Abstract
Azidothymidine (AZT) is an antiretroviral drug that affects cell proliferation, apoptosis, and the NF-κB pathway. As multiple myeloma (MM) presents with constitutive activation of NF-κB, we analyzed the effect of AZT on human MM cell lines. We evaluated the cytotoxic effect of AZT in human MM cell lines sensitive (8226/S) or resistant to doxorubicin (8226/DX5) and human T cell lymphoblast-like cells, uterine sarcoma cells, and HUVEC using MTT assay. Cytotoxicity was also evaluated in vivo in nude mice xenografted with 8226/S tumor. The effect of AZT on the expression of genes involved in cell proliferation, apoptosis, angiogenesis, and the NF-κB pathway was analyzed in the xenografts using real-time polymerase chain reaction. AZT was effective against both 8226/S and 8226/DX5 cells in a dose and time-dependent manner (p = 0.02) in vitro and promoted cell cycle arrest in S phase in these cells. The tumor volume was lower in mice treated with AZT compared to untreated mice (p = 0.0003). AZT down-regulated the pro-proliferative genes encoding AKT1, MYC, STAT1, MAPK8, MAPK9, CCL-3, Bcl-3, and cyclin D2; pro-angiogenenic genes encoding VEGF and IL8; and genes involved in cell adhesion (ICAM1 and FN1) and the NF-κB pathway. AZT up-regulated the expression of tumor suppressor gene FOXP1 and the pro-apoptotic genes encoding BID, Bcl-10, and caspase-8. Thus, we demonstrated the cytotoxic effect of AZT in human MM cell lines for the first time. Our data may provide the rationale for future clinical trials of AZT for treating MM.
Keywords: Multiple myeloma, Zidovudine, Cell proliferation, Apoptosis, Angiogenesis, Cytotoxic, Trizol, bortezomib, NF-kB/2, FOXP1
Anti-Cancer Agents in Medicinal Chemistry
Title:Azidothymidine is Effective Against Human Multiple Myeloma: A New Use for an Old Drug?
Volume: 13 Issue: 1
Author(s): Juliana Pereira, Debora Levy, Jorge L.M. Ruiz, Graciela A. Brocardo, Kleber A. Ferreira, Renata O. Costa, Rodrigo G. Queiroz, Durvanei A. Maria, Abrahao E. Hallack Neto, Dalton A.F. Chamone and Sergio P. Bydlowski
Affiliation:
Keywords: Multiple myeloma, Zidovudine, Cell proliferation, Apoptosis, Angiogenesis, Cytotoxic, Trizol, bortezomib, NF-kB/2, FOXP1
Abstract: Azidothymidine (AZT) is an antiretroviral drug that affects cell proliferation, apoptosis, and the NF-κB pathway. As multiple myeloma (MM) presents with constitutive activation of NF-κB, we analyzed the effect of AZT on human MM cell lines. We evaluated the cytotoxic effect of AZT in human MM cell lines sensitive (8226/S) or resistant to doxorubicin (8226/DX5) and human T cell lymphoblast-like cells, uterine sarcoma cells, and HUVEC using MTT assay. Cytotoxicity was also evaluated in vivo in nude mice xenografted with 8226/S tumor. The effect of AZT on the expression of genes involved in cell proliferation, apoptosis, angiogenesis, and the NF-κB pathway was analyzed in the xenografts using real-time polymerase chain reaction. AZT was effective against both 8226/S and 8226/DX5 cells in a dose and time-dependent manner (p = 0.02) in vitro and promoted cell cycle arrest in S phase in these cells. The tumor volume was lower in mice treated with AZT compared to untreated mice (p = 0.0003). AZT down-regulated the pro-proliferative genes encoding AKT1, MYC, STAT1, MAPK8, MAPK9, CCL-3, Bcl-3, and cyclin D2; pro-angiogenenic genes encoding VEGF and IL8; and genes involved in cell adhesion (ICAM1 and FN1) and the NF-κB pathway. AZT up-regulated the expression of tumor suppressor gene FOXP1 and the pro-apoptotic genes encoding BID, Bcl-10, and caspase-8. Thus, we demonstrated the cytotoxic effect of AZT in human MM cell lines for the first time. Our data may provide the rationale for future clinical trials of AZT for treating MM.
Export Options
About this article
Cite this article as:
Pereira Juliana, Levy Debora, L.M. Ruiz Jorge, A. Brocardo Graciela, A. Ferreira Kleber, O. Costa Renata, G. Queiroz Rodrigo, A. Maria Durvanei, E. Hallack Neto Abrahao, A.F. Chamone Dalton and P. Bydlowski Sergio, Azidothymidine is Effective Against Human Multiple Myeloma: A New Use for an Old Drug?, Anti-Cancer Agents in Medicinal Chemistry 2013; 13 (1) . https://dx.doi.org/10.2174/1871520611307010186
DOI https://dx.doi.org/10.2174/1871520611307010186 |
Print ISSN 1871-5206 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5992 |
Call for Papers in Thematic Issues
Induction of cell death in cancer cells by modulating telomerase activity using small molecule drugs
Telomeres are distinctive but short stretches present at the corners of chromosomes and aid in stabilizing chromosomal makeup. Resynthesis of telomeres supported by the activity of reverse transcriptase ribonucleoprotein complex telomerase. There is no any telomerase activity in human somatic cells, but the stem cells and germ cells undergone telomerase ...read more
Role of natural compounds as anti anti-cancer agents
Cancer is considered the leading cause of worldwide mortality, accounting for nearly 10 million deaths in 2022. Cancer outcome can be improved through an appropriate screening and early detection and through an efficient clinical treatment. Chemotherapy remains an important approach in treatment o f several types of cancers, even though ...read more
Signaling and enzymatic modulators in cancer treatment
Cancer accounts for nearly 10 million deaths in 2022 and is considered the leading cause of worldwide mortality. Cancer outcome can be improved through an appropriate screening and early detection and through an efficient clinical treatment. Chemotherapy, radiotherapy and surgery are the most important approach for the treatment of several ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
Biosynthetic and Metabolic Alterations in Cancer Growth
Current Angiogenesis (Discontinued) Membrane Transporters as Determinants of the Pharmacology of Platinum Anticancer Drugs
Current Cancer Drug Targets Animal Venoms have Potential to Treat Cancer
Current Topics in Medicinal Chemistry Synthesis and Biological Activities of Organotin(IV) Complexes as Antitumoral and Antimicrobial Agents. A Review
Mini-Reviews in Medicinal Chemistry Therapeutic Potential of Endophytic Compounds: A Special Reference to Drug Transporter Inhibitors
Current Topics in Medicinal Chemistry Viral Based Gene Therapy for Prostate Cancer
Current Gene Therapy Hematopoietic Stem Cells Therapies
Current Stem Cell Research & Therapy The Use of the Bone Seeking Radiopharmaceutical 153-Samarium-EDTMP as an Adjuvant Treatment for Osteosarcoma: A Review
Current Medical Imaging Recent Progress in Molecular Mechanisms of Angiotensin II Type 1 and 2 Receptors
Current Pharmaceutical Design Inhibition of Hedgehog/Gli Signaling by Botanicals: A Review of Compounds with Potential Hedgehog Pathway Inhibitory Activities
Current Cancer Drug Targets Emerging Therapeutic Approaches Based on Nanotechnology for the Treatment of Diseases Associated with Telomere Dysfunction
Mini-Reviews in Medicinal Chemistry Photochemical Reactions: Synthesis of Six-membered N-heterocycles
Current Organic Synthesis TNF α Signaling Beholds Thalidomide Saga: A Review of Mechanistic Role of TNF-α Signaling Under Thalidomide
Current Topics in Medicinal Chemistry Competition Between Tumor and Mononuclear Phagocyte System Causing the Low Tumor Distribution of Nanoparticles and Strategies to Improve Tumor Accumulation
Current Drug Delivery AZT: An Old Drug with New Perspectives
Current Clinical Pharmacology Transgenic Mouse Models of Tauopathy in Drug Discovery
CNS & Neurological Disorders - Drug Targets Imaging Virus-Associated Cancer
Current Pharmaceutical Design Review of Selected Patents for Cancer Therapy Targeting Tumor Angiogenesis
Recent Patents on Anti-Cancer Drug Discovery Studies on the Mechanism of Action of Benzamide Riboside: A Novel Inhibitor of IMP Dehydrogenase
Current Medicinal Chemistry Oncolytic Viruses for Induction of Anti-Tumor Immunity
Current Pharmaceutical Biotechnology