The steroid hormone receptors (SHRs) among nuclear hormone receptors (NHRs) are steroid ligand-dependent transcription factors that play important roles in the regulation of transcription of genes promoted via hormone responsive elements in our genome. Aberrant expression patterns and contextspecific regulation of these receptors in cancer, have been routinely reported by multiple research groups. These gave an window of opportunity to target those receptors in the context of developing novel, targeted anticancer therapeutics. Besides the development of a plethora of SHR-targeting synthetic ligands and the availability of their natural, hormonal ligands, development of many SHR-targeted, anticancer nano-delivery systems and theranostics, especially based on small molecules, have been reported. It is intriguing to realize that these cytoplasmic receptors have become a hot target for cancer selective delivery. This is in spite of the fact that these receptors do not fall in the category of conventional, targetable cell surface bound or transmembrane receptors that enjoy over-expression status. Glucocorticoid receptor (GR) is one such exciting SHR that in spite of it being expressed ubiquitously in all cells, we discovered it to behave differently in cancer cells, thus making it a truly druggable target for treating cancer. This review selectively accumulates the knowledge generated in the field of SHR-targeting as a major focus for cancer treatment with various anticancer small molecules and nanotherapeutics on progesterone receptor, mineralocorticoid receptor, and androgen receptor while selectively emphasizing on GR and estrogen receptor. This review also briefly highlights lipid-modification strategy to convert ligands into SHRtargeted cancer nanotherapeutics.
Cimetidine, a histamine-2 (H2) receptor antagonist, has
been found
to have anticancer properties against a number of cancer-type cells.
In this report, we have demonstrated that cimetidine can acts as a
hydrophilic domain in cationic lipids and targetable to the gastric
system by carrying reporter genes and therapeutic genes through in
vitro transfection. Two lipids, namely, Toc-Cim and Chol-Cim consisting
cimetidine as the main head group and hydrophobic moieties as alpha-tocopherol
or cholesterol, respectively, were designed and synthesized. 1,2-Dioleoyl-
sn
-glycero-3-phosphoethanolamine (DOPE) is a well-known
co-lipid employed to produce liposomes as uniform vesicles. The liposomes
and lipoplexes were structurally and functionally evaluated for global
surface charges and hydrodynamic diameters, and results found that
both liposome and lipoplex size and surface charges are optimal to
screen the transfection potentials. DNA-binding studies were analyzed
as complete binding at all formulated N/P ratios. The liposomes and
lipoplexes of both the lipids Toc-Cim and Chol-Cim show minimal cytotoxicity
even though at higher concentrations. The results of the transfection
experiments revealed that tocopherol-based cationic lipids (Toc-Cim)
show finer transfection efficacy with optimized N/P ratios (2:1 and
4:1) in the colon cancer cell line. Toc-Cim lipoplexes show higher
cellular uptake compare to Chol-Cim in the colon cancer cell line
at 2:1 and 4:1 N/P ratios. Toc-Cim and Chol-Cim lipids showed highly
compatible serum, examined up to 50% of the serum concentration. To
evaluate the apoptotic cell death in CT-26 cells, exposed to Toc-Cim:p53
and Chol-Cim:p53 lipoplexes at 2:1 N/P ratios, superior results showed
with Toc-Cim:p53. An effect of TP53 protein expression in CT-26 cell
lines assayed by western blot, transfected with Toc-Cim:p53 and Chol-Cim:p53
lipoplexes, demonstrated the superior efficacy of Toc-Cim. All of
the findings suggest that Toc-Cim lipid is relatively secure and is
an effective transfection agent to colon cancer gene delivery.
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