Cationic lipid-conjugated hydrocortisone as selective antitumor agent

Rathore, Bhowmira; Jaggarapu, Madhan Mohan Chandra Sekhar; Ganguly, Anirban; Rachamalla, Hari Krishnareddy; Banerjee, Rajkumar

doi:10.1016/j.ejmech.2015.11.033

Cited by 19 publications

(28 citation statements)

References 22 publications

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“…In the framework of solid tumors and the associated leaky vasculature, recent work in metastatic prostate cancer bone lesions shows that liposomal encapsulated dexamethasone is delivered to these malignant bone lesions and sometimes inhibits in vivo tumor growth more efficiently than systemic administration of dexamethasone [ 153 ]. Also the recent research proving the anti-cancer effect of cationic lipid- conjugated hydrocortisone, which selectively targets cancer cells endorses the possibility of cell-type specific GR-targeting compounds [ 154 ].…”

Section: Discussionmentioning

confidence: 99%

Selective glucocorticoid receptor-activating adjuvant therapy in cancer treatments

et al. 2016

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Although adverse effects and glucocorticoid resistance cripple their chronic use, glucocorticoids form the mainstay therapy for acute and chronic inflammatory disorders, and play an important role in treatment protocols of both lymphoid malignancies and as adjuvant to stimulate therapy tolerability in various solid tumors. Glucocorticoid binding to their designate glucocorticoid receptor (GR), sets off a plethora of cell-specific events including therapeutically desirable effects, such as cell death, as well as undesirable effects, including chemotherapy resistance, systemic side effects and glucocorticoid resistance. In this context, selective GR agonists and modulators (SEGRAMs) with a more restricted GR activity profile have been developed, holding promise for further clinical development in anti-inflammatory and potentially in cancer therapies. Thus far, the research into the prospective benefits of selective GR modulators in cancer therapy limped behind. Our review discusses how selective GR agonists and modulators could improve the therapy regimens for lymphoid malignancies, prostate or breast cancer. We summarize our current knowledge and look forward to where the field should move to in the future. Altogether, our review clarifies novel therapeutic perspectives in cancer modulation via selective GR targeting.

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Section: Discussionmentioning

confidence: 99%

Selective glucocorticoid receptor-activating adjuvant therapy in cancer treatments

et al. 2016

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“…Our molecule, which is structurally modified at the C17α position with a bulk cationic twin chain lipid, has its inherent cytotoxic activity, synergizing properties, and drug-sensitizing effects. The molecule in combination with drugs like docetaxel and doxorubicin showed potent synergistic effects and also regulated the expression of drug-metabolizing enzymes CYP3A4 and CYP1A1 and drug efflux gene, MDR-1, indicating its potential in inhibiting the drug-resistance mechanisms of tumors and improving the therapeutic response to drugs.…”

Section: Discussionmentioning

confidence: 99%

“…On the contrary, the ubiquitous distribution of GR in almost all cells of the body poses a potential challenge for the selective targeting of cancer-associated GR. Still, previous studies from our group have shown that the functional modification of GCs by associating them with cationic lipid formulations could exert tumor-selective beneficial effects via modulation of GR − and can also be utilized for cancer cell-selective gene delivery . Such GC-associated formulations led to GR-mediated drug sensitization and also induced the reversal of epithelial to mesenchymal transition (EMT) in late-stage, aggressive pancreatic and skin tumors and in drug-resistant cancer-stem-cell-like cells. , Additionally, cationic lipid conjugates of GC ligands showed multifaceted therapeutic effects in the form of cancer cell-selective anti-proliferative activity, the induction of apoptosis in tumor and tumor-associated cells, the enhancement of p53 levels, potent anti-angiogenic activity, and the effective regression of tumor growth in mice. , …”

Section: Introductionmentioning

confidence: 99%

Self-Assembling Derivative of Hydrocortisone as Glucocorticoid Receptor-Targeted Nanotherapeutics for Synergistic, Combination Therapy against Colorectal Tumor

et al. 2020

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Hydrocortisone, a natural glucocorticoid secreted by adrenal and extra-adrenal tissues, locally governs the transcription of genes involved in inflammation, immune response, metabolism, and energy homeostasis via binding to its cognate glucocorticoid receptor (GR). In this study, we show that modified hydrocortisone (HC16), a cancer-selective cytotoxic molecule, showed synergism in combination with drugs like Doxorubicin and docetaxel, self-assembled into vesicles, entrapped docetaxel and complexed with anti-cancer plasmid DNA for enhanced killing of cancer cells. These vesicles exhibited GR-mediated nuclear localization, delivery of the p53 gene, and also inhibited cell viability selectively in RKO, HCT15, and CT26 colon cancer cells but not in normal cells like CHO and HEK293T. Apart from exerting its own anti-cancer activity, the self-assembled HC16 vesicles loaded with docetaxel sensitized the cancer cells to its drug cargo by downregulating the drug metabolizing CYP3A4 gene. This indirectly reduces the risk of nonspecific adverse effects in normal cells, as the viability of sensitized cancer cells could be significantly reduced even in low doses of cytotoxic docetaxel. The near infrared (NIR)-dye-associated self-assemblies accumulated in a colon tumor with higher orders of NIR intensity compared to those in a colon of healthy mice. Thereafter, the treatment of HC16− docetaxel−p53 vesicle/DNA complex led to significant tumor regression, which resulted in a cecum/body weight ratio in tumorbearing mice similar to that of healthy mice measured at 24 h postcompletion of treatment. There was an up to 2.5-fold enhancement in the overall survivability of colon-tumor-bearing mice treated with HC16−docetaxel−p53 vesicle/DNA complexes when compared against the pristine docetaxel-treated groups. Further, the HC16−docetaxel−p53 vesicle/DNA complex-treated group showed reduced nuclear accumulation of cell proliferation marker Ki67, reduced protein levels of prosurvival and mesenchymal proteins like Bcl-2, PARP, vimentin, and N-cadherin, and increased the levels of pro-apoptotic activated caspases as compared to the pristine docetaxel-treated groups. The therapeutic package described herein is expected to find future use as a rational, multifaceted, GR-targeted approach for inhibiting colon tumor progression.

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“…Queuing up, we sought to check if GR endogenous ligand, hydrocortisone also behaves similarly, we modified hydrocortisone with cationic lipids of varied size. SAR study indicated HYC16, the aliphatic 16 carbon chain based cationic lipid-modified hydrocortisone, to be the most potent and selective in killing cancer cells and potently inhibiting angiogenesis (Rathore et al, 2016). As shown by other cationic lipid-modified GCs, for example, DX10, the same molecule HYC16 also exhibits potent drug sensitizing ability in cancer cells through reversal of EMT (Sridharan et al, 2021).…”

Section: Dermatological Medicationsmentioning

confidence: 98%

“…We earlier discussed about the generation of a GR-targeted, anticancer drug (called, HYC16) by chemically modifying the endogenous GR-hormone, hydrocortisone by conjugation with C16 aliphatic carbon chain (Rathore et al, 2016). The ethanol solution of HYC16 when injected in aqueous solution undergoes self-aggregation and forms a stable clear suspension that can complex with DNA.…”

Section: Gr-targeted Nanotherapeutics For Cancermentioning

confidence: 99%

Targeting steroid hormone receptors for anti‐cancer therapy—A review on small molecules and nanotherapeutic approaches

Mahadik

Bhattacharya

Padmanabhan

et al. 2021

WIREs Nanomed Nanobiotechnol

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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.

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Cationic lipid-conjugated hydrocortisone as selective antitumor agent

Cited by 19 publications

References 22 publications

Selective glucocorticoid receptor-activating adjuvant therapy in cancer treatments

Selective glucocorticoid receptor-activating adjuvant therapy in cancer treatments

Self-Assembling Derivative of Hydrocortisone as Glucocorticoid Receptor-Targeted Nanotherapeutics for Synergistic, Combination Therapy against Colorectal Tumor

Targeting steroid hormone receptors for anti‐cancer therapy—A review on small molecules and nanotherapeutic approaches

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