title: Hsp90-targeted miRNA-liposomal formulation for systemic antitumor effect.
abstract: Chaperone protein Hsp90 maintains functional integrity and maturation of a large number of cellular proteins including transcription factors, kinases, etc. It is often over-expressed in cancer cells for simultaneous maintenance of many non-regulated and/or genetically mutated proteins. Small molecule-based regimens inhibiting over-expressing Hsp90 in cancer cells often plagued with improper targeting leading to non-specific toxicity. Recently using a glucocorticoid receptor (GR)-targeted cationic lipoplex, we observed cancer cell-specific GR-transactivation and transgene expression by utilizing an unprecedentedly compromised chaperone-activity of cancer cell-associated Hsp90. In normal cells, GR is expressed ubiquitously and is highly regulated and chaperoned by Hsp90. This does not allow cancer cell-alike GR-mediated transgene expression. As a novel anticancer strategy, we showed that compromising Hsp90 in cancer cells can be utilized to selectively deplete its own level by delivering a specially designed artificial miRNA-plasmid against Hsp90 (amiR-Hsp90). Practically, GR-mediated delivery of amiR-Hsp90 plasmid in tumor-bearing mice, depleted Hsp90, critically down-regulated levels of Akt, VEGFR2 and other Hsp90-client proteins but up-regulated wild-type p53 in tumor. These enforced apoptosis in angiogenic vessels and in tumor mass and significantly shrunk tumor-volume. The present study describes gene therapy strategy against Hsp90 using a new GR-targeted liposome-amiR-Hsp90 lipoplex formulation for treating cancer.
authors.affiliation: Division of Lipid Science & Technology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.
authors.forename: Subrata Kumar
authors.initials: SK
authors.lastname: Pore
authors.forename: Ashwani
authors.initials: A
authors.lastname: Choudhary
authors.forename: Bhowmira
authors.initials: B
authors.lastname: Rathore
authors.forename: Anirban
authors.initials: A
authors.lastname: Ganguly
authors.forename: Pombala
authors.initials: P
authors.lastname: Sujitha
authors.forename: C Ganesh
authors.initials: CG
authors.lastname: Kumar
authors.forename: Sachin Bharat
authors.initials: SB
authors.lastname: Agawane
authors.forename: Jerald Mahesh
authors.initials: JM
authors.lastname: Kumar
authors.forename: Vinod
authors.initials: V
authors.lastname: Scaria
authors.forename: Beena
authors.initials: B
authors.lastname: Pillai
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Banerjee
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D015153:Blotting, Western; D019556:COS Cells; D045744:Cell Line, Tumor; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D008081:Liposomes / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D041681:NIH 3T3 Cells; D016133:Polymerase Chain Reaction; D011965:Receptors, Glucocorticoid / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D008081:Liposomes; D035683:MicroRNAs; D011965:Receptors, Glucocorticoid