title: Cationic lipid-conjugated dexamethasone as a selective antitumor agent.
abstract: 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 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.
authors.affiliation: Biomaterials Group, CSIR-Indian Institute of Chemical Technology (CSIR-IICT), Tarnaka, Uppal Road, Hyderabad, Andhra Pradesh 500007, India.
authors.forename: Samaresh
authors.initials: S
authors.lastname: Sau
authors.affiliation: Biomaterials Group, CSIR-Indian Institute of Chemical Technology (CSIR-IICT), Tarnaka, Uppal Road, Hyderabad, Andhra Pradesh 500007, India; Academy of Scientific and Innovative Research (AcSIR), 2 Rafi Marg, New Delhi 110 001, India. Electronic address: banerjee@iict.res.in.
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Banerjee
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003907:Dexamethasone / Q000737:chemistry* / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008055:Lipids / Q000737:chemistry*; D051379:Mice; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D008055:Lipids; D011965:Receptors, Glucocorticoid; D050791:STAT Transcription Factors; D016159:Tumor Suppressor Protein p53; D003907:Dexamethasone; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases
keywords: Apoptosis; Cationic lipid; Dexamethasone; Glucocorticoid receptor; Tumor