Inhibition of mitochondria induces apoptosis and reduces telomere length and activity in acute myeloid leukemia stem cells

Author:

Valipour Behnaz12ORCID,Davari Sahar3,Farahzadi Raheleh4,Pourrasol Shahram3,Mehran Niloofar3,Dizaji Asl Khadijeh5,Altaha Seyed Mansour3,Hojjati Zahra3,Nozad Charoudeh Hojjatollah6ORCID

Affiliation:

1. Department of Anatomical Sciences Sarab Faculty of Medical Sciences Sarab Iran

2. Department of Anatomical Sciences Faculty of Medicine, Tabriz University of Medical Sciences Tabriz Iran

3. Department of Microbiology Bonab Branch, Islamic Azad University Bonab Iran

4. Hematology and Oncology Research Center Tabriz University of Medical Sciences Tabriz Iran

5. Department of Histopathology and Anatomy Faculty of Medical Sciences, Tabriz Medical Sciences, Islamic Azad University Tabriz Iran

6. Drug Applied Research Center Tabriz University of Medical Sciences Tabriz Iran

Abstract

AbstractAcute myeloid leukemia (AML) is a highly lethal hematological malignancy in adults and children. Abnormal proliferation of leukemia stem cells (LSC) with CD34+ and CD38 phenotypes are the main clinical features of AML. Patients with AML face drug resistance and treatment failure due to a default in stem and progenitor cells. Therefore, defining LSC properties is necessary for targeting leukemia‐initiating cells. Mitochondrial mass and activity increase in AML initiating cells compared with normal stem cells. This idea has offered the inhibition of the mitochondrial translation machinery to reduce the number of leukemia‐initiating cells in patients with AML Tigecycline is an FDA‐approved microbial antibiotic that inhibits oxidative phosphorylation in mitochondria, resulting in the suppression of leukemia cell proliferation with little toxicity to normal cells. Thus, the present study was conducted to evaluate whether LSC is influenced by mitochondrial inhibition. We measured the IC50 of tigecycline in KG‐1a AML cell lines. KG‐1a AML cell lines were separated into CD34+ and CD34 cells by MACS. In the following, these cells were treated with 20 µM (IC50) tigecycline. The expression of Annexin/PI, Caspase 3, apoptotic genes (BCL2, BCLX, BAX, BAD, and P53) and proteins (P53, BAX, BCL2 and Caspase 9) was evaluated in CD34+, CD34 and KG‐1a AML cells. In addition, the telomere length and expression of hTERT were evaluated in this study. The results indicated that BCl2 (gene and protein) and BCLX gene dramatically decreased. In addition, BAD, BAX, and P53 gene and protein expression significantly increased in CD34+ AML cells compared to CD34 AML cells. The results also suggested that tigecycline induced intrinsic (Cleaved‐caspase 9/Pro‐Caspase 9 ratio) and p53‐mediated apoptosis. Furthermore, hTERT gene expression and telomere length decreased in the tigecycline‐treated groups. Taken together, our findings indicate that inhibition of mitochondrial activity with tigecycline can induce apoptosis in cancer stem cells and can be used as a novel method for cancer therapy.

Publisher

Wiley

Subject

Cell Biology,Clinical Biochemistry,General Medicine,Biochemistry

Cited by 2 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3