Cationic lipid-conjugated hydrocortisone as selective antitumor agent

• Published in: European journal of medicinal chemistry Vol. 108; pp. 309 - 321
• Main Authors: Rathore, Bhowmira, Chandra Sekhar Jaggarapu, Madhan Mohan, Ganguly, Anirban, Reddy Rachamalla, Hari Krishna, Banerjee, Rajkumar
• Format: Journal Article
• Language: English
• Published: PARIS Elsevier Masson SAS 27.01.2016; Elsevier
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Cationic lipid; Cations - chemistry; Cations - pharmacology; Cell Cycle - drug effects; Cell Proliferation - drug effects; Chemistry, Medicinal; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Glucocorticoid receptor; Hydrocortisone; Hydrocortisone - chemical synthesis; Hydrocortisone - chemistry; Hydrocortisone - pharmacology; Life Sciences & Biomedicine; Lipids - chemistry; Lipids - pharmacology; Molecular Structure; Pharmacology & Pharmacy; Science & Technology; Structure-Activity Relationship; Tumor; Tumor; Hydrocortisone; Cationic lipid; Glucocorticoid receptor; BREAST-CANCER; CELLS; DEXAMETHASONE; GLUCOCORTICOID-RECEPTOR; DIURNAL CORTISOL RHYTHM; MECHANISMS
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2015.11.033

Hydrocortisone, the endogenously expressed steroidal, hormonal ligand for glucocorticoid receptor (GR), is body's natural anti-inflammatory and xenobiotic metabolizing agent. It has both palliative as well as adverse effects in different cancer patients. Herein, we show that conjugation product of C16-carbon chain-associated cationic lipid and hydrocortisone (namely, HYC16) induces selective toxicity in cancer (e.g. melanoma, breast cancer and lung adenocarcinoma) cells with least toxicity in normal cells, through induction of apoptosis and cell cycle arrest at G2/M phase. Further, significant tumor growth inhibition was observed in syngeneic melanoma tumor model with considerable induction of apoptosis in tumor-associated cells. In contrast to hydrocortisone, significantly higher anti-angiogenic behavior of HYC16 helped in effective tumor shrinkage. This is the first demonstration to convert natural hormone hydrocortisone into a selective bioactive entity possessing anti-tumor effect. [Display omitted] •Cationic lipid-hydrocortisone conjugate, HYC16 exhibits high anticancer activity.•HYC16 triggers up-regulation of p53.•HYC16 down-regulates pro-angiogenic factor VEGFR2 and blood vessel formation.•HYC16 effectively regress tumor growth in mice.