Arsenic trioxide induces apoptosis and inhibits the growth of human liver cancer cells

Aims: As a fifth most common cancer type, Hepatocellularcarcinoma (HCC) ranked third leading cause of cancer deaths worldwide. Arsenic trioxide (As2O3) is known as chemotherapeutic agent against few cancer including Acute promyelocyticleukemia and solid tumors. But its effect and possible associated mechanism in HCC is meager. Present study aimed to assess As2O3 modulatory effect on liver cancer by assessing cell growth and viability. Methods: Liver normal (Chang liver) and cancerous cells (Hep3B) were exposed to different concentration's (0, 1, 5, 10 & 15 &mgr;M) of As2O3 at different intervals (24, 48 & 72 h). Cell growth was assessed microscopically, and Cytotoxicity assays were done through 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) and Water‐soluble tetrazolium salt (WST) growth inhibition assays. Cell viability was studied by trypan blue staining. Apoptosis was analyzed by Annexin V/PI assay, and expression of genes (Notch and anti‐apoptotic) were determined through western blotting and Q‐PCR method. Key findings: A significant reduction in cell growth and viability was reported in liver cancerous cells as compare to normal cells at 5 &mgr;M As2O3. Consistently, As2O3 induced apoptosis along with down‐regulation of anti‐apoptotic protein Bcl‐xL, and up regulates expression of Notch that leads towards apoptosis. Significance: Results clearly suggest that As2O3 restricted growth and induces apoptosis more in liver cancer cells as compared to normal cells. This finding suggests that it could be a promising potential therapeutic agent against liver cancer which need further testing by in‐vivo investigations.

[1]  B. D. Beck,et al.  Arsenic exposure and toxicology: a historical perspective. , 2011, Toxicological sciences : an official journal of the Society of Toxicology.

[2]  S. Altekruse,et al.  Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  V. Bencko.  Carcinogenic, teratogenic, and mutagenic effects of arsenic. , 1977, Environmental health perspectives.

[4]  A. Shraim,et al.  A global health problem caused by arsenic from natural sources. , 2003, Chemosphere.

[5]  C. Papa,et al.  Chronic arsenicism with vitiligo, hyperthyroidism, and cancer. , 1989, New Jersey medicine : the journal of the Medical Society of New Jersey.

[6]  P. Tchounwou,et al.  Invited Reviews: Carcinogenic and Systemic Health Effects Associated with Arsenic Exposure—A Critical Review , 2003, Toxicologic pathology.

[7]  Santosh Yadav,et al.  Arsenite induces apoptosis in human mesenchymal stem cells by altering Bcl-2 family proteins and by activating intrinsic pathway. , 2010, Toxicology and applied pharmacology.

[8]  Quanyi Lu,et al.  Arsenic trioxide inhibits the proliferation of myeloma cell line through notch signaling pathway , 2013, Cancer Cell International.

[9]  L. Hong,et al.  Arsenic trioxide induces apoptosis of rat hepatocellular carcinoma cells in vivo. , 2003, Journal of experimental & clinical cancer research : CR.

[10]  T. Kaise,et al.  Induction of chromosomal aberrations in cultured human fibroblasts by inorganic and organic arsenic compounds and the different roles of glutathione in such induction. , 1996, Mutation research.

[11]  C. Mathers,et al.  Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012 , 2015, International journal of cancer.

[12]  Mohammad Shahneawz Khan,et al.  Arsenic induced toxicity and histopathological changes in gill and liver tissue of freshwater fish, tilapia (Oreochromis mossambicus). , 2013, Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie.

[13]  Bin Bao,et al.  Arsenic Trioxide Inhibits Cell Growth and Induces Apoptosis through Inactivation of Notch Signaling Pathway in Breast Cancer , 2012, International journal of molecular sciences.

[14]  Kent D. Sugden,et al.  Inhibition by methylated organo-arsenicals of the respiratory 2-oxo-acid dehydrogenases. , 2009, Journal of organometallic chemistry.

[15]  Sarmishtha Chanda,et al.  DNA hypermethylation of promoter of gene p53 and p16 in arsenic-exposed people with and without malignancy. , 2006, Toxicological sciences : an official journal of the Society of Toxicology.

[16]  M. Nostro,et al.  Notch Signaling Induces Apoptosis in Primary Human CD34+ Hematopoietic Progenitor Cells , 2007, Stem cells.

[17]  L. Schwartz,et al.  Phase II Trial of Arsenic Trioxide in Patients with Metastatic Renal Cell Carcinoma , 2002, Investigational New Drugs.

[18]  W. Hahn,et al.  Activation of Notch-1 signaling maintains the neoplastic phenotype in human Ras-transformed cells , 2002, Nature Medicine.

[19]  Jie Liu,et al.  Focal adhesion kinase as a potential target in arsenic toxicity. , 2005, Toxicological sciences : an official journal of the Society of Toxicology.

[20]  M. Brzozowa-Zasada,et al.  Notch signalling pathway as an oncogenic factor involved in cancer development , 2016, Contemporary oncology.

[21]  K. M. McCarty,et al.  Arsenic geochemistry and human health in South East Asia , 2011, Reviews on environmental health.

[22]  N. Zeghal,et al.  In vitro Cytotoxic and Genotoxic Effects of Arsenic Trioxide on Human Keratinocytes , 2015 .

[23]  Rapid Reduction in Breast Cancer Mortality With Inorganic Arsenic in Drinking Water , 2014, EBioMedicine.

[24]  M. Izdebska,et al.  [Selected mechanisms of the therapeutic effect of arsenic trioxide in cancer treatment]. , 2008, Postepy higieny i medycyny doswiadczalnej.

[25]  R. Taylor,et al.  Growth inhibitory and cytotoxic effects of three arsenic compounds on cultured Chinese hamster ovary cells , 1985 .

[26]  Bickley Lk,et al.  Chronic arsenicism with vitiligo, hyperthyroidism, and cancer. , 1989 .

[27]  N. Dubrawsky.  Cancer statistics , 1989, CA: a cancer journal for clinicians.

[28]  J. Haller.  Therapeutic mule: the use of arsenic in the nineteenth century materia medica. , 1975, Pharmacy in history.

[29]  J. Seymour,et al.  Role of Arsenic Trioxide in Acute Promyelocytic Leukemia , 2013, Current Treatment Options in Oncology.

[30]  Franziska Michor,et al.  Evolution of Resistance to Targeted Anti-Cancer Therapies during Continuous and Pulsed Administration Strategies , 2009, PLoS Comput. Biol..

[31]  L. Ma,et al.  Arsenic and selenium toxicity and their interactive effects in humans. , 2014, Environment international.

[32]  Shi Wei,et al.  Effects of arsenic trioxide on human renal cell carcinoma lines in vitro , 2004 .

[33]  K. Pradhan,et al.  Notch Pathway Is Activated via Genetic and Epigenetic Alterations and Is a Therapeutic Target in Clear Cell Renal Cancer* , 2016, The Journal of Biological Chemistry.

[34]  Rebecca L. Siegel Mph,et al.  Cancer statistics, 2018 , 2018 .

[35]  Ping Wang,et al.  Synergistic antitumor effect of histone deacetylase inhibitor and Doxorubicin in peripheral T-cell lymphoma. , 2017, Leukemia research.

[36]  F. Goldwasser,et al.  Arsenic Trioxide Exerts Antitumor Activity through Regulatory T Cell Depletion Mediated by Oxidative Stress in a Murine Model of Colon Cancer , 2012, The Journal of Immunology.

[37]  K. Hede.  Chinese folk treatment reveals power of arsenic to treat cancer, new studies under way. , 2007, Journal of the National Cancer Institute.

[38]  Rebecca L. Siegel Mph,et al.  Cancer statistics, 2016 , 2016 .

[39]  I. Bernstein,et al.  Notch signalling in hematopoiesis. , 2003, Seminars in cell & developmental biology.

[40]  Haller Js.  Therapeutic mule: the use of arsenic in the nineteenth century materia medica. , 1975 .

[41]  R. Perez-soler,et al.  Arsenic trioxide produces polymerization of microtubules and mitotic arrest before apoptosis in human tumor cell lines. , 2002, Molecular pharmacology.