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

Sujan Kumar Mondal, Sudhakar Jinka, Krishnendu Pal, Swetha Nelli, Shamit Kumar Dutta, Enfeng Wang, Ajaz Ahmad, Khalid M. Alkharfy, Debabrata Mukhopadhyay, Rajkumar Banerjee

Research output: Contribution to journalArticle

7 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2507-2523
Number of pages17
JournalMolecular Pharmaceutics
Volume13
Issue number7
DOIs
StatePublished - Jul 5 2016

Keywords

  • EMT
  • Hsp90
  • drug-sensitivity
  • glucocorticoid receptor
  • liposome
  • tumor

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

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