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Indiana University School of Medicine

Safa Lab

The research lab of Ahmad R. Safa, PhD, studies the molecular and biochemical mechanisms of intrinsic and acquired resistance to chemotherapeutic drugs, apoptosis (cell death) in cancer cells, cancer stem cells, drug discovery and development, and cancer treatment. His lab is particularly interested in multi-targeted therapy of brain cancer, breast cancer and pancreatic tumors through modulation of the death receptor signaling pathway in cancer cells.

Active Research

The major focus of Safa’s research lab is to target multiple signaling pathways in glioblastoma (GBM), breast cancer, and pancreatic cancer cells and cancer stem cells (CSCs) to eradicate drug-sensitive and -resistant cells. Particularly, the lab team is interested in mechanisms of intrinsic and acquired resistance to chemotherapeutic agents and investigating molecular mechanisms of drug-induced apoptosis.

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One project involves investigating the role of the anti-apoptotic protein cellular FLICE-like inhibitory protein (c-FLIP), which is expressed as long form (c-FLIPL) and short form (c-FLIPS) isoforms in causing resistance to anticancer agents, as well as the cytokine tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). c-FLIP is required for GBM, breast cancer, and pancreatic cancer cell growth and is a relevant and important target for the treatment of these cancers. We use siRNAs and compounds that cause degrade or inhibit transcription of c-FLIP isoforms in combination with conventional anti-cancer agents as well as compounds that trigger apoptosis in CSCs to eradicate these cancers.

Another project is to target the histone deacetylase 6 (HDAC6), which is a cytoplasmic protein that regulates critical biological processes by deacetylating various non-histone proteins. The functional role and dysregulation of HDAC6 have recently been shown in the etiology of various cancers, Alzheimer’s and Parkinson’s diseases, and depression disorder. Therefore, HDAC6 is an excellent target against these diseases. Recent research uses a combination of HDAC6 inhibitors and cytotoxic anti-cancer drugs to eliminate cancer stem cells in GBM, breast cancer, and pancreatic cancer.

Recent Publications

  • 2017
    Bijangi-Vishehsaraei, K, Saadatzadeh MR, Wang H, Nguyen A, Kamocka MM, Cai W, Cohen-Gadol AA, Halum SL, Sarkaria JN, Pollok KE, and Safa AR.  Sulforaphane suppresses growth of glioblastoma multiforme (GBM) cells, GBM stem cell-like spheroids, and tumor xenografts through multiple cell signaling pathways. J Neurosurgery 2017; 6:1-12.

    Prabhu L, Han W, Chen L, Özlem D, Sandusky G, Sun E, Wang J, Mo J, Zeng L, Safa A, Amaro R, Korc M, Zhang Z-Y, Lu T.  Adapting AlphaLISA high throughput screen to discover a novel small-molecule inhibitor targeting protein arginine methyltransferase 5 in pancreatic and colorectal cancers. Oncotarget 2017; 8:39963-39977.

  • 2016
    Safa AR, Saadatzadeh MR, Cohen-Gadol AA, Pollok KE, Bijangi-Vishehsaraei K. Emerging targets for glioblastoma stem cell therapy. J Biomed Res. 2016, 30:19-31.
  • 2015
    Safa AR, Saadatzadeh MR, Cohen-Gadol AA, Pollok KE, Bijangi-Vishehsaraei K. Glioblastoma stem cells (GSCs) epigenetic plasticity and interconversion between differentiated non-GSCs and GSCs. Genes Dis. 2015; 2:152-163.

    Tonsing-Carter E, Bailey BJ, Saadatzadeh MR, Ding J, Wang H, Sinn AL, Peterman KM, Spragins TK, Silver JM, Sprouse AA, Georgiadis TM, Gunter TZ, Long EC, Minto RE, Marchal CC, Batuello CN, Safa AR, Hanenberg H, Territo PR, Sandusky GE, Mayo LD, Eischen CM, Shannon HE, Pollok KE. Potentiation of carboplatin-mediated DNA damage by the Mdm2 modulator Nutlin-3a in a humanized orthotopic breast-to-lung metastatic model. Mol Cancer Ther 2015; 14:2850-2863.

  • 2012
    Huang S, Bijangi-Vishehsaraei K, Saadatzadeh MR, Safa AR.  Human GM3 synthase attenuates Taxol-triggered apoptosis associated with downregulation of Caspase-3 in ovarian cancer cells.  J Cancer Therapy 2012; 3:504-510.
  • 2010
    Park S-J, Bijangi-Vishehsaraei K, and Safa AR.  Selective TRAIL-triggered apoptosis due to overexpression of TRAIL death receptor 5 (DR5) in P-glycoprotein-bearing multidrug resistant CEM/VBL1000 human leukemia cells.  Int J Biochem and Molec Biol 2010; 1:90-100.
  • 2009
    Huang S, Day TW, Choi MR, Safa AR.  Human beta-galactoside alpha-2,3-sialyltransferase (ST3Gal III) attenuated Taxol-induced apoptosis in ovarian cancer cells by downregulating caspase-8 activity.  Mol Cell Biochem 2009; 331:81-88.

    Shen F, Bailey BJ, Chu S, Bence AK, Xue X, Erickson P, Safa AR, Beck WT, Erickson LC.  Dynamic assessment of mitoxantrone resistance and modulation of multidrug resistance by PSC833 in multidrug resistant human cancer cells.  J Pharmacol Exp Ther. 2009; 330:423-429.

    Day TW, Wu C-H, Safa AR.  Etoposide induces protein kinase C δ- and caspase-3-dependent apoptosis in neuroblastoma cancer cells. Mol Pharmacol 2009; 76:632-640.

  • 2008
    Safa AR, Day, TW, Wu C-H.  Cellular FLICE-like inhibitory protein (c-FLIP): a novel target for cancer therapy.  Current Cancer Drug Targets 2008; 8:37-46.

    Choi M-R, Najafi F, Safa AR, Drexler HCA.  Analysis of changes in the proteome of HL-60 cells induced by the proteasome inhibitor PSI.  Biochem Pharmacol 2008; 75:2276-2288.

    Wu C-H, Kao C, Safa AR. TRAIL recombinant adenovirus triggered robust apoptosis in P-glycoprotein bearing multidrug resistant HL-60/Vinc cells preferentially through the death receptor DR5.  Hum Gene Ther 2008; 19:731-743.

    Day TW, Huang S, Safa AR. c-FLIP knockdown induces ligand-independent DR5-, FADD-, caspase-8-, and caspase-9-dependent apoptosis in breast cancer cells.  Biochem Pharmacol 2008; 76:1694-1704.

  • 2007
    Zhong X-L, Safa AR.  Phosphorylation of RNA helicase A by DNA-dependent protein kinase is indispensable for expression of the MDR1 gene product P-glycoprotein in multidrug resistant human leukemia cells. Biochemistry 2007; 46:5766-5775.
  • 2006
    Day TW, Najafi F, Wu C-H, Safa AR.  Cellular FLICE-like inhibitory protein (c-FLIP): A novel target for Taxol-induced apoptosis.  Biochem Pharmacol 2006; 71:1551-1561.

    Park S-J, Wu C-H, Choi M-R, Day T, Emami A, Najafi F, Safa AR.  P-glycoprotein enhances TRAIL-targeted apoptosis in multidrug resistant cells by interacting with the death receptor DR5.  Biochem Pharmacol 2006; 72:293-307

  • 2004
    Zhong X-L, Safa AR.  RNA helicase A in the MEF1 transcription factor complex up-regulates the MDR1 gene in multidrug-resistant cancer cells. J Biol Chem 2004; 279:17134-17141.

    Park S-J, Wu C-H, Gordon JD, Zhong X-L, Emami A, Safa AR.  Taxol induces caspase-10-dependent apoptosis. J Biol Chem 2004; 279:51057-51067.

  • 2002
    Wu C-H, Gordon J, Rastegar M, Ogretmen B, Safa AR.  Proteinase-3, a serine protease which mediates doxorubicin-induced apoptosis in the HL-60 leukemia cell line, and is downregulated in its doxorubicin resistant variant. Oncogene 2002; 21, 5160-5174.

Lab Team

14514-Safa, Ahmad

Ahmad R. Safa, PhD

Professor of Pharmacology & Toxicology

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