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1
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Cheney L, Barbaro JM, McDermott G, Berman JW. Antiretroviral Drugs Impact Autophagy: Opportunities for Drug Repurposing. FRONT BIOSCI-LANDMRK 2024; 29:242. [PMID: 39082334 PMCID: PMC11837255 DOI: 10.31083/j.fbl2907242] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 04/19/2024] [Accepted: 04/30/2024] [Indexed: 01/04/2025]
Abstract
Autophagy is an evolutionarily conserved process in which intracellular macromolecules are degraded in a lysosomal-dependent manner. It is central to cellular energy homeostasis and to quality control of intracellular components. A decline in autophagic activity is associated with aging, and contributes to the development of various age-associated pathologies, including cancer. There is an ongoing need to develop chemotherapeutic agents to improve morbidity and mortality for those diagnosed with cancer, as well as to decrease the cost of cancer care. Autophagic programs are altered in cancer cells to support survival in genetically and metabolically unstable environments, making autophagy an attractive target for new chemotherapy. Antiretroviral drugs, which have dramatically increased the life- and health spans of people with human immunodeficiency virus (HIV) (PWH), have offered promise in the treatment of cancer. One mechanism underlying the antineoplastic effects of antiretroviral drugs is the alteration of cancer cell autophagy that can potentiate cell death. Antiretroviral drugs could be repurposed into the cancer chemotherapy arsenal. A more complete understanding of the impact of antiretroviral drugs on autophagy is essential for effective repurposing. This review summarizes our knowledge of the effects of antiretroviral drugs on autophagy as potential adjunctive chemotherapeutic agents, and highlights gaps to be addressed to reposition antiretroviral drugs into the antineoplastic arsenal successfully.
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Affiliation(s)
- Laura Cheney
- Department of Medicine, Division of Infectious Diseases, Albert Einstein College of Medicine, Bronx, NY 10461, USA
- Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - John M. Barbaro
- Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | | | - Joan W. Berman
- Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
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Li T, Xiao P, Qiu D, Yang A, Chen Q, Lin J, Liu Y, Chen J, Zeng Z. NCX1/Ca 2+ promotes autophagy and decreases bortezomib activity in multiple myeloma through non-canonical NFκB signaling pathway. Cell Commun Signal 2024; 22:258. [PMID: 38711131 PMCID: PMC11075190 DOI: 10.1186/s12964-024-01628-4] [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: 12/19/2023] [Accepted: 04/21/2024] [Indexed: 05/08/2024] Open
Abstract
Although bortezomib (BTZ) is the cornerstone of anti-multiple myeloma (MM) therapy, the inevitable primary and secondary drug resistance still seriously affects the prognosis of patients. New treatment strategies are in need. Sodium-calcium exchanger 1 (NCX1) is a calcium-permeable ion transporter on the membrane, and our previous studies showed that low NCX1 confers inferior viability in MM cells and suppressed osteoclast differentiation. However, the effect of NCX1 on BTZ sensitivity of MM and its possible mechanism remain unclear. In this study, we investigated the effect of NCX1 on BTZ sensitivity in MM, focusing on cellular processes of autophagy and cell viability. Our results provide evidence that NCX1 expression correlates with MM disease progression and low NCX1 expression increases BTZ sensitivity. NCX1/Ca2+ triggered autophagic flux through non-canonical NFκB pathway in MM cells, leading to attenuated the sensitivity of BTZ. Knockdown or inhibition of NCX1 could potentiate the anti-MM activity of BTZ in vitro and vivo, and inhibition of autophagy sensitized NCX1-overexpressing MM cells to BTZ. In general, this work implicates NCX1 as a potential therapeutic target in MM with BTZ resistance and provides novel mechanistic insights into its vital role in combating BTZ resistance.
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Affiliation(s)
- Tingting Li
- Department of Hematology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Laboratory Medicine, Fuzhou, China
- Department of Hematology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Pingping Xiao
- Department of Hematology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Dongbiao Qiu
- Department of Blood Transfusion, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Apeng Yang
- Department of Hematology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Laboratory Medicine, Fuzhou, China
- Department of Hematology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Qingjiao Chen
- Department of Hematology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Laboratory Medicine, Fuzhou, China
- Department of Hematology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Junfang Lin
- Department of Hematology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Laboratory Medicine, Fuzhou, China
- Department of Hematology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Yao Liu
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China.
| | - Junmin Chen
- Department of Hematology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.
- Fujian Key Laboratory of Laboratory Medicine, Fuzhou, China.
- Department of Hematology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
| | - Zhiyong Zeng
- Department of Hematology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.
- Fujian Key Laboratory of Laboratory Medicine, Fuzhou, China.
- Department of Hematology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
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3
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Clavero E, Sanchez-Maldonado JM, Macauda A, Ter Horst R, Sampaio-Marques B, Jurczyszyn A, Clay-Gilmour A, Stein A, Hildebrandt MAT, Weinhold N, Buda G, García-Sanz R, Tomczak W, Vogel U, Jerez A, Zawirska D, Wątek M, Hofmann JN, Landi S, Spinelli JJ, Butrym A, Kumar A, Martínez-López J, Galimberti S, Sarasquete ME, Subocz E, Iskierka-Jażdżewska E, Giles GG, Rybicka-Ramos M, Kruszewski M, Abildgaard N, Verdejo FG, Sánchez Rovira P, da Silva Filho MI, Kadar K, Razny M, Cozen W, Pelosini M, Jurado M, Bhatti P, Dudzinski M, Druzd-Sitek A, Orciuolo E, Li Y, Norman AD, Zaucha JM, Reis RM, Markiewicz M, Rodríguez Sevilla JJ, Andersen V, Jamroziak K, Hemminki K, Berndt SI, Rajkumar V, Mazur G, Kumar SK, Ludovico P, Nagler A, Chanock SJ, Dumontet C, Machiela MJ, Varkonyi J, Camp NJ, Ziv E, Vangsted AJ, Brown EE, Campa D, Vachon CM, Netea MG, Canzian F, Försti A, Sainz J. Polymorphisms within Autophagy-Related Genes as Susceptibility Biomarkers for Multiple Myeloma: A Meta-Analysis of Three Large Cohorts and Functional Characterization. Int J Mol Sci 2023; 24:8500. [PMID: 37239846 PMCID: PMC10218542 DOI: 10.3390/ijms24108500] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Revised: 04/10/2023] [Accepted: 04/21/2023] [Indexed: 05/28/2023] Open
Abstract
Multiple myeloma (MM) arises following malignant proliferation of plasma cells in the bone marrow, that secrete high amounts of specific monoclonal immunoglobulins or light chains, resulting in the massive production of unfolded or misfolded proteins. Autophagy can have a dual role in tumorigenesis, by eliminating these abnormal proteins to avoid cancer development, but also ensuring MM cell survival and promoting resistance to treatments. To date no studies have determined the impact of genetic variation in autophagy-related genes on MM risk. We performed meta-analysis of germline genetic data on 234 autophagy-related genes from three independent study populations including 13,387 subjects of European ancestry (6863 MM patients and 6524 controls) and examined correlations of statistically significant single nucleotide polymorphisms (SNPs; p < 1 × 10-9) with immune responses in whole blood, peripheral blood mononuclear cells (PBMCs), and monocyte-derived macrophages (MDM) from a large population of healthy donors from the Human Functional Genomic Project (HFGP). We identified SNPs in six loci, CD46, IKBKE, PARK2, ULK4, ATG5, and CDKN2A associated with MM risk (p = 4.47 × 10-4-5.79 × 10-14). Mechanistically, we found that the ULK4rs6599175 SNP correlated with circulating concentrations of vitamin D3 (p = 4.0 × 10-4), whereas the IKBKErs17433804 SNP correlated with the number of transitional CD24+CD38+ B cells (p = 4.8 × 10-4) and circulating serum concentrations of Monocyte Chemoattractant Protein (MCP)-2 (p = 3.6 × 10-4). We also found that the CD46rs1142469 SNP correlated with numbers of CD19+ B cells, CD19+CD3- B cells, CD5+IgD- cells, IgM- cells, IgD-IgM- cells, and CD4-CD8- PBMCs (p = 4.9 × 10-4-8.6 × 10-4) and circulating concentrations of interleukin (IL)-20 (p = 0.00082). Finally, we observed that the CDKN2Ars2811710 SNP correlated with levels of CD4+EMCD45RO+CD27- cells (p = 9.3 × 10-4). These results suggest that genetic variants within these six loci influence MM risk through the modulation of specific subsets of immune cells, as well as vitamin D3-, MCP-2-, and IL20-dependent pathways.
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Affiliation(s)
- Esther Clavero
- Hematology Department, Virgen de las Nieves University Hospital, 18012 Granada, Spain; (E.C.); (M.J.)
| | - José Manuel Sanchez-Maldonado
- Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, PTS, 18016 Granada, Spain;
- Instituto de Investigación Biosanataria IBs, Granada, 18014 Granada, Spain
| | - Angelica Macauda
- Genomic Epidemiology Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; (A.M.); (A.S.); (F.C.)
| | - Rob Ter Horst
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands; (R.T.H.); (Y.L.); (M.G.N.)
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria
| | - Belém Sampaio-Marques
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal; (B.S.-M.); (P.L.)
| | - Artur Jurczyszyn
- Plasma Cell Dyscrasias Center, Department of Hematology, Jagiellonian University Medical College, 31-066 Kraków, Poland;
| | - Alyssa Clay-Gilmour
- Department of Biostatistics and Epidemiology, Arnold School of Public Health, University of South Carolina, Greenville, SC 29208, USA;
- Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55902, USA; (A.D.N.); (C.M.V.)
| | - Angelika Stein
- Genomic Epidemiology Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; (A.M.); (A.S.); (F.C.)
| | - Michelle A. T. Hildebrandt
- Department of Lymphoma–Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Niels Weinhold
- Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA;
- Department of Internal Medicine V, University of Heidelberg, 69120 Heidelberg, Germany
| | - Gabriele Buda
- Haematology Unit, Department of Clinical and Experimental Medicine, University of Pisa/AOUP, 56126 Pisa, Italy; (G.B.); (S.G.); (E.O.)
| | - Ramón García-Sanz
- Diagnostic Laboratory Unit in Hematology, University Hospital of Salamanca, IBSAL, CIBERONC, Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), 37007 Salamanca, Spain; (R.G.-S.); (M.E.S.)
| | - Waldemar Tomczak
- Department of Hematooncology and Bone Marrow Transplantation, Medical University of Lublin, 20-059 Lublin, Poland;
| | - Ulla Vogel
- National Research Centre for the Working Environment, DK-2100 Copenhagen, Denmark;
| | - Andrés Jerez
- Department of Hematology, Experimental Hematology Unit, Vall d’Hebron Institute of Oncology (VHIO), University Hospital Vall d’Hebron, 08035 Barcelona, Spain;
| | - Daria Zawirska
- Department of Hematology, University Hospital, 30-688 Kraków, Poland;
| | - Marzena Wątek
- Holycross Medical Oncology Center, 25-735 Kielce, Poland;
- Institute of Hematology and Transfusion Medicine, 00-791 Warsaw, Poland
| | - Jonathan N. Hofmann
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; (J.N.H.); (S.I.B.); (S.J.C.); (M.J.M.)
| | - Stefano Landi
- Department of Biology, University of Pisa, 56126 Pisa, Italy; (S.L.); (D.C.)
| | - John J. Spinelli
- Division of Population Oncology, BC Cancer, Vancouver, BC V5Z 4E6, Canada;
- School of Population and Public Health, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
| | - Aleksandra Butrym
- Department of Cancer Prevention and Therapy, Wroclaw Medical University, 50-367 Wroclaw, Poland;
- Alfred Sokolowski Specialist Hospital in Walbrzych Oncology Support Centre for Clinical Trials, 58-309 Walbrzych, Poland
| | - Abhishek Kumar
- Institute of Bioinformatics, International Technology Park, Bangalore 560066, India;
- Manipal Academy of Higher Education (MAHE), Manipal 576104, India
| | | | - Sara Galimberti
- Haematology Unit, Department of Clinical and Experimental Medicine, University of Pisa/AOUP, 56126 Pisa, Italy; (G.B.); (S.G.); (E.O.)
| | - María Eugenia Sarasquete
- Diagnostic Laboratory Unit in Hematology, University Hospital of Salamanca, IBSAL, CIBERONC, Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), 37007 Salamanca, Spain; (R.G.-S.); (M.E.S.)
| | - Edyta Subocz
- Department of Hematology, Military Institute of Medicine, 04-141 Warsaw, Poland;
| | | | - Graham G. Giles
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC 3004, Australia;
- Centre for Epidemiology and Biostatistics, School of Population and Global Health, The University of Melbourne, Melbourne, VIC 3010, Australia
- Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC 3168, Australia
| | - Malwina Rybicka-Ramos
- Department of Hematology, Specialist Hospital No. 1 in Bytom, Academy of Silesia, Faculty of Medicine, 40-055 Katowice, Poland;
| | - Marcin Kruszewski
- Department of Hematology, University Hospital No. 2, 85-168 Bydgoszcz, Poland;
| | - Niels Abildgaard
- Department of Hematology, Odense University Hospital, DK-5000 Odense, Denmark;
| | - Francisco García Verdejo
- Department of Medical Oncology, Complejo Hospitalario de Jaén, 23007 Jaén, Spain; (F.G.V.); (P.S.R.)
| | - Pedro Sánchez Rovira
- Department of Medical Oncology, Complejo Hospitalario de Jaén, 23007 Jaén, Spain; (F.G.V.); (P.S.R.)
| | - Miguel Inacio da Silva Filho
- Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, D-69120 Heidelberg, Germany;
| | | | - Małgorzata Razny
- Department of Hematology, Rydygier Hospital, 31-826 Cracow, Poland;
| | - Wendy Cozen
- Division of Hematology/Oncology, Department of Medicine, School of Medicine, Department of Pathology, School of Medicine, Susan and Henry Samueli College of Health Sciences, Chao Family Comprehensive Cancer Center, University of California at Irvine, Irvine, CA 92697, USA;
| | - Matteo Pelosini
- U.O. Dipartimento di Ematologia, Azienda USL Toscana Nord Ovest, 57124 Livorno, Italy;
| | - Manuel Jurado
- Hematology Department, Virgen de las Nieves University Hospital, 18012 Granada, Spain; (E.C.); (M.J.)
- Instituto de Investigación Biosanataria IBs, Granada, 18014 Granada, Spain
- Department of Medicine, University of Granada, 18012 Granada, Spain
| | - Parveen Bhatti
- Cancer Control Research, BC Cancer, Vancouver, BC V5Z 4E6, Canada;
- Program in Epidemiology, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
| | - Marek Dudzinski
- Department of Hematology, Institute of Medical Sciences, College of Medical Sciences, University of Rzeszow, 35-310 Rzeszow, Poland; (M.D.); (M.M.)
| | - Agnieszka Druzd-Sitek
- Department of Lymphoproliferative Diseases, Maria Skłodowska Curie National Research Institute of Oncology, 02-781 Warsaw, Poland;
| | - Enrico Orciuolo
- Haematology Unit, Department of Clinical and Experimental Medicine, University of Pisa/AOUP, 56126 Pisa, Italy; (G.B.); (S.G.); (E.O.)
| | - Yang Li
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands; (R.T.H.); (Y.L.); (M.G.N.)
- Centre for Individualised Infection Medicine (CiiM) & TWINCORE, Joint Ventures between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH), 30625 Hannover, Germany
| | - Aaron D. Norman
- Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55902, USA; (A.D.N.); (C.M.V.)
- Genetic Epidemiology and Risk Assessment Program, Mayo Clinic Comprehensive Cancer Center, Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55902, USA
| | - Jan Maciej Zaucha
- Department of Hematology and Transplantology, Medical University of Gdansk, 80-210 Gdansk, Poland;
| | - Rui Manuel Reis
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, 4710-057 Braga, Portugal and ICVS/3B’s-PT Government Associate Laboratory, 4710-057 Braga/Guimarães, Portugal;
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos 14784-400, Brazil
| | - Miroslaw Markiewicz
- Department of Hematology, Institute of Medical Sciences, College of Medical Sciences, University of Rzeszow, 35-310 Rzeszow, Poland; (M.D.); (M.M.)
| | | | - Vibeke Andersen
- Molecular Diagnostics and Clinical Research Unit, Institute of Regional Health Research, University Hospital of Southern Denmark, DK-6200 Aabenraa, Denmark;
| | - Krzysztof Jamroziak
- Department of Hematology, Transplantology and Internal Medicine, Medical University of Warsaw, 02-097 Warsaw, Poland;
| | - Kari Hemminki
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany;
- Faculty of Medicine and Biomedical Center in Pilsen, Charles University in Prague, 30605 Pilsen, Czech Republic
| | - Sonja I. Berndt
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; (J.N.H.); (S.I.B.); (S.J.C.); (M.J.M.)
| | - Vicent Rajkumar
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN 55902, USA; (V.R.); (S.K.K.)
| | - Grzegorz Mazur
- Department of Internal Diseases, Occupational Medicine, Hypertension and Clinical Oncology, Wroclaw Medical University, 50-368 Wroclaw, Poland;
| | - Shaji K. Kumar
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN 55902, USA; (V.R.); (S.K.K.)
| | - Paula Ludovico
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal; (B.S.-M.); (P.L.)
| | - Arnon Nagler
- Hematology Division, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel;
| | - Stephen J. Chanock
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; (J.N.H.); (S.I.B.); (S.J.C.); (M.J.M.)
| | - Charles Dumontet
- UMR INSERM 1052/CNRS 5286, University of Lyon, Hospices Civils de Lyon, 69008 Lyon, France;
| | - Mitchell J. Machiela
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; (J.N.H.); (S.I.B.); (S.J.C.); (M.J.M.)
| | | | - Nicola J. Camp
- Division of Hematology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA;
| | - Elad Ziv
- Department of Medicine, University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94143, USA;
| | - Annette Juul Vangsted
- Department of Hematology, Rigshospitalet, Copenhagen University, DK-2100 Copenhagen, Denmark;
| | - Elizabeth E. Brown
- Department of Pathology, Heersink School of Medicine, The University of Alabama at Birmingham, Birmingham, AL 35294, USA;
| | - Daniele Campa
- Department of Biology, University of Pisa, 56126 Pisa, Italy; (S.L.); (D.C.)
| | - Celine M. Vachon
- Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55902, USA; (A.D.N.); (C.M.V.)
| | - Mihai G. Netea
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands; (R.T.H.); (Y.L.); (M.G.N.)
- Department for Immunology & Metabolism, Life and Medical Sciences Institute (LIMES), University of Bonn, 53115 Bonn, Germany
| | - Federico Canzian
- Genomic Epidemiology Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; (A.M.); (A.S.); (F.C.)
| | - Asta Försti
- Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), 69120 Heidelberg, Germany;
- Hopp Children’s Cancer Center (KiTZ), 69120 Heidelberg, Germany
| | - Juan Sainz
- Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, PTS, 18016 Granada, Spain;
- Instituto de Investigación Biosanataria IBs, Granada, 18014 Granada, Spain
- Department of Biochemistry and Molecular Biology I, University of Granada, 18071 Granada, Spain
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4
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Hsieh CH, Huang YW, Tsai TF. Oral Conventional Synthetic Disease-Modifying Antirheumatic Drugs with Antineoplastic Potential: a Review. Dermatol Ther (Heidelb) 2022; 12:835-860. [PMID: 35381976 PMCID: PMC9021342 DOI: 10.1007/s13555-022-00713-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Indexed: 01/17/2023] Open
Abstract
There is an increasing trend of malignancy worldwide. Disease-modifying antirheumatic drugs (DMARDs) are the cornerstones for the treatment of immune-mediated inflammatory diseases (IMIDs), but risk of malignancy is a major concern for patients receiving DMARDs. In addition, many IMIDs already carry higher background risks of neoplasms. Recently, the black box warning of malignancies has been added for Janus kinase inhibitors. Also, the use of biologic DMARDs in patients with established malignancies is usually discouraged owing to exclusion of such patients in pivotal studies and, hence, lack of evidence. In contrast, some conventional synthetic DMARDs (csDMARDs) have been reported to show antineoplastic properties and can be beneficial for patients with cancer. Among the csDMARDs, chloroquine and hydroxychloroquine have been the most extensively studied, and methotrexate is an established chemotherapeutic agent. Even cyclosporine A, a well-known drug associated with cancer risk, can potentiate the effect of some chemotherapeutic agents. We review the possible mechanisms behind and clinical evidence of the antineoplastic activities of csDMARDs, including chloroquine and hydroxychloroquine, cyclosporine, leflunomide, mycophenolate mofetil, mycophenolic acid, methotrexate, sulfasalazine, and thiopurines. This knowledge may guide physicians in the choice of csDMARDs for patients with concurrent IMIDs and malignancies.
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Affiliation(s)
- Cho-Hsun Hsieh
- Department of Medical Education, National Taiwan University Hospital, Taipei, Taiwan
| | - Yi-Wei Huang
- Department of Dermatology, National Taiwan University Hospital, 7 Chung Shan S Rd, Taipei, 10048, Taiwan
| | - Tsen-Fang Tsai
- Department of Dermatology, National Taiwan University Hospital, 7 Chung Shan S Rd, Taipei, 10048, Taiwan. .,Department of Dermatology, National Taiwan University Hospital & National Taiwan University College of Medicine, Taipei, Taiwan.
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5
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Han Q, Bai H, Xu Y, Zhou M, Zhou H, Dong X, Chen B. Solamargine induces autophagy-mediated apoptosis and enhances bortezomib activity in multiple myeloma. Clin Exp Pharmacol Physiol 2022; 49:674-685. [PMID: 35294057 PMCID: PMC9310729 DOI: 10.1111/1440-1681.13643] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 03/04/2022] [Accepted: 03/09/2022] [Indexed: 11/29/2022]
Abstract
Multiple myeloma (MM) is an incurable plasma cell malignancy with a poor survival rate. Conventional chemotherapeutic agent‐induced adverse events, including toxicity, neuropathy or drug resistance, significantly decrease the patients' quality of life and can even lead to interruption of treatment. Therefore, novel therapeutic drugs and strategies are urgently needed to improve MM therapy and patient outcomes. Here, we show that solamargine (SM), a steroidal alkaloid glycoside isolated from a Chinese herb Solanum nigrum L., exhibits promising anti‐MM activity. In particular, SM suppressed the viability of MM cell lines (ARP‐1 and NCI‐H929) in a concentration‐ and time‐dependent manner, inducing apoptosis in these cells. RNA‐seq analysis showed that treatment with SM led to the upregulation of genes associated with cell death and autophagy in H929 cells. Further, we found that treatment with SM activated autophagy in the MM cells, as incubation with 3‐Methyladenine, an inhibitor of autophagy, significantly alleviated SM‐triggered apoptosis and inhibition of viability in MM cells. Interestingly, we also observed a synergistic effect between SM and bortezomib (BTZ), a common chemotherapeutic agent for MM, in both MM cells and human bone marrow CD138+ primary myeloma cells. We also confirmed the single‐agent efficacy of SM and the synergistic effects between SM and BTZ in an MM xenograft mouse model. Collectively, these findings indicate that SM exerts an anti‐MM effect, at least in part, by activating cell autophagy and reveal that SM alone or in combination with BTZ is a potential therapeutic strategy for treating MM.
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Affiliation(s)
- Qiaoyan Han
- Department of Hematology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.,Department of Hematology, Jingjiang People's Hospital, Jingjiang, Jiangsu, China
| | - Hua Bai
- Department of Hematology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Yong Xu
- Department of Hematology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Min Zhou
- Department of Hematology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - He Zhou
- Department of Hematology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Xiaoqing Dong
- Department of Hematology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Bing Chen
- Department of Hematology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
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Abstract
INTRODUCTION Calpain-1 and calpain-2 are prototypical classical isoforms of the calpain family of calcium-activated cysteine proteases. Their substrate proteins participate in a wide range of cellular processes, including transcription, survival, proliferation, apoptosis, migration, and invasion. Dysregulated calpain activity has been implicated in tumorigenesis, suggesting that calpains may be promising therapeutic targets. AREAS COVERED This review covers clinical and basic research studies implicating calpain-1 and calpain-2 expression and activity in tumorigenesis and metastasis. We highlight isoform specific functions and provide an overview of substrates and cancer-related signalling pathways affected by calpain-mediated proteolytic cleavage. We also discuss efforts to develop clinically relevant calpain specific inhibitors and spotlight the challenges facing inhibitor development. EXPERT OPINION Rationale for targeting calpain-1 and calpain-2 in cancer is supported by pre-clinical and clinical studies demonstrating that calpain inhibition has the potential to attenuate carcinogenesis and block metastasis of aggressive tumors. The wide range of substrates and cleavage products, paired with inconsistencies in model systems, underscores the need for more complete understanding of physiological substrates and how calpain cleavage alters their function in cellular processes. The development of isoform specific calpain inhibitors remains an important goal with therapeutic potential in cancer and other diseases.
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Affiliation(s)
- Ivan Shapovalov
- Department of Pathology and Molecular Medicine, Queen's University, Division of Cancer Biology and Genetics, Queen's Cancer Research Institute, 10 Stuart Street, Botterell Hall, Room A309, Kingston, Ontario, K7L 3N6 Canada
| | - Danielle Harper
- Department of Pathology and Molecular Medicine, Queen's University, Division of Cancer Biology and Genetics, Queen's Cancer Research Institute, 10 Stuart Street, Botterell Hall, Room A309, Kingston, Ontario, K7L 3N6 Canada
| | - Peter A Greer
- Department of Pathology and Molecular Medicine, Queen's University, Division of Cancer Biology and Genetics, Queen's Cancer Research Institute, 10 Stuart Street, Botterell Hall, Room A309, Kingston, Ontario, K7L 3N6 Canada
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Tian FQ, Chen ZR, Zhu W, Tang MQ, Li JH, Zhang XC, Jiang J, Cheng XH. Inhibition of hsa_circ_0003489 shifts balance from autophagy to apoptosis and sensitizes multiple myeloma cells to bortezomib via miR-874-3p/HDAC1 axis. J Gene Med 2021; 23:e3329. [PMID: 33625798 DOI: 10.1002/jgm.3329] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 02/03/2021] [Accepted: 02/03/2021] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND Circular RNAs (circRNAs) crucially regulate tumor progression. In this study, we examined the functional roles and mechanisms of hsa_circ_0003489 in multiple myeloma (MM). METHODS Upon altering the expressions of hsa_circ_0003489, miR-874-3p, and/or histone deacetylase 1 (HDAC1) in MM1.R cells and treating them with bortezomib (BTZ), cell viability was examined by CCK-8 assay; cell proliferation by Ki-67 immunofluorescence; apoptosis by TUNEL staining, flow cytometry, and western blot; and autophagy by electron microscopy and western blot. The interaction between hsa_circ_0003489 and miR-874-3p as well as that between miR-874-3p and HDAC1 was examined by expressional analysis, dual luciferase reporter assay, and RNA immunoprecipitation. The in vivo impacts of hsa_circ_0003489 on MM growth and sensitivity to BTZ were examined using an MM xenograft mouse model. RESULTS Knocking down hsa_circ_0003489 significantly inhibited the viability, cell proliferation, and autophagy, while promoting the apoptosis of MM cells in vitro and MM xenograft in vivo. Suppressing hsa_circ_0003489 also further boosted the cytotoxic effects of BTZ in MM cells and reversed its promoting effect on autophagy. Mechanically, hsa_circ_0003489 acted as a sponge of miR-874-3p and positively regulated the expression of miR-874-3p target, HDAC1. MiR-874-3p and HDAC1 essentially mediated the effects of hsa_circ_0003489 on cell viability, proliferation, apoptosis, and autophagy. CONCLUSION The hsa_circ_0003489/miR-874-3p/HDAC1 axis critically regulates the balance between apoptosis and autophagy. Silencing hsa_circ_0003489 sensitizes MM cells to BTZ by inhibiting autophagy and thus may boost the therapeutic effects of BTZ.
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Affiliation(s)
- Fa-Qing Tian
- Department of Hematology, Longgang District People's Hospital of Shenzhen, Shenzhen, Guangdong Province, China
| | - Zi-Ren Chen
- Department of Hematological Oncology, Shenzhen University General Hospital, Shenzhen, Guangdong Province, China
| | - Wei Zhu
- Department of Pathology, School of Basic Medicine, Guangdong Medical University, Dongguan, Guangdong Province, China
| | - Mei-Qin Tang
- Department of Hematology, Longgang District People's Hospital of Shenzhen, Shenzhen, Guangdong Province, China
| | - Ju-Heng Li
- Department of Hematology, Longgang District People's Hospital of Shenzhen, Shenzhen, Guangdong Province, China
| | - Xu-Chang Zhang
- Department of Hematology, Longgang District People's Hospital of Shenzhen, Shenzhen, Guangdong Province, China
| | - Jian Jiang
- Department of Hematology, Longgang District People's Hospital of Shenzhen, Shenzhen, Guangdong Province, China
| | - Xiao-Hui Cheng
- Department of Hematology, Longgang District People's Hospital of Shenzhen, Shenzhen, Guangdong Province, China
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8
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The Anti-Cancer Properties of the HIV Protease Inhibitor Nelfinavir. Cancers (Basel) 2020; 12:cancers12113437. [PMID: 33228205 PMCID: PMC7699465 DOI: 10.3390/cancers12113437] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Revised: 11/12/2020] [Accepted: 11/16/2020] [Indexed: 12/13/2022] Open
Abstract
Simple Summary To this day, cancer remains a medical challenge despite the development of cutting-edge diagnostic methods and therapeutics. Thus, there is a continual demand for improved therapeutic options for managing cancer patients. However, novel drug development requires decade-long time commitment and financial investments. Repurposing approved and market-available drugs for cancer therapy is a way to reduce cost and the timeframe for developing new therapies. Nelfinavir is an anti-infective agent that has extensively been used to treat acquired immunodeficiency syndrome (AIDS) in adult and pediatric patients. In addition to its anti-infective properties, nelfinavir has demonstrated potent off-target anti-cancer effects, suggesting that it could be a suitable candidate for drug repurposing for cancer. In this review, we systematically compiled the therapeutic benefits of nelfinavir against cancer as a single drug or in combination with chemoradiotherapy, and outlined the possible underlying mechanistic pathways contributing to the anti-cancer effects. Abstract Traditional cancer treatments may lose efficacy following the emergence of novel mutations or the development of chemoradiotherapy resistance. Late diagnosis, high-cost of treatment, and the requirement of highly efficient infrastructure to dispense cancer therapies hinder the availability of adequate treatment in low-income and resource-limited settings. Repositioning approved drugs as cancer therapeutics may reduce the cost and timeline for novel drug development and expedite the availability of newer, efficacious options for patients in need. Nelfinavir is a human immunodeficiency virus (HIV) protease inhibitor that has been approved and is extensively used as an anti-infective agent to treat acquired immunodeficiency syndrome (AIDS). Yet nelfinavir has also shown anti-cancer effects in in vitro and in vivo studies. The anti-cancer mechanism of nelfinavir includes modulation of different cellular conditions, such as unfolded protein response, cell cycle, apoptosis, autophagy, the proteasome pathway, oxidative stress, the tumor microenvironment, and multidrug efflux pumps. Multiple clinical trials indicated tolerable and reversible toxicities during nelfinavir treatment in cancer patients, either as a monotherapy or in combination with chemo- or radiotherapy. Since orally available nelfinavir has been a safe drug of choice for both adult and pediatric HIV-infected patients for over two decades, exploiting its anti-cancer off-target effects will enable fast-tracking this newer option into the existing repertoire of cancer chemotherapeutics.
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[Cdc37 Contributes to bortezomib resistance in multiple myeloma via autophagy]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2020; 41:583-588. [PMID: 32810966 PMCID: PMC7449775 DOI: 10.3760/cma.j.issn.0253-2727.2020.07.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
目的 探索细胞分裂周期蛋白37（Cdc37）通过调控细胞自噬参与多发性骨髓瘤（MM）对硼替佐米（BTZ）耐药的机制，为MM的治疗提供新的思路。 方法 应用实时荧光定量PCR（qRT-PCR）和Western blot（WB）技术测定BTZ耐药细胞株ANBL-6.BR中Cdc37及自噬相关基因LC3b的表达水平。采用慢病毒转染技术上调ANBL-6.BR细胞中Cdc37的表达水平，WB技术检测LC3b的表达，流式细胞术检测BTZ诱导的细胞凋亡。采用shRNA干扰技术下调MM细胞株NCI-H929中Cdc37的表达水平，CCK-8法进一步验证Cdc37低表达与BTZ耐药相关，WB技术检测AKT/mTOR信号通路及自噬相关蛋白的表达变化；通过流式细胞术检测自噬抑制剂氯喹（CQ）是否可以增加耐药MM细胞对BTZ的敏感性。 结果 Cdc37在BTZ耐药细胞株ANBL-6.BR中低表达，而自噬相关基因LC3b在耐药株中高表达。上调ANBL-6.BR细胞中Cdc37的表达水平可抑制LC3b的表达，且增加了MM细胞对BTZ的敏感性。在MM细胞系NCI-H929中抑制Cdc37的表达导致BTZ耐药，同时引起自噬水平升高。而自噬抑制剂CQ可逆转Cdc37下调所引起的BTZ耐药。 结论 Cdc37可能通过调控细胞自噬参与MM细胞对BTZ的耐药过程。
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10
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Bortezomib Treatment Modulates Autophagy in Multiple Myeloma. J Clin Med 2020; 9:jcm9020552. [PMID: 32085480 PMCID: PMC7073518 DOI: 10.3390/jcm9020552] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 02/12/2020] [Accepted: 02/13/2020] [Indexed: 12/11/2022] Open
Abstract
Although the introduction of bortezomib as a therapeutic strategy has improved the overall survival of multiple myeloma (MM) patients, 15–20% of high-risk patients do not respond to bortezomib over time or become resistant to treatment. Therefore, the development of new therapeutic strategies, such as combination therapies, is urgently needed. Methods: Given that bortezomib resistance may be mediated by activation of the autophagy pathway as an alternative mechanism of protein degradation, and that an enormous amounts of misfolded protein is generated in myeloma plasma cells (PCs), we investigated the effect of the simultaneous inhibition of proteasome by bortezomib and autophagy by hydroxychloroquine (HCQ) treatment on PCs and endothelial cells (ECs) isolated from patients with monoclonal gammopathy of undetermined significance (MGUS) and MM. Results: We found that bortezomib combined with HCQ induces synergistic cytotoxicity in myeloma PCs whereas this effect is lost on ECs. Levels of microtubule-associated protein light chain beta (LC3B) and p62 are differentially modulated in PCs and ECs, with effects on cell viability and proliferation. Conclusions: Our results suggest that treatment with bortezomib and HCQ should be associated with an anti-angiogenic drug to prevent the pro-angiogenic effect of bortezomib, the proliferation of a small residual tumor PC clone, and thus the relapse.
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11
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Saavedra-García P, Martini F, Auner HW. Proteasome inhibition in multiple myeloma: lessons for other cancers. Am J Physiol Cell Physiol 2019; 318:C451-C462. [PMID: 31875696 DOI: 10.1152/ajpcell.00286.2019] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Cellular protein homeostasis (proteostasis) depends on the controlled degradation of proteins that are damaged or no longer required by the ubiquitin-proteasome system (UPS). The 26S proteasome is the principal executer of substrate-specific proteolysis in eukaryotic cells and regulates a myriad of cellular functions. Proteasome inhibitors were initially developed as chemical tools to study proteasomal function but rapidly became widely used anticancer drugs that are now used at all stages of treatment for the bone marrow cancer multiple myeloma (MM). Here, we review the mechanisms of action of proteasome inhibitors that underlie their preferential toxicity to MM cells, focusing on endoplasmic reticulum stress, depletion of amino acids, and effects on glucose and lipid metabolism. We also discuss mechanisms of resistance to proteasome inhibition such as autophagy and metabolic rewiring and what lessons we may learn from the success and failure of proteasome inhibition in MM for treating other cancers with proteostasis-targeting drugs.
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Affiliation(s)
- Paula Saavedra-García
- Cancer Cell Metabolism Group, Hugh and Josseline Langmuir Centre for Myeloma Research, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - Francesca Martini
- Department of Translational Research on New Technologies in Medicine and Surgery, Hematology Unit, Ospedale Santa Chiara, Pisa, Italy
| | - Holger W Auner
- Cancer Cell Metabolism Group, Hugh and Josseline Langmuir Centre for Myeloma Research, Faculty of Medicine, Imperial College London, London, United Kingdom
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12
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Cloos J, Roeten MS, Franke NE, van Meerloo J, Zweegman S, Kaspers GJ, Jansen G. (Immuno)proteasomes as therapeutic target in acute leukemia. Cancer Metastasis Rev 2018; 36:599-615. [PMID: 29071527 PMCID: PMC5721123 DOI: 10.1007/s10555-017-9699-4] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The clinical efficacy of proteasome inhibitors in the treatment of multiple myeloma has encouraged application of proteasome inhibitor containing therapeutic interventions in (pediatric) acute leukemia. Here, we summarize the positioning of bortezomib, as first-generation proteasome inhibitor, and second-generation proteasome inhibitors in leukemia treatment from a preclinical and clinical perspective. Potential markers for proteasome inhibitor sensitivity and/or resistance emerging from leukemia cell line models and clinical sample studies will be discussed focusing on the role of immunoproteasome and constitutive proteasome (subunit) expression, PSMB5 mutations, and alternative mechanisms of overcoming proteolytic stress.
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Affiliation(s)
- Jacqueline Cloos
- Departments of Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, The Netherlands.
- Departments of Hematology, VU University Medical Center, Amsterdam, The Netherlands.
| | - Margot Sf Roeten
- Departments of Hematology, VU University Medical Center, Amsterdam, The Netherlands
| | - Niels E Franke
- Departments of Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, The Netherlands
| | - Johan van Meerloo
- Departments of Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, The Netherlands
- Departments of Hematology, VU University Medical Center, Amsterdam, The Netherlands
| | - Sonja Zweegman
- Departments of Hematology, VU University Medical Center, Amsterdam, The Netherlands
| | - Gertjan Jl Kaspers
- Departments of Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, The Netherlands
- Princess Màxima Center, Utrecht, The Netherlands
| | - Gerrit Jansen
- Amsterdam Rheumatology and Immunology Center, VU University Medical Center, Amsterdam, The Netherlands
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13
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Nikesitch N, Lee JM, Ling S, Roberts TL. Endoplasmic reticulum stress in the development of multiple myeloma and drug resistance. Clin Transl Immunology 2018; 7:e1007. [PMID: 29484184 PMCID: PMC5822402 DOI: 10.1002/cti2.1007] [Citation(s) in RCA: 72] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2017] [Revised: 12/17/2017] [Accepted: 12/21/2017] [Indexed: 12/13/2022] Open
Abstract
Multiple myeloma (MM) is a haematological malignancy of mature antibody‐secreting plasma cells. Currently, MM is incurable, but advances in drug treatments have increased patient lifespan. One of the characteristics of MM is the excessive production of monoclonal immunoglobulin (also referred to as paraprotein). This high level of protein production induces endoplasmic reticulum (ER) stress, and proteasomal degradation of the paraprotein is required to avoid ER stress‐induced cell death. Consequently, proteasomal inhibitors such as bortezomib have been particularly effective therapies. Unfortunately development of resistance to bortezomib is common. In this review, we address how control of endoplasmic reticulum stress is important in the development of MM and how the unfolded protein response and its associated stress response pathways are involved in the development of bortezomib resistance.
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Affiliation(s)
- Nicholas Nikesitch
- Ingham Institute for Applied Medical Research and School of Medicine Western Sydney University Liverpool NSW Australia
| | - James M Lee
- Ingham Institute for Applied Medical Research and School of Medicine Western Sydney University Liverpool NSW Australia
| | - Silvia Ling
- Ingham Institute for Applied Medical Research and School of Medicine Western Sydney University Liverpool NSW Australia.,Department of Haematology Sydney South West Pathology Service NSW Pathology Liverpool Hospital Liverpool NSW Australia.,School of Medicine SWS Clinical School University of New South Wales Kensington NSW Australia
| | - Tara Laurine Roberts
- Ingham Institute for Applied Medical Research and School of Medicine Western Sydney University Liverpool NSW Australia.,School of Medicine SWS Clinical School University of New South Wales Kensington NSW Australia.,Centre for Clinical Research University of Queensland Herston Qld Australia
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14
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Targeting autophagy in multiple myeloma. Leuk Res 2017; 59:97-104. [PMID: 28599191 DOI: 10.1016/j.leukres.2017.06.002] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Revised: 05/24/2017] [Accepted: 06/01/2017] [Indexed: 02/06/2023]
Abstract
Autophagy plays an important role in plasma cell ontogeny and in the pathophysiology of multiple myeloma. Autophagy is usually considered a pro-survival mechanism, and cooperates with the ubiquitin proteasome system in maintaining the homeostasis of myeloma cells by degrading excessive and misfolded proteins for energy recycling. Therefore, the inhibition of autophagy could effectively induce death in myeloma cells, and could synergize with proteasome inhibitors. However, the excessive activation of autophagy could also lead to the extreme degradation of the organelles that induce autophagic cell death. Hence, the activation of autophagic cell death might also represent a promising approach for treating myeloma. Recent studies have demonstrated that autophagy also mediates drug resistance in myeloma cells and the complications of myeloma, while the inhibition of autophagy may reverse the response to drugs. In this study, we have mainly reviewed recent research on autophagy in relationship to the therapeutic effect, the reversal of drug resistance, and the mediation of complications.
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15
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Marcassa E, Raimondi M, Anwar T, Eskelinen EL, Myers MP, Triolo G, Schneider C, Demarchi F. Calpain mobilizes Atg9/Bif-1 vesicles from Golgi stacks upon autophagy induction by thapsigargin. Biol Open 2017; 6:551-562. [PMID: 28302665 PMCID: PMC5450315 DOI: 10.1242/bio.022806] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
CAPNS1 is essential for stability and function of the ubiquitous calcium-dependent proteases micro- and milli-calpain. Upon inhibition of the endoplasmic reticulum Ca2+ ATPase by 100 nM thapsigargin, both micro-calpain and autophagy are activated in human U2OS osteosarcoma cells in a CAPNS1-dependent manner. As reported for other autophagy triggers, thapsigargin treatment induces Golgi fragmentation and fusion of Atg9/Bif-1-containing vesicles with LC3 bodies in control cells. By contrast, CAPNS1 depletion is coupled with an accumulation of LC3 bodies and Rab5 early endosomes. Moreover, Atg9 and Bif-1 remain in the GM130-positive Golgi stacks and Atg9 fails to interact with the endocytic route marker transferrin receptor and with the core autophagic protein Vps34 in CAPNS1-depleted cells. Ectopic expression of a Bif-1 point mutant resistant to calpain processing is coupled to endogenous p62 and LC3-II accumulation. Altogether, these data indicate that calpain allows dynamic flux of Atg9/Bif-1 vesicles from the Golgi toward the budding autophagosome. Summary: ER stress triggers calpain-dependent Bif-1 activation and induction of autophagosome maturation by promoting ATG9/Bif-1 vesicle trafficking and fusion with LC3 bodies.
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Affiliation(s)
- Elena Marcassa
- C.I.B. National Laboratory, AREA Science Park, Padriciano 99, Trieste 34149, Italy
| | - Marzia Raimondi
- C.I.B. National Laboratory, AREA Science Park, Padriciano 99, Trieste 34149, Italy
| | - Tahira Anwar
- Department of Biosciences, University of Helsinki, PO Box 56, Helsinki 00014, Finland
| | - Eeva-Liisa Eskelinen
- Department of Biosciences, University of Helsinki, PO Box 56, Helsinki 00014, Finland
| | - Michael P Myers
- International Centre for Genetic Engineering and Biotechnology, AREA Science Park - Padriciano 99, Trieste 34149, Italy
| | - Gianluca Triolo
- International Centre for Genetic Engineering and Biotechnology, AREA Science Park - Padriciano 99, Trieste 34149, Italy
| | - Claudio Schneider
- C.I.B. National Laboratory, AREA Science Park, Padriciano 99, Trieste 34149, Italy
| | - Francesca Demarchi
- C.I.B. National Laboratory, AREA Science Park, Padriciano 99, Trieste 34149, Italy
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Research progress of hydroxychloroquine and autophagy inhibitors on cancer. Cancer Chemother Pharmacol 2016; 79:287-294. [PMID: 27889812 DOI: 10.1007/s00280-016-3197-1] [Citation(s) in RCA: 97] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Accepted: 11/11/2016] [Indexed: 12/17/2022]
Abstract
PURPOSE Hydroxychloroquine (HCQ), the analog of chloroquine, augments the effect of chemotherapies and radiotherapy on various tumors identified in the current clinical trials. Meanwhile, the toxicity of HCQ retinopathy raises concern worldwide. Thus, the potent autophagy inhibitors are urgently needed. METHODS A systematic review was related to 'hydroxychloroquine' or 'chloroquine' with 'clinical trials,' 'retinopathy' and 'new autophagy inhibitors.' This led to many cross-references involving HCQ, and these data have been incorporated into the following study. RESULTS Many preclinical studies indicate that the combination of HCQ with chemotherapies or radiotherapies may enhance the effect of anticancer, providing base for launching cancer clinical trials involving HCQ. The new and more sensitive diagnostic techniques report a prevalence of HCQ retinopathy up to 7.5%. Lys05, SAR405, verteporfin, VATG-027, mefloquine and spautin-1 may be potent autophagy inhibitors. CONCLUSION Additional mechanistic studies of HCQ in preclinical models are still required in order to answer these questions whether HCQ actually inhibits autophagy in non-selective tumors and whether the extent of inhibition would be sufficient to alter chemotherapy or radiotherapy sensitivity.
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Roy M, Liang L, Xiao X, Peng Y, Luo Y, Zhou W, Zhang J, Qiu L, Zhang S, Liu F, Ye M, Zhou W, Liu J. Lycorine Downregulates HMGB1 to Inhibit Autophagy and Enhances Bortezomib Activity in Multiple Myeloma. Am J Cancer Res 2016; 6:2209-2224. [PMID: 27924158 PMCID: PMC5135444 DOI: 10.7150/thno.15584] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2016] [Accepted: 08/12/2016] [Indexed: 12/21/2022] Open
Abstract
Multiple myeloma (MM) is largely incurable and drug-resistant. Novel therapeutic approaches such as inhibiting autophagy or rational drug combinations are aimed to overcome this issue. In this study, we found that lycorine exhibits a promising anti-proliferative activity against MM in vitro and in vivo by inhibiting autophagy. We identified High mobility group box 1 (HMGB1), an important regulator of autophagy, as the most aberrantly expressed protein after lycorine treatment and as a critical mediator of lycorine activity. Gene expression profiling (GEP) analysis showed that higher expression of HMGB1 is linked with the poor prognosis of MM. This correlation was further confirmed in human bone marrow CD138+ primary myeloma cells and MM cell lines. Mechanistically, proteasomal degradation of HMGB1 by lycorine inhibits the activation of MEK-ERK thereby decreases phosphorylation of Bcl-2 resulting in constitutive association of Bcl-2 with Beclin-1. In addition, we observed higher HMGB1 expression in bortezomib resistant cells and the combination of bortezomib plus lycorine was highly efficient in vitro and in vivo myeloma models as well as in re-sensitizing resistant cells to bortezomib. These observations indicate lycorine as an effective autophagy inhibitor and reveal that lycorine alone or in combination with bortezomib is a potential therapeutic strategy.
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18
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Hu J, Han H, Lau MY, Lee H, MacVeigh-Aloni M, Ji C. Effects of combined alcohol and anti-HIV drugs on cellular stress responses in primary hepatocytes and hepatic stellate and kupffer cells. Alcohol Clin Exp Res 2016; 39:11-20. [PMID: 25623401 DOI: 10.1111/acer.12608] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2014] [Accepted: 10/18/2014] [Indexed: 12/19/2022]
Abstract
BACKGROUND Certain anti-HIV drugs alone or in combination are often associated with liver damages, which are frequently worsened by alcohol consumption. We previously found an endoplasmic reticulum (ER) stress mechanism for the drug- and alcohol-induced hepatic injuries in animal models and in vitro hepatocytes. However, it is unknown whether anti-HIV drugs and alcohol induce similar cellular stress responses and injuries in liver nonparenchymal cells. METHODS Primary mouse hepatocytes (PMH), kupffer cells (KC), and hepatocellular stellate cells (HSC) were freshly isolated from mouse liver and treated with DMSO, stress-inducing pharmaceutical agents, alcohol alone, or in combination with antiviral ritonavir (RIT), lopinavir (LOP), or efavirenz (EFV). Expression of cellular stress markers, protein colocalization, and cell death were analyzed with immunoblotting, immunocytochemistry, and positive double staining with Sytox green and Hoechst blue, respectively. RESULTS Expression of the ER stress markers of BiP, CHOP, and SERCA and the autophagy marker LC3 was significantly changed in PMH in response to combined alcohol, RIT, and LOP, which was companied by increased cell death compared with control. In contrast, although pharmaceutical agents induced ER stress and cell death, no significant ER stress or cell death was found in KC treated with alcohol, RIT, LOP, and EFV singly or in combination. In HSC, alcohol, RIT, LOP, or EFV induced BiP, but not CHOP, SERCA, or cell death compared with vehicle control. Further in PMH, RIT and LOP or in combination with alcohol-induced dose-dependent inhibition of β-actin. Inhibition of β-actin by RIT and LOP was companied with an inhibited nuclear expression of the antioxidant response regulator Nrf2 and reduced GST downstream of Nrf2. Ascorbic acid treatment reduced the alcohol-, RIT-, and LOP-induced cell death. CONCLUSIONS The data suggest for the first time that sensitivities of hepatocytes and nonparenchymal cells to alcohol and anti-HIV drugs in vitro are different in terms of cellular stress response and cell death injury. Oxidative stress mediated by Nrf2 contributes to the alcohol- and drug-induced toxicity in the hepatocytes.
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Affiliation(s)
- Jay Hu
- GI/Liver Division, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California
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Hassan M, Selimovic D, Hannig M, Haikel Y, Brodell RT, Megahed M. Endoplasmic reticulum stress-mediated pathways to both apoptosis and autophagy: Significance for melanoma treatment. World J Exp Med 2015; 5:206-217. [PMID: 26618107 PMCID: PMC4655250 DOI: 10.5493/wjem.v5.i4.206] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2015] [Revised: 06/29/2015] [Accepted: 09/08/2015] [Indexed: 02/06/2023] Open
Abstract
Melanoma is the most aggressive form of skin cancer. Disrupted intracellular signaling pathways are responsible for melanoma's extraordinary resistance to current chemotherapeutic modalities. The pathophysiologic basis for resistance to both chemo- and radiation therapy is rooted in altered genetic and epigenetic mechanisms that, in turn, result in the impairing of cell death machinery and/or excessive activation of cell growth and survival-dependent pathways. Although most current melanoma therapies target mitochondrial dysregulation, there is increasing evidence that endoplasmic reticulum (ER) stress-associated pathways play a role in the potentiation, initiation and maintenance of cell death machinery and autophagy. This review focuses on the reliability of ER-associated pathways as therapeutic targets for melanoma treatment.
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20
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Grigoreva TA, Tribulovich VG, Garabadzhiu AV, Melino G, Barlev NA. The 26S proteasome is a multifaceted target for anti-cancer therapies. Oncotarget 2015; 6:24733-49. [PMID: 26295307 PMCID: PMC4694792 DOI: 10.18632/oncotarget.4619] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2015] [Accepted: 07/10/2015] [Indexed: 12/30/2022] Open
Abstract
Proteasomes play a critical role in the fate of proteins that are involved in major cellular processes, including signal transduction, gene expression, cell cycle, replication, differentiation, immune response, cellular response to stress, etc. In contrast to non-specific degradation by lysosomes, proteasomes are highly selective and destroy only the proteins that are covalently labelled with small proteins, called ubiquitins. Importantly, many diseases, including neurodegenerative diseases and cancers, are intimately connected to the activity of proteasomes making them an important pharmacological target. Currently, the vast majority of inhibitors are aimed at blunting the proteolytic activities of proteasomes. However, recent achievements in solving structures of proteasomes at very high resolution provided opportunities to design new classes of small molecules that target other physiologically-important enzymatic activities of proteasomes, including the de-ubiquitinating one. This review attempts to catalog the information available to date about novel classes of proteasome inhibitors that may have important pharmacological ramifications.
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Affiliation(s)
- Tatyana A Grigoreva
- St. Petersburg State Technological Institute (Technical University), St. Petersburng, Russia
| | | | | | - Gerry Melino
- St. Petersburg State Technological Institute (Technical University), St. Petersburng, Russia
- University of Rome Tor Vergata, Roma, Italy
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21
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Muñoz-Galván S, Gutierrez G, Perez M, Carnero A. MAP17 (PDZKIP1) Expression Determines Sensitivity to the Proteasomal Inhibitor Bortezomib by Preventing Cytoprotective Autophagy and NFκB Activation in Breast Cancer. Mol Cancer Ther 2015; 14:1454-65. [PMID: 25837675 DOI: 10.1158/1535-7163.mct-14-1053] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2014] [Accepted: 03/24/2015] [Indexed: 11/16/2022]
Abstract
MAP17 is a small nonglycosylated membrane protein that is overexpressed in a high percentage of carcinomas. High levels of MAP17 enhance the tumorigenic properties of tumor cells by increasing oxidative stress, which is dependent on Na(+)-coupled cotransport. Here, we show that MAP17 is associated with proteins involved in protein degradation and that proteasome inhibition induces autophagy. To analyze whether MAP17 could also alter this process, we used the proteasome inhibitor bortezomib (Velcade, PS-341), which is approved for the treatment of multiple myeloma and mantle cell lymphoma, although it has a high rate of resistance emergence and poor efficacy in solid tumors. We provide evidence that bortezomib induces a cytoprotective effect by activating autophagy and NFκB nuclear translocation, responses that are repressed in the presence of high levels of MAP17 both in vitro and in vivo. Indeed, patients with multiple myeloma treated with bortezomib showed higher response rates and a longer time to progression associated with increased levels of MAP17 expression. The MAP17-induced sensitivity to bortezomib is dependent on the oxidative status of the cells and the activity of Na(+)-coupled transporters because treatment with antioxidants or the inhibitor furosemide restores the cytoprotective activity induced by bortezomib. Therefore, bortezomib induces a prosurvival response through cytoprotective autophagy and NFκB nuclear translocation, which is repressed by high levels of MAP17. We propose that the levels of MAP17 could be used as a prognostic marker to predict the response to bortezomib in hematologic malignancies and in other tissues that are not commonly responsive to the drug.
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Affiliation(s)
- Sandra Muñoz-Galván
- Instituto de Biomedicina de Sevilla, IBIS/Hospital Universitario Virgen del Rocio/Universidad de Sevilla/Consejo Superior de Investigaciones Cientificas, Seville, Spain
| | | | - Marco Perez
- Instituto de Biomedicina de Sevilla, IBIS/Hospital Universitario Virgen del Rocio/Universidad de Sevilla/Consejo Superior de Investigaciones Cientificas, Seville, Spain
| | - Amancio Carnero
- Instituto de Biomedicina de Sevilla, IBIS/Hospital Universitario Virgen del Rocio/Universidad de Sevilla/Consejo Superior de Investigaciones Cientificas, Seville, Spain.
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22
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Abstract
OBJECTIVE To review the mechanisms of anti-cancer activity of nelfinavir and other protease inhibitors (PIs) based on evidences reported in the published literature. METHODS We extensively reviewed the literature concerning nelfinavir (NFV) as an off target anti-cancer drug and other PIs. A classification of PIs based on anti-cancer mode of action was proposed. Controversies regarding nelfinavir mode of action were also addressed. CONCLUSIONS The two main mechanisms involved in anti-cancer activity are endoplasmic reticulum stress-unfolded protein response pathway and Akt inhibition. However there are many other effects, partially dependent and independent of those mentioned, that may be useful in cancer treatment, including MMP-9 and MMP-2 inhibition, down-regulation of CDK-2, VEGF, bFGF, NF-kB, STAT-3, HIF-1 alfa, IGF, EGFR, survivin, BCRP, androgen receptor, proteasome, fatty acid synthase (FAS), decrease in cellular ATP concentration and upregulation of TRAIL receptor DR5, Bax, increased radiosensitivity, and autophagy. The end result of all these effects is slower growth, decreased angiogenesis, decreased invasion and increased apoptosis, which means reduced proliferation and increased cancer cells death. PIs may be classified according to their anticancer activity at clinically achievable doses, in AKT inhibitors, ER stressors and Akt inhibitors/ER stressors. Beyond the phase I trials that have been recently completed, adequately powered and well-designed clinical trials are needed in the various cancer type settings, and specific trials where NFV is tested in association with other known anti-cancer pharmaceuticals should be sought, in order to find an appropriate place for NFV in cancer treatment. The analysis of controversies on the molecular mechanisms of NFV hints to the possibility that NFV works in a different way in tumor cells and in hepatocytes and adipocytes.
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Affiliation(s)
- Tomas Koltai
- Centro de Diagnostico y Tratamiento de la Obra Social del Personal de la Alimentación, Talar de Pacheco, Buenos Aires, 1618, Argentina
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23
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Tümer Y, Koç LY, Asmafiliz N, Kılıç Z, Hökelek T, Soltanzade H, Açık L, Yola ML, Solak AO. Phosphorus-nitrogen compounds: part 30. Syntheses and structural investigations, antimicrobial and cytotoxic activities and DNA interactions of vanillinato-substituted NN or NO spirocyclic monoferrocenyl cyclotriphosphazenes. J Biol Inorg Chem 2015; 20:165-178. [PMID: 25491284 DOI: 10.1007/s00775-014-1223-5] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2014] [Accepted: 11/22/2014] [Indexed: 01/12/2023]
Abstract
The gradual Cl replacement reactions of NN (1-3) or NO spirocyclic monoferrocenyl cyclotriphosphazenes (4 and 5) with the potassium salt of 4-hydroxy-3-methoxybenzaldehyde (potassium vanillinate) resulted in the mono (1a-5a), geminal (gem-1b-5b), non-geminal (cis-5b and trans -1b-4b), tri (1c, 3c-5c) and tetra-vanillinato-substituted phosphazenes (1d-5d). All the phosphazene derivatives have stereogenic P-center(s), except tetra-substituted ones. The vanillinatophosphazenes have reversible voltammograms with one-electron anodic and cathodic peaks which are attributed to ferrocenyl redox probe. The structures of the new phosphazene compounds were determined by FTIR, MS, (1)H, (13)C{(1)H} and (31)P{(1)H} NMR spectral data. The solid-state structure of cis -5b was examined by single-crystal X-ray diffraction techniques. In addition, the compounds were tested in HeLa cancer cell lines using MTT assay. The 12 phosphazene derivatives were screened for antimicrobial activity, and 3c was very effective against S. aureus even at 4.88 µM concentration, taking into account the MIC values. Besides, interactions between the phosphazenes and pBR322 plasmid DNA were also investigated.
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Affiliation(s)
- Yasemin Tümer
- Department of Chemistry, Karabük University, 78050, Karabük, Turkey
| | - L Yasemin Koç
- Department of Biology, Ankara University, 06100, Ankara, Turkey
| | - Nuran Asmafiliz
- Department of Chemistry, Ankara University, 06100, Ankara, Turkey
| | - Zeynel Kılıç
- Department of Chemistry, Ankara University, 06100, Ankara, Turkey.
| | - Tuncer Hökelek
- Department of Physics, Hacettepe University, 06800, Ankara, Turkey
| | | | - Leyla Açık
- Department of Biology, Gazi University, 06500, Ankara, Turkey
| | - Mehmet Lütfi Yola
- Department of Metallurgical and Materials Engineering, Sinop University, 57000, Sinop, Turkey.,Department of Analytical Chemistry, Hacettepe University, 06100, Ankara, Turkey
| | - Ali Osman Solak
- Department of Chemical Engineering, Kyrgyzstan-Turkey Manas University, Bishkek, Kyrgyzstan
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24
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Elmas G, Okumuş A, Koç LY, Soltanzade H, Kılıç Z, Hökelek T, Dal H, Açık L, Üstündağ Z, Dündar D, Yavuz M. Phosphorus-nitrogen compounds. Part 29. Syntheses, crystal structures, spectroscopic and stereogenic properties, electrochemical investigations, antituberculosis, antimicrobial and cytotoxic activities and DNA interactions of ansa-spiro-ansa cyclotetraphosphazenes. Eur J Med Chem 2014; 87:662-76. [PMID: 25305333 DOI: 10.1016/j.ejmech.2014.10.005] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2014] [Revised: 09/29/2014] [Accepted: 10/02/2014] [Indexed: 10/24/2022]
Abstract
A number of novel ansa-spiro-ansa (asa) cyclotetraphosphazenes (1a-5b) was prepared in the range of 63-90 % yields. The structures of the compounds were verified by MS, FTIR, (1)H, (13)C{(1)H} and (31)P{(1)H} NMR, heteronuclear single quantum coherence (HSQC), and heteronuclear multiple-bond correlation (HMBC) techniques. The crystal structures of 1b, 2c and 5a were determined by X-ray crystallography. The compound 2c was analyzed by the changes in the (31)P{(1)H}NMR spectrum in addition of the chiral solvating agent; (R)-(+)-2,2,2-trifluoro-1-(9'-anthryl)-ethanol (CSA), to investigate its stereogenic properties. The result supports that compound 2c was found to be in the racemic mixture. Cyclic voltammetric and chronoamperometric data of the mono-ferrocenyl-spiro-asa-cyclotetraphosphazenes exhibited electrochemically reversible one-electron oxidation of Fe redox centres. The mono-ferrocenyl-spiro-asa compounds (3a-5b) were evaluated for antituberculosis activity against reference strain Mycobacterium tuberculosis H37Rv and M. tuberculosis clinical strain, which is resistant to rifampicin and isoniazid. These compounds appear not to be good candidates for being antituberculosis agents to clinical strains. All of the compounds were screened for antibacterial activities against G(+) and G(-) bacteria, and for antifungal activities against yeast strains. They seem to be more active against Gram positive bacteria than Gram negative. The interactions of the phosphazenes with plasmid DNA and the evaluations for cytotoxic activity against MCF-7 breast cancer cell lines were investigated. The compounds 1b, 2b, 3a and 4a were found to be more effective than Cisplatin against MCF-7 breast cancer cell lines at lower concentrations.
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Affiliation(s)
- Gamze Elmas
- Department of Chemistry, Ankara University, 06100 Ankara, Turkey
| | - Aytuğ Okumuş
- Department of Chemistry, Ankara University, 06100 Ankara, Turkey
| | - L Yasemin Koç
- Department of Biology, Ankara University, 06100 Ankara, Turkey
| | | | - Zeynel Kılıç
- Department of Chemistry, Ankara University, 06100 Ankara, Turkey.
| | - Tuncer Hökelek
- Department of Physics, Hacettepe University, 06800 Ankara, Turkey
| | - Hakan Dal
- Department of Chemistry, Anadolu University, 26470 Eskişehir, Turkey
| | - Leyla Açık
- Department of Biology, Gazi University, 06500 Ankara, Turkey
| | - Zafer Üstündağ
- Department of Chemistry, Dumlupınar University, 43270 Kütahya, Turkey
| | - Devrim Dündar
- Department of Clinical Microbiology, Kocaeli University, 41380 Kocaeli, Turkey
| | - Makbule Yavuz
- Department of Clinical Microbiology, Kocaeli University, 41380 Kocaeli, Turkey
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25
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Vogl DT, Stadtmauer EA, Tan KS, Heitjan DF, Davis LE, Pontiggia L, Rangwala R, Piao S, Chang YC, Scott EC, Paul TM, Nichols CW, Porter DL, Kaplan J, Mallon G, Bradner JE, Amaravadi RK. Combined autophagy and proteasome inhibition: a phase 1 trial of hydroxychloroquine and bortezomib in patients with relapsed/refractory myeloma. Autophagy 2014; 10:1380-90. [PMID: 24991834 DOI: 10.4161/auto.29264] [Citation(s) in RCA: 312] [Impact Index Per Article: 28.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
The efficacy of proteasome inhibition for myeloma is limited by therapeutic resistance, which may be mediated by activation of the autophagy pathway as an alternative mechanism of protein degradation. Preclinical studies demonstrate that autophagy inhibition with hydroxychloroquine augments the antimyeloma efficacy of the proteasome inhibitor bortezomib. We conducted a phase I trial combining bortezomib and hydroxychloroquine for relapsed or refractory myeloma. We enrolled 25 patients, including 11 (44%) refractory to prior bortezomib. No protocol-defined dose-limiting toxicities occurred, and we identified a recommended phase 2 dose of hydroxychloroquine 600 mg twice daily with standard doses of bortezomib, at which we observed dose-related gastrointestinal toxicity and cytopenias. Of 22 patients evaluable for response, 3 (14%) had very good partial responses, 3 (14%) had minor responses, and 10 (45%) had a period of stable disease. Electron micrographs of bone marrow plasma cells collected at baseline, after a hydroxychloroquine run-in, and after combined therapy showed therapy-associated increases in autophagic vacuoles, consistent with the combined effects of increased trafficking of misfolded proteins to autophagic vacuoles and inhibition of their degradative capacity. Combined targeting of proteasomal and autophagic protein degradation using bortezomib and hydroxychloroquine is therefore feasible and a potentially useful strategy for improving outcomes in myeloma therapy.
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Affiliation(s)
- Dan T Vogl
- Abramson Cancer Center; University of Pennsylvania; Philadelphia, PA USA
| | | | - Kay-See Tan
- Department of Biostatistics and Epidemiology; University of Pennsylvania; Philadelphia, PA USA
| | - Daniel F Heitjan
- Department of Biostatistics and Epidemiology; University of Pennsylvania; Philadelphia, PA USA
| | - Lisa E Davis
- Department of Pharmacy Practice and Pharmacy Administration; University of the Sciences in Philadelphia; Philadelphia, PA USA
| | - Laura Pontiggia
- Department of Mathematics, Physics and Statistics; University of the Sciences in Philadelphia; Philadelphia, PA USA
| | - Reshma Rangwala
- Abramson Cancer Center; University of Pennsylvania; Philadelphia, PA USA
| | - Shengfu Piao
- Abramson Cancer Center; University of Pennsylvania; Philadelphia, PA USA
| | - Yunyoung C Chang
- Abramson Cancer Center; University of Pennsylvania; Philadelphia, PA USA
| | - Emma C Scott
- Abramson Cancer Center; University of Pennsylvania; Philadelphia, PA USA
| | - Thomas M Paul
- Abramson Cancer Center; University of Pennsylvania; Philadelphia, PA USA
| | - Charles W Nichols
- Abramson Cancer Center; University of Pennsylvania; Philadelphia, PA USA
| | - David L Porter
- Abramson Cancer Center; University of Pennsylvania; Philadelphia, PA USA
| | - Janeen Kaplan
- Abramson Cancer Center; University of Pennsylvania; Philadelphia, PA USA
| | - Gayle Mallon
- Abramson Cancer Center; University of Pennsylvania; Philadelphia, PA USA
| | - James E Bradner
- Division of Hematologic Neoplasia; Dana-Farber Cancer Institute; Boston, MA USA
| | - Ravi K Amaravadi
- Abramson Cancer Center; University of Pennsylvania; Philadelphia, PA USA
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26
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Autophagy inhibition contributes to the synergistic interaction between EGCG and doxorubicin to kill the hepatoma Hep3B cells. PLoS One 2014; 9:e85771. [PMID: 24465696 PMCID: PMC3897495 DOI: 10.1371/journal.pone.0085771] [Citation(s) in RCA: 93] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2013] [Accepted: 12/05/2013] [Indexed: 02/07/2023] Open
Abstract
(-)-Epigallocatechin-3-O-gallate(EGCG), the highest catechins from green tea, has promisingly been found to sensitize the efficacy of several chemotherapy agents like doxorubicin (DOX) in hepatocellular carcinoma (HCC) treatment. However, the detailed mechanisms by which EGCG augments the chemotherapeutic efficacy remain unclear. Herein, this study was designed to determine the synergistic impacts of EGCG and DOX on hepatoma cells and particularly to reveal whether the autophagic flux is involved in this combination strategy for the HCC. Electron microscopy and fluorescent microscopy confirmed that DOX significantly increased autophagic vesicles in hepatoma Hep3B cells. Western blot and trypan blue assay showed that the increasing autophagy flux by DOX impaired about 45% of DOX-induced cell death in these cells. Conversely, both qRT-PCR and western blotting showed that EGCG played dose-dependently inhibitory role in autophagy signaling, and that markedly promoted cellular growth inhibition. Amazingly, the combined treatment caused a synergistic effect with 40 to 60% increment on cell death and about 45% augmentation on apoptosis versus monotherapy pattern. The DOX-induced autophagy was abolished by this combination therapy. Rapamycin, an autophagic agonist, substantially impaired the anticancer effect of either DOX or combination with EGCG treatment. On the other hand, using small interference RNA targeting chloroquine autophagy-related gene Atg5 and beclin1 to inhibit autophagy signal, hepatoma cell death was dramatically enhanced. Furthermore, in the established subcutaneous Hep3B cells xenograft tumor model, about 25% reduction in tumor growth as well as 50% increment of apoptotic cells were found in combination therapy compared with DOX alone. In addition, immunohistochemistry analysis indicated that the suppressed tendency of autophagic hallmark microtubule-associated protein light chain 3 (LC3) expressions was consistent with thus combined usage in vitro. Taken together, the current study suggested that EGCG emerges as a chemotherapeutic augmenter and synergistically enhances DOX anticancer effects involving autophagy inhibition in HCC.
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27
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Liu T, Mendes DE, Berkman CE. Prolonged androgen deprivation leads to overexpression of calpain 2: implications for prostate cancer progression. Int J Oncol 2013; 44:467-72. [PMID: 24297527 PMCID: PMC3898865 DOI: 10.3892/ijo.2013.2196] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2013] [Accepted: 10/18/2013] [Indexed: 11/30/2022] Open
Abstract
Understanding the molecular mechanism of prostate cancer progression from androgen dependence to independence may lead to developing more effective treatments against prostate cancer. Herein, our previous in vitro model was employed to assess the effects of continuous androgen-deprivation on developing the metastatic phenotype from androgen-dependent prostate cancer cells (LNCaP). The results indicated that long-term androgen deprivation resulted in overexpression of calpain 2 and increased expression of filamin A (FlnA), but not for calpain 1. The enhanced activity of calpain 2 was confirmed by the accumulation of cleaved FlnA fragments, which could be effectively blocked by calpeptin (an inhibitor of calpain 2). Therefore, the combination of calpain 2 inhibitor and androgen deprivation may provide new therapeutic strategy for patients to prevent or postpone prostate cancer progression.
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Affiliation(s)
- Tiancheng Liu
- Department of Chemistry, Washington State University, Pullman, WA 99164, USA
| | - Desiree E Mendes
- Department of Chemistry, Washington State University, Pullman, WA 99164, USA
| | - Clifford E Berkman
- Department of Chemistry, Washington State University, Pullman, WA 99164, USA
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28
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Li J, Wang Z, Cao J, Dong Y, Chen Y. Melatonin receptor subtypes Mel1a and Mel1c but not Mel1b are associated with monochromatic light-induced B-lymphocyte proliferation in broilers. Domest Anim Endocrinol 2013; 45:206-15. [PMID: 24209505 DOI: 10.1016/j.domaniend.2013.09.003] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2013] [Revised: 09/10/2013] [Accepted: 09/12/2013] [Indexed: 11/17/2022]
Abstract
This study determined the effects of melatonin (MEL) and its receptors on monochromatic light-induced bursal B-lymphocyte proliferation in broiler chickens. In vivo, green light (GL) enhanced the proliferation of B lymphocytes in bursas by 16.49% to 30.83% and the expression of MEL receptor subtypes 1a (Mel1a), Mel1b, and Mel1c receptors in bursas by 6.91% to 366.98% than other light colors. However, pinealectomy reduced these parameters and eliminated the differences between GL and other light groups. In vitro, the MEL-induced bursal B-lymphocyte proliferation was most suppressed by prazosin (P = 0.001, selective Mel1c antagonist), followed by luzindole (P = 0.022, nonselective Mel1a/Mel1b antagonist), but not by 4-phenyl-2-propionamideotetralin (P = 0.144, selective Mel1b antagonist). Similarly, dibutyryl-cyclic adenosine monophosphate (cAMP; analog of cAMP; P = 0.017) but not 8-(4-chloro-phenylthio)-2'-O-methyladenosine-3',5'-cyclic monophosphate (P = 0.736; activator of exchange protein directly activated by cAMP) significantly inhibited bursal B-lymphocyte proliferation. These results suggest that MEL mediates GL-induced bursal B-lymphocyte proliferation through Mel1c and Mel1a receptors but not Mel1b receptors by activating the cAMP/protein kinase A pathway.
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Affiliation(s)
- J Li
- Laboratory of Anatomy of Domestic Animals, College of Animal Medicine, China Agricultural University, Haidian, Beijing 100193, China
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29
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Akbaş H, Okumuş A, Kılıç Z, Hökelek T, Süzen Y, Koç LY, Açık L, Celik ZB. Phosphorus-nitrogen compounds part 27. Syntheses, structural characterizations, antimicrobial and cytotoxic activities, and DNA interactions of new phosphazenes bearing secondary amino and pendant (4-fluorobenzyl)spiro groups. Eur J Med Chem 2013; 70:294-307. [PMID: 24161706 DOI: 10.1016/j.ejmech.2013.09.046] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2013] [Revised: 09/20/2013] [Accepted: 09/28/2013] [Indexed: 11/17/2022]
Abstract
A number of partly (7-9) and fully (10a-12d, Scheme 1) substituted mono(4-fluorobenzyl)spiro cyclotriphosphazenes was prepared. The structures of the compounds were determined by MS, FTIR, 1D and 2D NMR techniques. The crystal structures of 9, 11b and 12b were verified by X-ray diffraction analysis. In vitro cytotoxic activity of the phosphazenes (10a-12d) against HeLa cervical cancer cell lines was evaluated. Compound 12c was found to be the most effective, as it is a cytotoxic reagent that might activate apoptosis by altering mitochondrial membrane potential. Compounds 10b, 11b and 12b showed very good activity against yeast strains Candida tropicalis and Candida albicans. BamHI and HindIII digestion results demonstrate that the compounds (10a-12a, 10b-12b, 10d-12d), and (9, 10c-12c) bind with G/G and A/A nucleotides, respectively.
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Affiliation(s)
- Hüseyin Akbaş
- Department of Chemistry, Gaziosmanpaşa University, 60150 Taşlıçiftlik Kampüsü, Tokat, Turkey
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