Skip to main content
SpringerLink
Log in

Arsenic trioxide promotes mitochondrial DNA mutation and cell apoptosis in primary APL cells and NB4 cell line

  • Research Paper
  • Published:
Science China Life Sciences Aims and scope Submit manuscript

Abstract

This study aimed to investigate the effects of arsenic trioxide (As2O3) on the mitochondrial DNA (mtDNA) of acute promyelocytic leukemia (APL) cells. The NB4 cell line was treated with 2.0 μmol/L As2O3in vitro, and the primary APL cells were treated with 2.0 μmol/L As2O3in vitro and 0.16 mg kg−1 d−1 As2O3in vivo. The mitochondrial DNA of all the cells above was amplified by PCR, directly sequenced and analyzed by Sequence Navigatore and Factura software. The apoptosis rates were assayed by flow cytometry. Mitochondrial DNA mutation in the D-loop region was found in NB4 and APL cells before As2O3 use, but the mutation spots were remarkably increased after As2O3 treatment, which was positively correlated to the rates of cellular apoptosis, the correlation coefficient: rNB4-As2O3=0.973818, and rAPL-As2O3=0.934703. The mutation types include transition, transversion, codon insertion or deletion, and the mutation spots in all samples were not constant and regular. It is revealed that As2O3 aggravates mtDNA mutation in the D-loop region of acute promyelocytic leukemia cells both in vitro and in vivo. Mitochondrial DNA might be one of the targets of As2O3 in APL treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Liu J, Lu Y, Wu Q, et al. Mineral arsenicals in traditional medicines: Orpiment, realgar, and arsenolite. J Pharmacol Exp Ther, 2008, 326: 363–368, 10.1124/jpet.108.139543, 1:CAS:528:DC%2BD1cXpsVWru7o%3D, 18463319

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Chou W C, Chen H Y, Yu S L, et al. Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood, 2005, 106: 304–310, 10.1182/blood-2005-01-0241, 1:CAS:528:DC%2BD2MXlvVWjtrg%3D, 15761015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Zhou P, Kalakonda N, Comenzo R L. Changes in gene expression profiles of multiple myeloma cells induced by arsenic trioxide (ATO): Possible mechanisms to explain ATO resistance in vivo. Br J Haematol, 2005, 128: 636–644, 10.1111/j.1365-2141.2005.05369.x, 1:CAS:528:DC%2BD2MXjtVGqsrc%3D, 15725085

    Article  CAS  PubMed  Google Scholar 

  4. Park W H, Seol J G, Kim E S, et al. Arsenic trioxide-mediated growth inhibition in MC/CAR myeloma cells via cell cycle arrest in association with induction of cyclin-dependent kinase inhibitor, p21, and apoptosis. Cancer Res, 2000, 60: 3065–3071, 1:CAS:528:DC%2BD3cXjvFOltLo%3D, 10850458

    CAS  PubMed  Google Scholar 

  5. Yim E K, Tong S Y, Ho E M, et al. Anticancer effects on TACC3 by treatment of paclitaxel in HPV-18 positive cervical carcinoma cells. Oncol Rep, 2009, 21: 549–557, 1:CAS:528:DC%2BD1MXit1GrtL4%3D, 19148534

    CAS  PubMed  Google Scholar 

  6. Yoon P, Giafis N, Smith J, et al. Activation of mammalian target of rapamycin and the p70 S6 kinase by arsenic trioxide in BCR-ABL-expressing cells. Mol Cancer Ther, 2006, 5: 2815–2823, 10.1158/1535-7163.MCT-06-0263, 1:CAS:528:DC%2BD28Xht1els7bL, 17121928

    Article  CAS  PubMed  Google Scholar 

  7. Patlolla A K, Tchounwou P B. Cytogenetic evaluation of arsenic trioxide toxicity in Sprague-Dawley rats. Mutat Res. 2005, 587: 126–133, 1:CAS:528:DC%2BD2MXhtFKmsrfI, 16213187

    Article  CAS  PubMed  Google Scholar 

  8. Rigoli L, DiBella C, Verginelli F, et al. Histological heterogeneity and somatic mtDNA mutations in gastric intraepithelial neoplasia. Mod Pathol, 2008, 21: 733–741, 10.1038/modpathol.2008.58, 1:CAS:528:DC%2BD1cXmtFGntLo%3D, 18425082

    Article  CAS  PubMed  Google Scholar 

  9. Luciane R C, Bertrand C L. Mutagenesis, tumorigenicity and apoptosis: Are the mitochondria involved? Mutat Res, 1998, 398: 19–26

    Article  Google Scholar 

  10. Singh K K, Kulawiec M. Mitochondrial DNA polymorphism and risk of cancer. Methods Mol Biol, 2009, 471: 291–303, 10.1007/978-1-59745-416-2_15, 1:CAS:528:DC%2BD1cXhsVGgur7L, 19109786

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Mayr J A, Meierhofer D, Zimmermann F, et al. Loss of complex I due to mitochondrial DNA mutations in renal oncocytoma. Clin Cancer Res, 2008, 14: 2270–2275, 10.1158/1078-0432.CCR-07-4131, 1:CAS:528:DC%2BD1cXkvFGmt7Y%3D, 18413815

    Article  CAS  PubMed  Google Scholar 

  12. Nirajan B G, Bhat N K, Avadhani N G. Preferential attack of mitochondrial DNA by aflatoxin B1 during hepatocarcinogenesis. Science, 1982, 215: 73–75, 10.1126/science.6797067

    Article  Google Scholar 

  13. Dasgupta S, Hoque M O, Upadhyay S, et al. Mitochondrial cytochrome B gene mutation promotes tumor growth in bladder cancer. Cancer Res, 2008, 68: 700–706, 10.1158/0008-5472.CAN-07-5532, 1:CAS:528:DC%2BD1cXhtlygs7w%3D, 18245469

    Article  CAS  PubMed  Google Scholar 

  14. Backer J M, Weinstein I B. Mitochondrial DNA is a major cellular target for a dihydrodiol-epoxide derivative of benzopyrene. Science, 1980, 209: 297–299, 10.1126/science.6770466, 1:CAS:528:DyaL3cXlt1Kku7g%3D, 6770466

    Article  CAS  PubMed  Google Scholar 

  15. Wheelhouse N M, Lai P B, Wigmore S J, et al. Mitochondrial D-loop mutations and deletion profiles of cancerous and noncancerous liver tissue in hepatitis B virus-infected liver. Br J Cancer, 2005, 92: 1268–1272, 10.1038/sj.bjc.6602496, 1:CAS:528:DC%2BD2MXivFWltL0%3D, 15785740

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Yu M, Shi Y, Zhang F, et al. Sequence variations of mitochondrial DNA D-loop region are highly frequent events in familial breast cancer. J Biomed Sci, 2008, 15: 535–543, 10.1007/s11373-007-9229-4, 1:CAS:528:DC%2BD1cXptVWisLg%3D, 18157618

    Article  CAS  PubMed  Google Scholar 

  17. Chen G F, Chan F L, Hong B F, et al. Mitochondrial DNA mutations in chemical carcinogen-induced rat bladder and human bladder cancer. Oncol Rep, 2004, 12: 463–472, 1:CAS:528:DC%2BD2cXms1Kitbc%3D, 15254717

    CAS  PubMed  Google Scholar 

  18. Zhou Jin, Meng Ran, Li Limin, et al. Mitochondrial D-loop mutations in patients with acute myeloid leukemia. Chin J Endemiol, 2006, 25: 90–93, 1:CAS:528:DC%2BD2sXksVaitb8%3D

    CAS  Google Scholar 

  19. Lu D P. The Iatreusiology of Leukemia. Beijing: The Beijing Science and Technology Publishing Company, 1990. 28–29

    Google Scholar 

  20. Ni J H, Chen G Q, Shen Z X, et al. Pharmacokinetics of intravenous arsenic trioxide in the treatment of acute promyelocytic leukemia. Chin J Hematol, 1997, 18: 250–253, 1:CAS:528:DyaK1cXmslegsw%3D%3D

    CAS  Google Scholar 

  21. Zhou J, Meng R, Yang B F. Comparing two arsenic trioxide administration methods in APL therapy. CMJ, 2004, 117: 1101–1104

    Google Scholar 

  22. Ingman M, Kaessmann H, Paabo S, et al. Mitochondrial genome variation and the origin of modern humans. Nature, 2000, 408: 708–713, 10.1038/35047064, 1:CAS:528:DC%2BD3cXptVCrsr4%3D, 11130070

    Article  CAS  PubMed  Google Scholar 

  23. Park I C, Park M J, Woo S H, et al. Tetraarsenic oxide induces apoptosis in U937 leukemic cells through a reactive oxygen species-dependent pathway. Int J Oncol, 2003, 23: 943–948, 1:CAS:528:DC%2BD3sXovV2gtbg%3D, 12963972

    CAS  PubMed  Google Scholar 

  24. Zhou J, Meng R, Sui X H, et al. Effects of protein tyrosine kinase, protein tyrosine phosphatase and protein kinase C on the apoptosis of arsenic trioxide treated NB4 cells and human cortex neurons. Chin J Hematol, 2004, 25: 600–604

    Google Scholar 

  25. Zhou J, Meng R, Sui X H, et al. The effects of administration styles of arsenic trioxide on intracellular arsenic concentration, cell differentiation and apoptosis. Haematologica, 2005, 90: 1277–1279, 1:CAS:528:DC%2BD2MXhtFGrtLvO, 16154855

    CAS  PubMed  Google Scholar 

  26. Zhou J, Meng R, Sui X H, et al. Various tolerances to arsenic trioxide between human cortical neurons and leukemic cells. Sci China Ser C-Life Sci, 2006, 49: 567–572, 10.1007/s11427-006-2034-x, 1:CAS:528:DC%2BD2sXitlOktw%3D%3D

    Article  CAS  Google Scholar 

  27. Ishikawa K, Takenaga K, Akimoto M, et al. ROS-generating mitochondrial DNA mutations can regulate tumor cell metastasis. Science, 2008, 320: 661–664, 10.1126/science.1156906, 1:CAS:528:DC%2BD1cXltFyisrc%3D, 18388260

    Article  CAS  PubMed  Google Scholar 

  28. Hung W Y, Lin J C, Lee L M, et al. Tandem duplication/triplication correlated with poly-cytosine stretch variation in human mitochondrial DNA D-loop regi93n. Mutagenesis, 2008, 23: 137–142, 10.1093/mutage/gen002, 1:CAS:528:DC%2BD1cXktlWht78%3D, 18252697

    Article  CAS  PubMed  Google Scholar 

  29. Kwong J Q, Henning M S, Starkov A A, et al.The mitochondrial respiratory chain is a modulator of apoptosis. J Cell Biol, 2007, 179: 1163–1177, 10.1083/jcb.200704059, 1:CAS:528:DC%2BD2sXhsVOgtL7P, 18086914

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Neurology, the Ninth Clinical Medical College of Beijing University (Shijitan Hospital), Beijing, 100038, China

    Ran Meng & GuoSheng Feng

  2. The First Hospital of Harbin Medical University, Harbin, 150001, China

    Jin Zhou & BaoFeng Yang

  3. Management Information System, University of International Business and Economics, Beijing, 100029, China

    Meng Sui

  4. Department of Radiology, Cambridge University Hospitals NHS Foundation Trust Box 219 Level 5, Addenbrooke’s Hospital, Cambridge, CB2 0QQ, UK

    ZhiYong Li

Authors
  1. Ran Meng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jin Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Meng Sui
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. ZhiYong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. GuoSheng Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. BaoFeng Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Ran Meng or Jin Zhou.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Meng, R., Zhou, J., Sui, M. et al. Arsenic trioxide promotes mitochondrial DNA mutation and cell apoptosis in primary APL cells and NB4 cell line. Sci. China Life Sci. 53, 87–93 (2010). https://doi.org/10.1007/s11427-010-0004-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11427-010-0004-9

Keywords

Search

Navigation