Cationic lipid-conjugated dexamethasone as a selective antitumor agent

Dexamethasone (Dex) is one of the highly potent synthetic glucocorticoids. It exhibits prominent anti-inflammatory but moderate anti-proliferative activities. It is widely used along side chemotherapy to alleviate toxic side effects. Additionally, Dex is also a potent inducer of gluconeogenesis. However, its overuse critically desensitizes cells against chemotherapy. Herein, we report on the development of a new class of cationic lipid-Dex conjugates in which the C-8 carbon chain analogue (DX8) exhibited Glucocorticoid Receptor (GR)-mediated, caspase-3-assisted, Cancer cell-selective anti-proliferative activity. Melanoma tumors in DX8-treated mice exhibited significantly reduced tumor aggressiveness with respect to tumors in Dex-treated mice. Tumor lysates prepared from DX8-treated group showed elevated levels of p53. DX8-treated Cancer cells showed clear degradation of kinase JAK3/STAT3 protein levels. Additionally, DX8-treatment decreased the level of VEGFR2/KDR/Flk-1 in tumor-endothelial cells implying DX8's anti-proliferative roles in both tumor cells and tumor neovascular cells. Collectively, our results demonstrate potent anti-angiogenic, and selective JAK3/STAT3 down-regulating Anticancer characteristics of DX8, a new dexamethasone-based antitumor molecule.

Apoptosis; Cationic lipid; Dexamethasone; Glucocorticoid receptor; Tumor.