Induction of Apoptosis in the Rat Bone Marrow Mesenchymal Stem Cells Following Sodium Arsenite Treatment with the Dose Lesser than that Used for Treatment of Malignant Patient

Document Type: Original Article


Biology Department, Faculty of Sciences, Arak University, Arak 38156-8-8349, Markazi Province, Arak, Iran


Arsenic compounds are potent human carcinogen and produce a variety of stress responses in mammalian cells. Recently sodium arsenite has been recommended to be used as anti malignancy drug by American food and drug administration (FDA). In this study, we aimed to determine the apoptosis inducing effect of sodium arsenite on rat bone marrow mesenchymal stem cells exposed in vitro.
Cell morphology was studied with the help of Hoechst and propidium iodide as well as with single cell gel electrophoresis (comet assay), TUNEL assay and caspase activity base on immunocytochemistry using commercial kit were considered to study the mechanism of cell death.
Our result showed that the sodium arsenite with concentration of 0.1 µM in 36 hr induces caspase dependent apoptosis in rat bone marrow mesenchymal stem cells. This concentration is the lowest level of sodium arsenite to be reported with apoptosis induction ability in stem cells.
Since sodium arsenite is used in therapy, more research should be carried out on the effect of this chemical on stem cells, especially MSCs.


1. Tchounwou PB, Centeno JA, Patlla AK. Arsenic toxicity, mutagenesis, and carcinogenesis a health risk assessment and management approach. Mol Cell Biochem 2004; 255:47-55.

2. Kann S, Estes C, Reichard JF, Huang MY, Sartor MA, Schwemberger S, et al. Butylhydroquinone protects cells genetically deficient in glutathione biosynthesis from arsenite-induced apoptosis without significantly changing their prooxidant status. Toxicol Sci 2005; 87:365-384.

3. Okoji RS, Yu RC, Maronpot RR, Froines JR. Sodium arsenite administration via water increases genome-wide and Ha-ras DNA hypomethylation in methyl deficient C57BL/6J mice. Carcinogenesis 2002; 23:777-785.

4. Sidhu GS, Ponce RA, Vredevoogd MA, Yu X, Gribble E, Hong SW, et al. Cell cycle inhibition by sodium atsenite in primary embryonic rat midbrain neuroepithelial cells. Toxicol Sci 2006; 89:475-484.

5. Rael LT, Fierro FA, Carter DE. The effects of sulfur, thiol, and thiol inhibitor compounds on arsine-induced toxicity in the human erythrocyte membrane. Toxicol Sci 2000, 55:468-477.

6. Roy P, Saha A. Metabolism and toxicity of arsenic: a human carcinogen. Curr Sci 2002; 82:38-45.

7. Antman KH. Introduction: the history of arsenic trioxide in cancer therapy. Oncologist  2001; 6:1-2.

8. Zhang TD, Chen GQ, Wang ZG, Wang ZY, Chen SJ ,Chen Z. Arsenic trioxide, a therapeutic agent  for APL. Oncogene 2001; 20:7146-7153.

9. Collum Mc, Keng G, States PC, CabeMc. Arsenite delayes progression through each cell cycle phase and induces apoptosis following G2/M arrest in U937 myeloid leukemia cells J Pharmacol Exp Ther 2005;313,877-887.

10. Shen ZX, Chen GQ, Ni J, Li XS, Xiong SM. Qiu QY, Zhu J, et al. Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapced patients. Blood 1997; 89:3354-3360.

11. Yadav S, Shi Y, Wang F, Wang H. Arsenite induces apoptosis in human mesenchymal stem cells by altering Bcl-2 family proteins and by activating intrinsic pathway. Toxicol Appl Pharmacol 2010; 244:263–272.

12. Abnosi MH, Soleimani Mehranjani M, Momeni HR, Najafabadi M, Shojafar E, Barati M. Effect of sodium arsenite on rat bone marrow mesenchymal stem cells: cells viability and morphological study. Sci J Hamedan Univ Med Sci 2010; 17:10. abstract in English.

13. Eslaminejad MB, Nazarian H, Falahi F, Taghiyar L, Daneshzadeh MT. Ex vivo expansion and differentiation of mesenchymal stem cells from goat bone marrow. Iran J Basic Med Sci 2009; 12:70-79.

14. Eslaminejad MB, Talkhabi M, Zeynali B. Effect of lithium chloride on prolioferation and bone differentiation of rat marrow –derived mesenchymal stem cellsin culture. Iran J Basic Med Sci 2008; 11:143-151.

15. Golipoor Z, Kashani IR, Akbari M, Hassanzadeh G, Malek F, Mahmoudi R. Differentiation of adipose-derived stem cells into schwann cell phenotype in comparison with bone marrow stem cells. Iran J Basic Med Sci 2010; 13:76-84.

16. Lynn S, Gurr JR, Lai HT, Jan KY. NADH oxidase activation is involved in arsenite-indused oxidative DNA damage in human vascular smooth muscle cells. Circ Res 2000; 86:514-519.

17. Cemazar M, Parkins CS, Holder AL, Chain DJ, Tozer GM, Sersa G. Electroporation of human, microvascular endothelial cells:evidence for an ati-vascular mechanism of electrochemotherapy . Br J Cancer 2001; 84:565-570.

18. Michael J, Mccabe JR, Kameshwar P, Srikar AS, Chelladurai RB, Joel G, et al. Sensitivityof Myelomonocytic leukemia cells to arsenite induced cell cycle disruption, apoptosis, and enhanced differentiation is dependent on the inter-relationship between arsenicconcentration, duration of treatment, and cell cycle phase. JPET 2000; 295:724-733.

19. Zhu XH, Shen YL, Jing YK, Cai X, Jia PM, Y Tang HW,  et al. Apoptosis and growth inhibition in malignant lymphocytes after treatment with arsenic trioxide at clinically achievable concentrations. National Cancer Institute 1999; 91:772-778.

20. Yancy SL, Shelden EA, Gilmont RR, Welsh MJ. Sodium arsenite exposure alters cellmigration, focal adhesion localization and decreases tyrosin kinase in H9C2 myoblasts. Toxicol Sci  2005; 84:278-286.

21. Wilson H, Miller J, Hyman M, Schipper M, Lee JS, Singer J, et al. Mechanisms of action of arsenic trioxide. Cancer Res 2002; 62:3893-3903.

22.  Ruchaud S, Korafali N, Valli P, Kottke TJ, Dingwall C, Kaufmann SH, et al. Caspas-6 gene disruption reveal a requirement for lamin A cleavage in apoptotic chromatin condensation. EMBO J 2002; 21:1967-1977.

23. Yih LH, Ho IC, Lee TC. Sodium arsenite disturbs mitosis and induces chromosome loss in human fibroblast. Cancer Res 1997; 57:5051-5059.

24.  Salvesen GS. Caspase: opening the boxes and interpreting the arrows. Cell Death Differ 2001; 9:3-5.

25.  Ghavami S, Hashemi M, Ande SR. Apoptosis and cancer:mutations within caspase genes. J Med Genet 2009; 46:497-510.