Selective Cancer Targeting via Aberrant Behavior of Cancer Cell-associated Glucocorticoid Receptor

Abstract

Glucocorticoid receptors (GRs) are ubiquitous, nuclear hormone receptors residing in cell types of both cancer and noncancerous origin. It is not known whether cancer cell-associated GR alone can be selectively manipulated for delivery of exogenous genes to its nucleus for eliciting anticancer effect. We find that GR ligand, dexamethasone (Dex) in association with cationic lipoplex (termed as targeted lipoplex) could selectively manipulate GR in cancer cells alone for the delivery of transgenes in the nucleus, a phenomenon that remained unobserved in normal cells. The targeted lipoplex (i) showed GR-targeted transfections in all cancer cells experimented (P < 0.01), (ii) significantly diminished transfection in cancer cells when GR is downregulated (P < 0.01), and (iii) elicited specific nuclear translocation of targeted lipoplex in cancer cells, followed by upregulated transactivation of glucocorticoid response element (GRE)- promoted gene. Using anticancer gene, targeted lipoplex induced significant tumor growth retardation in mice in comparison to different control groups (P < 0.05). Interestingly, cell surface-associated Hsp90 in cancer cells assisted the intracellular uptake of GR-targeted lipoplex. Moreover, selective inhibition of Hsp90 in noncancer cells resulted in cancer cell-like, aberrant, GR activation. The current study discovers a therapeutically important, unique property of cancer cell associated-GR that may be linked to a compromised role of Hsp90.Molecular Therapy (2009) 17 4, 623-631 doi:10.1038/mt.2009.4.

A Lipid-Modified Estrogen Derivative that Treats Breast Cancer Independent of Estrogen Receptor Expression through Simultaneous Induction of Autophagy and Apoptosis

“…In a recent study, we could selectively manipulate glucocorticoid receptor (GR), a nuclear hormone receptor (NHR), in cancer cells using a cationic liposomal formulation associated with GR-ligand dexamethasone for selective access to the GR response element in cancer cells’ nuclei (36). In trying to replicate a similar observation with breast cancer cell-associated NHR, ER using its endogenous ligand, ES, we found to our surprise that ES in mere association with an eight-carbon, twin-chain, quaternary ammonium cationic lipid could efficiently kill both ER-positive and ER-negative breast cancer cells.…”

Quantification of lipid modified estrogenic derivative (ESC8) in rat plasma by LC‐MS: application to a pharmacokinetic study

“…All of the liposomes were prepared following the previous protocol (Mukherjee et al ., ). The DX liposomes contained DODEAC–Chol–Dex in 1:1:0.75 mol ratios, where DODEAC is N , N ‐dioctadecyl‐ N , N ‐dihydroxyethyl ammonium chloride, Chol is cholesterol and Dex is dexamethasone.…”

“…Interestingly, in ANV‐1 cells, neuropilin‐1 co‐receptors are expressed at least 4‐fold more than parental mucosal mast cells with epithelial character. This estrogenic (ER) drug‐mediated killing of ER‐negative breast cancer cells prompted us to conduct an in‐depth mechanistic study in ER‐negative MDA‐MB‐231 (Mukherjee et al ., ; Sinha et al ., ). The breast cancer cell line MDA‐MB‐231 is a highly malignant, ER‐negative cell line.…”

Targeted delivery of in situ PCR-amplified Sleeping Beauty transposon genes to cancer cells with lipid-based nanoparticle-like protocells

“…For FA modification, 5% FA-PEG 2000 -DSPE of total lipid was added in chloroform to make the thin film for protocell preparation. To integrate DEX into the protocells, DEX, instead of cholesterol, was added in chloroform with other lipid to prepare the thin film [18,19]. Then, the PCR solution, containing the transposon/transposase DNA template (0.1 ng/µL), primers (0.8 µM), dNTPs (0.2 mM each) and polymerase (0.025 U/µl), was added and the thin film was hydrated and dispersed by vortex mixing.…”