In-vitro and in-vivo investigations into the carbene-gold anticancer drug candidates NHC*-Au-SCSNMe2 and NHC*-Au-S-GLUC against advanced prostate cancer PC3. Issue 7 (August 2020)

• Record Type: Journal Article
• Authors: Walther, Wolfgang; Althagafi, Dhiyaa; Curran, Danielle; O'Beirne, Cillian; Mc Carthy, Cian; Ott, Ingo; Basu, Uttara; Büttner, Britta; Sterner-Kock, Anja; Müller-Bunz, Helge; Sánchez-Sanz, Goar; Zhu, Xiangming; Tacke, Matthias
• Is Part Of: Anti-cancer drugs. Volume 31:Issue 7(2020)
• Publication Date: 2020-08
• Subjects: carbene-gold anticancer drug -- NCI 60 cancer cell panel -- advanced prostate cancer -- thioredoxin reductase -- xenograft mouse model; Antineoplastic agents -- Periodicals; Cancer -- Chemotherapy -- Periodicals; Antineoplastic Agents -- therapeutic use -- Periodicals; Drug Therapy -- Periodicals; 616.994061
• DOI: 10.1097/CAD.0000000000000930
• Languages: English
• ISSNs: 0959-4973

Abstract

Abstract : The anticancer drug candidates 1, 3-dibenzyl-4, 5-diphenyl-imidazol-2-ylidene gold(I) dimethylamino dithiocarbamate and 2, 3, 4, 6-tetra-O-acetyl-α-D-glucopyranosyl-1-thiolate derivative exhibited nanomolar in-vitro activity against prostate cancer cells advanced prostate cancer (PC3) and micromolar inhibition of mammalian thioredoxin reductase. Encouraging maximum tolerable dose experiments led to human prostate cancer subcutaneous xenograft experiments; 1, 3-dibenzyl-4, 5-diphenyl-imidazol-2-ylidene gold(I) dimethylamino dithiocarbamate and 2, 3, 4, 6-tetra-O-acetyl-α-D-glucopyranosyl-1-thiolate derivative were applied twelve times at two doses in groups of n = 5 PC3 to tumor-bearing NMRI:nu/nu mice. 1, 3-dibenzyl-4, 5-diphenyl-imidazol-2-ylidene gold(I) dimethylamino dithiocarbamate and 2, 3, 4, 6-tetra-O-acetyl-α-D-glucopyranosyl-1-thiolate derivative at the dose of 10 and 20 mg/kg showed good tolerability, while no significant body weight loss was seen in both groups. In particular, for the drug 1, 3-dibenzyl-4, 5-diphenyl-imidazol-2-ylidene gold(I) dimethylamino dithiocarbamate the tumor growth inhibition suggested to be dose dependent, reflected by the respective optimal T/C values of 0.45 at the dose of 10 mg/kg and of 0.31 at the dose of 20 mg/kg. By contrast, the 2, 3, 4, 6-tetra-O-acetyl-α-D-glucopyranosyl-1-thiolate derivative treated groups showed no indication for dose-dependent antitumoral activity, as reflected by the optimal T/C values of 0.44 for the 10 mg/kg and for the 20 mg/kg treated mice. Immunohistochemical experiments involving Ki67 staining of tumor tissue showed that both compounds reduced PC3 cell proliferation against the difficult to treat advanced human prostate tumors derived from PC3. Abstract : Supplemental Digital Content is available in the text.