title: Scriptaid overcomes hypoxia-induced cisplatin resistance in both wild-type and mutant p53 lung cancer cells.
abstract: Non-small cell lung cancer (NSCLC), comprising 85% of lung cancer cases, has been associated with resistance to chemo/radiotherapy. The hypoxic tumor micro-environment, where insufficient vasculature results in poor drug penetrance and sub-optimal chemotherapy in the tumor interiors contributes heavily to this resistance. Additionally, epigenetic changes in tumorigenic cells also change their response to different forms of therapy. In our study, we have investigated the effectiveness of a combination of cisplatin with scriptaid [a pan-Histone Deacetylase inhibitor (HDACi)] in a model that mimics the tumor microenvironment of hypoxia and sub-lethal chemotherapy. Scriptaid synergistically increases the efficacy of cisplatin in normoxia as well as hypoxia, accompanied with reduced metastasis and enhanced DNA damage. Addition of scriptaid also overcomes the cisplatin resistance exhibited in lung cancer cells with stabilized hypoxia inducible factor 1 (HIF1)-α (mutant) and mutant p53. Molecular studies showed that the combination treatment increased apoptotic cell death in both normoxia and hypoxia with a dual role of p38MAPK. Together, our results suggest that the combination of low dose cisplatin and scriptaid is cytotoxic to NSCLC lines, can overcome hypoxia induced resistance and mutant p53- induced instability often associated with this cancer, and has the potential to be an effective therapeutic modality.
authors.affiliation: Department of Genetics, University of Delhi South Campus, New Delhi, India.
authors.forename: Shrikant
authors.initials: S
authors.lastname: Pradhan
authors.affiliation: Department of Genetics, University of Delhi South Campus, New Delhi, India.
authors.forename: Divyank
authors.initials: D
authors.lastname: Mahajan
authors.affiliation: Department of Genetics, University of Delhi South Campus, New Delhi, India.
authors.forename: Prabhjot
authors.initials: P
authors.lastname: Kaur
authors.affiliation: Department of Genetics, University of Delhi South Campus, New Delhi, India.
authors.forename: Namita
authors.initials: N
authors.lastname: Pandey
authors.affiliation: Centre for Bio-design and Diagnostics, Translational Health Science and Technology Institute, Faridabad, Haryana, India.
authors.forename: Chandresh
authors.initials: C
authors.lastname: Sharma
authors.affiliation: Department of Genetics, University of Delhi South Campus, New Delhi, India.
authors.forename: Tapasya
authors.initials: T
authors.lastname: Srivastava
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D002452:Cell Count; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D016158:Genes, p53; D056572:Histone Deacetylase Inhibitors / Q000276:immunology* / Q000494:pharmacology; D006801:Humans; D006898:Hydroxylamines / Q000008:administration & dosage / Q000494:pharmacology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D009154:Mutation; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology*; D059016:Tumor Microenvironment
chemical_list: C497442:HIF1A protein, human; D056572:Histone Deacetylase Inhibitors; D006898:Hydroxylamines; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011804:Quinolines; C410733:scriptaid; D002945:Cisplatin
keywords: cisplatin; hypoxia; lung cancer; metastasis; scriptaid