title: Identification of heat shock protein 90 inhibitors to sensitize drug resistant side population tumor cells using a cell based assay platform.
abstract: Current cancer therapeutics are identified based on initial tumor regression screens that mostly kill differentiated tumor cells, sparing the rare cancer stem cells (CSCs). Being rare and difficult to characterize, it remains a challenge to identify compounds active against them. Side population (SP) cells identified in multiple cancer cell line panels expressing mitochondrial Cytochrome C-EGFP were evaluated for identifying possible drug candidates utilizing high-throughput imaging. We identified heat shock protein 90 inhibitors as potential agents to sensitize SP cells to anticancer drugs. Hsp90 inhibitors induced down regulation of Akt leading to proteasomal degradation of survivin and consequent mitochondrial apoptosis. A successful screening platform for identifying compounds targeting drug resistant side population cells was developed.
authors.affiliation: Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India.
authors.forename: Praveen K
authors.initials: PK
authors.lastname: Sobhan
authors.forename: Mahendra
authors.initials: M
authors.lastname: Seervi
authors.forename: Jeena
authors.initials: J
authors.lastname: Joseph
authors.forename: Bhavya Balan
authors.initials: BB
authors.lastname: Chandrika
authors.forename: Saneesh
authors.initials: S
authors.lastname: Varghese
authors.forename: T R
authors.initials: TR
authors.lastname: Santhoshkumar
authors.forename: M
authors.initials: M
authors.lastname: Radhakrishna Pillai
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045304:Cytochromes c / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005260:Female; D005434:Flow Cytometry; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D045325:HCT116 Cells; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006367:HeLa Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D058985:Side-Population Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000077022:Survivin; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D018841:HSP90 Heat-Shock Proteins; D051034:Inhibitor of Apoptosis Proteins; D011993:Recombinant Fusion Proteins; D000077022:Survivin; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D045304:Cytochromes c; D051057:Proto-Oncogene Proteins c-akt; D046988:Proteasome Endopeptidase Complex