title: Glucocorticoid Receptor-Targeted Liposomal Codelivery of Lipophilic Drug and Anti-Hsp90 Gene: Strategy to Induce Drug-Sensitivity, EMT-Reversal, and Reduced Malignancy in Aggressive Tumors.
abstract: Many cancers including the late stage ones become drug-resistant and undergo epithelial-to-mesenchymal transition (EMT). These lead to enhanced invasion, migration, and metastasis toward manifesting its aggressiveness and malignancy. One of the key hallmarks of cancer is its overdependence on glycolysis as its preferred energy metabolism pathway. The strict avoidance of alternate energy pathway gluconeogenesis by cancer cells points to a yet-to-be hoisted role of glucocorticoid receptor (GR) especially in tumor microenvironment, where cells are known to become drug-sensitive through induction of gluconeogenesis. However, since GR is involved in metabolism, anti-inflammatory reactions, immunity besides inducing gluconeogenesis, a greater role of GR in tumor microenvironment is envisaged. We have shown previously that GR, although ubiquitously expressed in all cells; afford to be an effective cytoplasmic target for killing cancer cells selectively. Herein, we report the therapeutic use of a newly developed GR-targeted liposomal concoction (DXE) coformulating a lipophilic drug (ESC8) and an anti-Hsp90 anticancer gene against aggressive tumor models. This induced drug-sensitivity and apoptosis while reversing EMT in tumor cells toward effective retardation of aggressive growth in pancreas and skin tumor models. Additionally, the ESC8-free lipid formulation upon cotreatment with hydrophilic drugs, gemcitabine and doxorubicin, could effectively sensitize and kill pancreatic cancer and melanoma cells, respectively. The formulation-triggered EMT-reversal was GR-dependent. Overall, we found a new strategy for drug sensitization that led to the advent of new GR-targeted anticancer therapeutics.
authors.affiliation: Biomaterials Group, CSIR-Indian Institute of Chemical Technology , Hyderabad 500 007, India.|Academy of Scientific & Innovative Research (AcSIR) , 2 Rafi Marg, New Delhi 110001, India.
authors.forename: Sujan Kumar
authors.initials: SK
authors.lastname: Mondal
authors.affiliation: Biomaterials Group, CSIR-Indian Institute of Chemical Technology , Hyderabad 500 007, India.|Academy of Scientific & Innovative Research (AcSIR) , 2 Rafi Marg, New Delhi 110001, India.
authors.forename: Sudhakar
authors.initials: S
authors.lastname: Jinka
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic , Jacksonville, Florida 32224, United States.
authors.forename: Krishnendu
authors.initials: K
authors.lastname: Pal
authors.affiliation: Biomaterials Group, CSIR-Indian Institute of Chemical Technology , Hyderabad 500 007, India.
authors.forename: Swetha
authors.initials: S
authors.lastname: Nelli
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic , Jacksonville, Florida 32224, United States.
authors.forename: Shamit Kumar
authors.initials: SK
authors.lastname: Dutta
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic , Jacksonville, Florida 32224, United States.
authors.forename: Enfeng
authors.initials: E
authors.lastname: Wang
authors.affiliation: Department of Clinical Pharmacy, King Saud University , Riyadh 11451, Saudi Arabia.
authors.forename: Ajaz
authors.initials: A
authors.lastname: Ahmad
authors.affiliation: Department of Clinical Pharmacy, King Saud University , Riyadh 11451, Saudi Arabia.
authors.forename: Khalid M
authors.initials: KM
authors.lastname: AlKharfy
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic , Jacksonville, Florida 32224, United States.
authors.forename: Debabrata
authors.initials: D
authors.lastname: Mukhopadhyay
authors.affiliation: Biomaterials Group, CSIR-Indian Institute of Chemical Technology , Hyderabad 500 007, India.|Academy of Scientific & Innovative Research (AcSIR) , 2 Rafi Marg, New Delhi 110001, India.
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Banerjee
mesh_terms: D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D004247:DNA / Q000737:chemistry; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics / Q000502:physiology*; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008081:Liposomes / Q000008:administration & dosage / Q000737:chemistry*; D051379:Mice; D016133:Polymerase Chain Reaction; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D000093542:Gemcitabine
chemical_list: D018841:HSP90 Heat-Shock Proteins; D008081:Liposomes; D011965:Receptors, Glucocorticoid; D003841:Deoxycytidine; D004317:Doxorubicin; D004247:DNA; D000093542:Gemcitabine
keywords: EMT; Hsp90; drug-sensitivity; glucocorticoid receptor; liposome; tumor