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.

Pseudopterosin Inhibits Proliferation and 3D Invasion in Triple-Negative Breast Cancer by Agonizing Glucocorticoid Receptor Alpha

“…The clinical use of GCs is discussed controversially due to extensive side effects, chemotherapy resistance, and survival of cancer cells [ 21 , 23 , 31 ]. However, the recent literature indicates the beneficial effects of GCs to be strongly dependent on the tumor entity: survival in patients receiving GC combined with anthracycline-based chemotherapy was improved [ 25 ].…”

Pseudopterosin Inhibits Proliferation and 3D Invasion in Triple Negative Breast Cancer by Agonizing Glucocorticoid Receptor Alpha

“…The clinical use of glucocorticoids (GC) is discussed controversially, due to extensive side effects, chemotherapy resistance and survival of cancer cells 21,23,31 . However, recent literature indicates the beneficial effects of GCs to be strongly dependent on the tumor entity: survival in patients receiving GC combined with anthracycline-based chemotherapy was improved 25 .…”

Marine Compounds and Cancer

“…For instance, high expression levels not only lead to poor prognosis for ER − breast cancer patients, but are also associated with better outcomes in patients with ER + breast cancer [55]. Suppression of chemotherapy induced apoptosis for example is correlated with high GR expression and poor prognosis [37,55,56]. On the other hand, glucocorticoids can suppress migration, invasion and angiogenesis via down-regulation of IL-6 and IL-8.…”