technology Research Center for Silk Biomaterials and Regenerative Medicine, Southwest University, Beibei, Chongqing 400716, China
| | - Lin Li
- State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, Southwest University, Beibei, Chongqing 400716, China
- Cancer Center, Medical Research Institute, Southwest University, Beibei, Chongqing 400716, China
- Engineering Research Center for Cancer Biomedical and Translational Medicine, Southwest University, Beibei, Chongqing 400716, China
- Chongqing Engineering and Technology Research Center for Silk Biomaterials and Regenerative Medicine, Southwest University, Beibei, Chongqing 400716, China
| | - Li Tan
- State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, Southwest University, Beibei, Chongqing 400716, China
- Cancer Center, Medical Research Institute, Southwest University, Beibei, Chongqing 400716, China
- Engineering Research Center for Cancer Biomedical and Translational Medicine, Southwest University, Beibei, Chongqing 400716, China
- Chongqing Engineering and Technology Research Center for Silk Biomaterials and Regenerative Medicine, Southwest University, Beibei, Chongqing 400716, China
| | - Hongjuan Cui
- State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, Southwest University, Beibei, Chongqing 400716, China.
- Cancer Center, Medical Research Institute, Southwest University, Beibei, Chongqing 400716, China.
- Engineering Research Center for Cancer Biomedical and Translational Medicine, Southwest University, Beibei, Chongqing 400716, China.
- Chongqing Engineering and Technology Research Center for Silk Biomaterials and Regenerative Medicine, Southwest University, Beibei, Chongqing 400716, China.
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Lee M, Hirpara JL, Eu JQ, Sethi G, Wang L, Goh BC, Wong AL. Targeting STAT3 and oxidative phosphorylation in oncogene-addicted tumors. Redox Biol 2019; 25:101073. [PMID: 30594485 PMCID: PMC6859582 DOI: 10.1016/j.redox.2018.101073] [Citation(s) in RCA: 87] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Revised: 11/08/2018] [Accepted: 12/07/2018] [Indexed: 02/07/2023] Open
Abstract
Drug resistance invariably limits the response of oncogene-addicted cancer cells to targeted therapy. The upregulation of signal transducer and activator of transcription 3 (STAT3) has been implicated as a mechanism of drug resistance in a range of oncogene-addicted cancers. However, the development of inhibitors against STAT3 has been fraught with challenges such as poor delivery or lack of specificity. Clinical experience with small molecule STAT3 inhibitors has seen efficacy signals, but this success has been tempered by drug limiting toxicities from off-target adverse events. It has emerged in recent years that, contrary to the Warburg theory, certain tumor types undergo metabolic reprogramming towards oxidative phosphorylation (OXPHOS) to satisfy their energy production. In particular, certain drug-resistant oncogene-addicted tumors have been found to rely on OXPHOS as a mechanism of survival. Multiple cellular signaling pathways converge on STAT3, hence the localization of STAT3 to the mitochondria may provide the link between oncogene-induced signaling pathways and cancer cell metabolism. In this article, we review the role of STAT3 and OXPHOS as targets of novel therapeutic strategies aimed at restoring drug sensitivity in treatment-resistant oncogene-addicted tumor types. Apart from drugs which have been re-purposed as OXPHOS inhibitors for-anti-cancer therapy (e.g., metformin and phenformin), several novel compounds in the drug-development pipeline have demonstrated promising pre-clinical and clinical activity. However, the clinical development of OXPHOS inhibitors remains in its infancy. The further identification of compounds with acceptable toxicity profiles, alongside the discovery of robust companion biomarkers of OXPHOS inhibition, would represent tangible early steps in transforming the therapeutic landscape of cancer cell metabolism.
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Affiliation(s)
- Matilda Lee
- Department of Haematology-Oncology, National University Health System, Singapore; Haematology-Oncology Research Group, National University Cancer Institute of Singapore, National University Health System, Singapore
| | | | | | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | | | - Boon-Cher Goh
- Department of Haematology-Oncology, National University Health System, Singapore; Haematology-Oncology Research Group, National University Cancer Institute of Singapore, National University Health System, Singapore; Cancer Science Institute, Singapore; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Andrea L Wong
- Department of Haematology-Oncology, National University Health System, Singapore; Haematology-Oncology Research Group, National University Cancer Institute of Singapore, National University Health System, Singapore; Cancer Science Institute, Singapore.
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40
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Campos EDV, Pinto R. Targeted therapy with a selective BCL-2 inhibitor in older patients with acute myeloid leukemia. Hematol Transfus Cell Ther 2018; 41:169-177. [PMID: 31084767 PMCID: PMC6517609 DOI: 10.1016/j.htct.2018.09.001] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Revised: 05/15/2018] [Accepted: 09/11/2018] [Indexed: 12/24/2022] Open
Abstract
Background Older patients with acute myeloid leukemia are particularly difficult to treat, as they have a high risk of comorbidities, poor performance status and less tolerability to chemotherapy, as well as a more aggressive disease biology, responsible for the resistance to treatment. There is a need to explore novel therapeutic agents that are more effective and tolerable. Venetoclax, a BCL-2 inhibitor is a promising agent, as BCL-2 overexpression is present in 84% of acute myeloid leukemia patients at diagnosis and 95% of patients at relapse and has been associated with leukemia cell survival, chemotherapy resistance and poor prognosis. Objective To review the available data about venetoclax in acute myeloid leukemia and how it can influence the treatment in older patients. Methods Using the Pubmed database, we selected 29 articles published within the last 15 years, considering preclinical and clinical trials and review studies that combined venetoclax with acute myeloid leukemia. Results Venetoclax has demonstrated promising results in preclinical and clinical trials, especially in patients with poor prognosis and the IDH mutation, with an excellent side-effect profile. However, resistance seems to develop rapidly with venetoclax monotherapy, because of antiapoptotic escape mechanisms. Conclusions While the results with the use of venetoclax seem encouraging, it is not likely that targeting a single pathway will result in long-term disease control. The solution includes the use of combined therapy to block resistance mechanisms and enhance apoptosis, by reducing MCL-1, increasing BIM or inhibiting the complex IV in the mitochondria.
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41
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Di Carlo C, Brandi J, Cecconi D. Pancreatic cancer stem cells: Perspectives on potential therapeutic approaches of pancreatic ductal adenocarcinoma. World J Stem Cells 2018; 10:172-182. [PMID: 30631392 PMCID: PMC6325076 DOI: 10.4252/wjsc.v10.i11.172] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Revised: 09/10/2018] [Accepted: 10/17/2018] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma is one of the most aggressive solid tumours of the pancreas, characterised by a five-year survival rate less than 8%. Recent reports that pancreatic cancer stem cells (PCSCs) contribute to the tumorigenesis, progression, and chemoresistance of pancreatic cancer have prompted the investigation of new therapeutic approaches able to directly target PCSCs. In the present paper the non-cancer related drugs that have been proposed to target CSCs that could potentially combat pancreatic cancer are reviewed and evaluated. The role of some pathways and deregulated proteins in PCSCs as new therapeutic targets are also discussed with a focus on selected specific inhibitors. Finally, advances in the development of nanoparticles for targeting PCSCs and site-specific drug delivery are highlighted, and their limitations considered.
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Affiliation(s)
- Claudia Di Carlo
- Department of Biotechnology, Proteomics and Mass Spectrometry Laboratory, University of Verona, Verona 37134, Italy
| | - Jessica Brandi
- Department of Biotechnology, Proteomics and Mass Spectrometry Laboratory, University of Verona, Verona 37134, Italy.
| | - Daniela Cecconi
- Department of Biotechnology, Proteomics and Mass Spectrometry Laboratory, University of Verona, Verona 37134, Italy
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42
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Baquero P, Dawson A, Helgason GV. Autophagy and mitochondrial metabolism: insights into their role and therapeutic potential in chronic myeloid leukaemia. FEBS J 2018; 286:1271-1283. [PMID: 30222247 DOI: 10.1111/febs.14659] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2018] [Revised: 08/07/2018] [Accepted: 09/14/2018] [Indexed: 12/11/2022]
Abstract
Despite the development of selective BCR-ABL-targeting tyrosine kinase inhibitors (TKIs) transforming the management of chronic myeloid leukaemia (CML), therapy-resistant leukaemic stem cells (LSCs) persist after TKI treatment and present an obstacle to a CML cure. Recently, we and others have made significant contributions to the field by unravelling survival dependencies in LSCs to work towards the goal of eradicating LSCs in CML patients. In this review, we describe these findings focusing on autophagy and mitochondrial metabolism, which have recently been uncovered as two essential processes for LSCs quiescence and survival respectively. In addition, we discuss the therapeutic potential of autophagy and mitochondrial metabolism inhibition as a strategy to eliminate CML cells in patients where the resistance to TKI is driven by BCR-ABL-independent mechanism(s).
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Affiliation(s)
- Pablo Baquero
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, UK
| | - Amy Dawson
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, UK
| | - Gudmundur Vignir Helgason
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, UK.,Paul O'Gorman Leukemia Research Centre, Institute of Cancer Sciences, University of Glasgow, UK
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43
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Karabulutoglu M, Finnon R, Imaoka T, Friedl AA, Badie C. Influence of diet and metabolism on hematopoietic stem cells and leukemia development following ionizing radiation exposure. Int J Radiat Biol 2018; 95:452-479. [PMID: 29932783 DOI: 10.1080/09553002.2018.1490042] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE The review aims to discuss the prominence of dietary and metabolic regulators in maintaining hematopoietic stem cell (HSC) function, long-term self-renewal, and differentiation. RESULTS Most adult stem cells are preserved in a quiescent, nonmotile state in vivo which acts as a "protective state" for stem cells to reduce endogenous stress provoked by DNA replication and cellular respiration as well as exogenous environmental stress. The dynamic balance between quiescence, self-renewal and differentiation is critical for supporting a functional blood system throughout life of an organism. Stress-conditions, for example ionizing radiation exposure can trigger the blood forming HSCs to proliferate and migrate through extramedullary tissues to expand the number of HSCs and increase hematopoiesis. In addition, a wealth of investigation validated that deregulation of this balance plays a critical pathogenic role in various different hematopoietic diseases including the leukemia development. CONCLUSION The review summarizes the current knowledge on how alterations in dietary and metabolic factors could alter the risk of leukemia development following ionizing radiation exposure by inhibiting or even reversing the leukemic progression. Understanding the influence of diet, metabolism, and epigenetics on radiation-induced leukemogenesis may lead to the development of practical interventions to reduce the risk in exposed populations.
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Affiliation(s)
- Melis Karabulutoglu
- a Cancer Mechanisms and Biomarkers group, Biological Effects Department, Centre for Radiation, Chemical and Environmental Hazards , Public Health England , Didcot , UK.,b CRUK & MRC Oxford Institute for Radiation Oncology, Department of Oncology , University of Oxford , Oxford , UK
| | - Rosemary Finnon
- a Cancer Mechanisms and Biomarkers group, Biological Effects Department, Centre for Radiation, Chemical and Environmental Hazards , Public Health England , Didcot , UK
| | - Tatsuhiko Imaoka
- c Department of Radiation Effects Research, National Institute of Radiological Sciences , National Institutes for Quantum and Radiological Science and Technology , Chiba , Japan
| | - Anna A Friedl
- d Department of Radiation Oncology , University Hospital, LMU Munich , Munich , Germany
| | - Christophe Badie
- a Cancer Mechanisms and Biomarkers group, Biological Effects Department, Centre for Radiation, Chemical and Environmental Hazards , Public Health England , Didcot , UK
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44
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Anderson RG, Ghiraldeli LP, Pardee TS. Mitochondria in cancer metabolism, an organelle whose time has come? Biochim Biophys Acta Rev Cancer 2018; 1870:96-102. [PMID: 29807044 PMCID: PMC6420819 DOI: 10.1016/j.bbcan.2018.05.005] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Revised: 05/14/2018] [Accepted: 05/21/2018] [Indexed: 12/20/2022]
Abstract
Mitochondria have long been controversial organelles in cancer. Early discoveries in cancer metabolism placed much emphasis on cytosolic contributions. Initial debate focused on if mitochondria had a role in cancer formation and progression at all. More recently the contributions of mitochondria to cancer development and progression have become firmly established. This has led to the identification of novel targets and inhibitors being studied as new therapeutic approaches. This review will summarize the role of mitochondria in cancer and highlight several agents under development.
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Affiliation(s)
- Rebecca G Anderson
- Department of Cancer Biology, Comprehensive Cancer Center of Wake Forest University, United States
| | - Lais P Ghiraldeli
- Department of Cancer Biology, Comprehensive Cancer Center of Wake Forest University, United States
| | - Timothy S Pardee
- Department of Cancer Biology, Comprehensive Cancer Center of Wake Forest University, United States; Section on Hematology and Oncology, Comprehensive Cancer Center of Wake Forest University, United States; Rafael Pharmaceuticals, Newark, NJ, United States.
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45
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Prieto-Bermejo R, Romo-González M, Pérez-Fernández A, Ijurko C, Hernández-Hernández Á. Reactive oxygen species in haematopoiesis: leukaemic cells take a walk on the wild side. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2018; 37:125. [PMID: 29940987 PMCID: PMC6019308 DOI: 10.1186/s13046-018-0797-0] [Citation(s) in RCA: 83] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Accepted: 06/15/2018] [Indexed: 02/08/2023]
Abstract
Oxidative stress is related to ageing and degenerative diseases, including cancer. However, a moderate amount of reactive oxygen species (ROS) is required for the regulation of cellular signalling and gene expression. A low level of ROS is important for maintaining quiescence and the differentiation potential of haematopoietic stem cells (HSCs), whereas the level of ROS increases during haematopoietic differentiation; thus, suggesting the importance of redox signalling in haematopoiesis. Here, we will analyse the importance of ROS for haematopoiesis and include evidence showing that cells from leukaemia patients live under oxidative stress. The potential sources of ROS will be described. Finally, the level of oxidative stress in leukaemic cells can also be harnessed for therapeutic purposes. In this regard, the reliance of front-line anti-leukaemia chemotherapeutics on increased levels of ROS for their mechanism of action, as well as the active search for novel compounds that modulate the redox state of leukaemic cells, will be analysed.
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Affiliation(s)
- Rodrigo Prieto-Bermejo
- Department of Biochemistry and Molecular Biology, University of Salamanca, Lab. 122, Edificio Departamental, Plaza Doctores de la Reina s/n, 37007, Salamanca, Spain.,IBSAL (Instituto de investigación Biomédica de Salamanca), Salamanca, Spain
| | - Marta Romo-González
- Department of Biochemistry and Molecular Biology, University of Salamanca, Lab. 122, Edificio Departamental, Plaza Doctores de la Reina s/n, 37007, Salamanca, Spain.,IBSAL (Instituto de investigación Biomédica de Salamanca), Salamanca, Spain
| | - Alejandro Pérez-Fernández
- Department of Biochemistry and Molecular Biology, University of Salamanca, Lab. 122, Edificio Departamental, Plaza Doctores de la Reina s/n, 37007, Salamanca, Spain.,IBSAL (Instituto de investigación Biomédica de Salamanca), Salamanca, Spain
| | - Carla Ijurko
- Department of Biochemistry and Molecular Biology, University of Salamanca, Lab. 122, Edificio Departamental, Plaza Doctores de la Reina s/n, 37007, Salamanca, Spain.,IBSAL (Instituto de investigación Biomédica de Salamanca), Salamanca, Spain
| | - Ángel Hernández-Hernández
- Department of Biochemistry and Molecular Biology, University of Salamanca, Lab. 122, Edificio Departamental, Plaza Doctores de la Reina s/n, 37007, Salamanca, Spain. .,IBSAL (Instituto de investigación Biomédica de Salamanca), Salamanca, Spain.
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Ravà M, D’Andrea A, Nicoli P, Gritti I, Donati G, Doni M, Giorgio M, Olivero D, Amati B. Therapeutic synergy between tigecycline and venetoclax in a preclinical model of MYC/BCL2 double-hit B cell lymphoma. Sci Transl Med 2018; 10:10/426/eaan8723. [DOI: 10.1126/scitranslmed.aan8723] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Revised: 11/08/2017] [Accepted: 12/28/2017] [Indexed: 01/10/2023]
Abstract
High-grade B cell lymphomas with concurrent activation of the MYC and BCL2 oncogenes, also known as double-hit lymphomas (DHL), show dismal prognosis with current therapies. MYC activation sensitizes cells to inhibition of mitochondrial translation by the antibiotic tigecycline, and treatment with this compound provides a therapeutic window in a mouse model of MYC-driven lymphoma. We now addressed the utility of this antibiotic for treatment of DHL. BCL2 activation in mouse Eμ-myc lymphomas antagonized tigecycline-induced cell death, which was specifically restored by combined treatment with the BCL2 inhibitor venetoclax. In line with these findings, tigecycline and two related antibiotics, tetracycline and doxycycline, synergized with venetoclax in killing human MYC/BCL2 DHL cells. Treatment of mice engrafted with either DHL cell lines or a patient-derived xenograft revealed strong antitumoral effects of the tigecycline/venetoclax combination, including long-term tumor eradication with one of the cell lines. This drug combination also had the potential to cooperate with rituximab, a component of current front-line regimens. Venetoclax and tigecycline are currently in the clinic with distinct indications: Our preclinical results warrant the repurposing of these drugs for combinatorial treatment of DHL.
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de Beauchamp L, Baquero P, Kuntz EM, Gottlieb E, Helgason GV. Auto-Commentary on: "Targeting mitochondrial oxidative phosphorylation eradicates therapy-resistant chronic myeloid leukemia stem cells". Mol Cell Oncol 2017; 5:e1403532. [PMID: 29404396 PMCID: PMC5791851 DOI: 10.1080/23723556.2017.1403532] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Accepted: 10/30/2017] [Indexed: 12/17/2022]
Abstract
We have recently uncovered an abnormal increase in mitochondrial oxidative metabolism in therapy-resistant chronic myeloid leukaemia stem cells (LSCs). By simultaneously disrupting mitochondrial respiration and inhibiting BCR-ABL kinase activity using the antibiotic tigecycline and imatinib respectively, we effectively eradicated LSCs and prevented disease relapse in pre-clinical animal models.
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Affiliation(s)
- Lucie de Beauchamp
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow UK
| | - Pablo Baquero
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow UK
| | - Elodie M. Kuntz
- Cancer Research UK, Beatson Institute, Garscube Estate, Switchback Road, Glasgow, UK
| | - Eyal Gottlieb
- Cancer Research UK, Beatson Institute, Garscube Estate, Switchback Road, Glasgow, UK
- Technion Integrated Cancer Center, Faculty of Medicine, Technion – Israel Institute of Technology, Haifa, Israel
| | - G. Vignir Helgason
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow UK
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Kavanagh S, Murphy T, Law A, Yehudai D, Ho JM, Chan S, Schimmer AD. Emerging therapies for acute myeloid leukemia: translating biology into the clinic. JCI Insight 2017; 2:95679. [PMID: 28931762 PMCID: PMC5621868 DOI: 10.1172/jci.insight.95679] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Acute myeloid leukemia (AML) is an aggressive hematological malignancy with a poor outcome; overall survival is approximately 35% at two years and some subgroups have a less than 5% two-year survival. Recently, significant improvements have been made in our understanding of AML biology and genetics. These fundamental discoveries are now being translated into new therapies for this disease. This review will discuss recent advances in AML biology and the emerging treatments that are arising from biological studies. Specifically, we will consider new therapies that target molecular mutations in AML and dysregulated pathways such as apoptosis and mitochondrial metabolism. We will also discuss recent advances in immune and cellular therapy for AML.
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49
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Rota SG, Roma A, Dude I, Ma C, Stevens R, MacEachern J, Graczyk J, Espiritu SMG, Rao PN, Minden MD, Kreinin E, Hess DA, Doxey AC, Spagnuolo PA. Estrogen Receptor β Is a Novel Target in Acute Myeloid Leukemia. Mol Cancer Ther 2017; 16:2618-2626. [DOI: 10.1158/1535-7163.mct-17-0292] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Revised: 07/11/2017] [Accepted: 08/16/2017] [Indexed: 11/16/2022]
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50
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Abstract
Mitochondria play fundamental roles in the regulation of life and death of eukaryotic cells. They mediate aerobic energy conversion through the oxidative phosphorylation (OXPHOS) system, and harbor and control the intrinsic pathway of apoptosis. As a descendant of a bacterial endosymbiont, mitochondria retain a vestige of their original genome (mtDNA), and its corresponding full gene expression machinery. Proteins encoded in the mtDNA, all components of the multimeric OXPHOS enzymes, are synthesized in specialized mitochondrial ribosomes (mitoribosomes). Mitoribosomes are therefore essential in the regulation of cellular respiration. Additionally, an increasing body of literature has been reporting an alternative role for several mitochondrial ribosomal proteins as apoptosis-inducing factors. No surprisingly, the expression of genes encoding for mitoribosomal proteins, mitoribosome assembly factors and mitochondrial translation factors is modified in numerous cancers, a trait that has been linked to tumorigenesis and metastasis. In this article, we will review the current knowledge regarding the dual function of mitoribosome components in protein synthesis and apoptosis and their association with cancer susceptibility and development. We will also highlight recent developments in targeting mitochondrial ribosomes for the treatment of cancer.
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