Biotin-Pt (IV)-indomethacin hybrid: A targeting anticancer prodrug providing enhanced cancer cellular uptake and reversing cisplatin resistance

• Published in: Journal of inorganic biochemistry Vol. 175; pp. 47 - 57
• Main Authors: Hu, Weiwei, Fang, Lei, Hua, Wuyang, Gou, Shaohua
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2017
• Subjects: A549 Cells; Antiangiogenic; Biotin; Biotin - chemistry; Biotin - pharmacokinetics; Biotin - pharmacology; Cisplatin; COX inhibitor; Drug resistance; Drug Resistance, Neoplasm - drug effects; Hep G2 Cells; Humans; Indomethacin - chemistry; Indomethacin - pharmacokinetics; Indomethacin - pharmacology; Neoplasms - drug therapy; Neoplasms - metabolism; Neoplasms - pathology; Organoplatinum Compounds - chemical synthesis; Organoplatinum Compounds - chemistry; Organoplatinum Compounds - pharmacokinetics; Organoplatinum Compounds - pharmacology; Prodrugs - chemical synthesis; Prodrugs - chemistry; Prodrugs - pharmacokinetics; Prodrugs - pharmacology; Targeting antitumor Pt(IV) prodrug; COX inhibitor; Biotin; Drug resistance; Antiangiogenic; Targeting antitumor Pt(IV) prodrug; CZIHGJNXMXKBHW-UHFFFAOYSA-D
• ISSN: 0162-0134; 1873-3344
• DOI: 10.1016/j.jinorgbio.2017.07.002

A Pt(IV) prodrug (2) composed of cancer-targeting biotin and nonsteroidal anti-inflammatory drug indomethacin in the axial positions of the six-coordinated octahedral geometry derived from cisplatin was developed, which could be highly accumulated in cancer cells more than normal ones and activated by endogenous reducing molecules to release cisplatin and indomethacin moieties simultaneously to inhibit tumor progression synergistically. In vitro assays revealed that 2 exhibited significantly selective inhibition to the tested cancer cell lines and sensitivity to cisplatin resistant cancer cells. Moreover, 2 presented cyclooxygenases inhibition properties to reduce tumor-associated inflammation, reduced the invasiveness of the highly aggressive PC-3 cells, and disrupted capillary-like tube formation in EA.hy926 cells. In all, this study offers a new strategy to enhance sensitivity and reduce toxicity of cisplatin. Pt(IV) prodrug 2 highly accumulate in cancer cells than normal ones and activated by endogenous reducing molecules to release cisplatin and indomethacin simultaneously, exhibiting selective inhibition to cancer cell lines and sensitivity to cisplatin-resistant cancer cells. Moreover, this prodrug reduces the invasiveness of tumor cells and disrupts capillary-like tube formation. [Display omitted] •Pt(IV) prodrug 2 composed of cancer-targeting moiety and anti-inflammatory drug•Prodrug 2 could be highly accumulated in cancer cells than normal ones.•Prodrug 2 selectively inhibits cancer cell lines.•Prodrug 2 sensitive to cisplatin resistant cancer cells•Prodrug 2 reduces invasiveness of tumor cells and disrupts capillary-like tube formation.