Chemical and cellular investigations of trans-ammine-pyridine-dichlorido-platinum(II), the likely metabolite of the antitumor active cis-diammine-pyridine-chorido-platinum(II)

• Published in: Journal of inorganic biochemistry 2013-12, Vol.129, p.15-22
• Main Authors: Xu, Dechen, Min, Yuanzeng, Cheng, Qinqin, Shi, Hongdong, Wei, Kaiju, Arnesano, Fabio, Natile, Giovanni, Liu, Yangzhong
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antitumor; Cell Line, Tumor; DNA; DNA Adducts - metabolism; DNA, Neoplasm - metabolism; HMGB1; HMGB1 Protein - metabolism; Humans; Kinetics; Neoplasm Proteins - metabolism; Neoplasms - drug therapy; Neoplasms - metabolism; Platinum - chemistry; Platinum - pharmacology; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Trans Platinum Complexes
• ISSN: 0162-0134; 1873-3344
• DOI: 10.1016/j.jinorgbio.2013.07.040

It has been proposed that the well-studied monofunctional platinum complex cis-[PtCl(NH3)2(py)]+ (cDPCP) forms DNA adducts similar to those of the trans platinum complex trans-[PtCl2(NH3)(py)] (ampyplatin, py=pyridine). Thus this latter could be the active form of cDPCP. Detailed studies on the mechanism of ampyplatin action were performed in this work. Results indicate that ampyplatin has significantly higher antiproliferative activity than cDPCP and is comparable to cisplatin. Cellular uptake experiments indicate that ampyplatin can be efficiently accumulated in A549 cancer cells. Binding of ampyplatin to DNA mainly produces monofunctional adducts; remarkably, these adducts can be recognized by the HMGB1 protein. Kinetic studies on the reaction with GMP indicate that the reactivity of ampyplatin is much lower than that of transplatin and is more similar to that of trans-[PtCl2{E-HN=C(Me)OMe}2] (trans-EE), a widely investigated antitumor active trans-oriented platinum complex. In addition, the hydrolysis of ampyplatin is significantly suppressed, whereas the hydrolysis of the mono-GMP adduct is highly enhanced. These results indicate that the mechanism of ampyplatin differs not only from that of antitumor inactive transplatin but also from that of antitumor active trans-EE and this could account for the remarkable activity of parent cDPCP. Ampyplatin shows greater antiproliferative activity than the parent drug cDPCP and forms monofunctional DNA adducts recognized by HMG proteins. [Display omitted] •Ampyplatin shows greater antiproliferative activity than its parent drug cDPCP.•Ampyplatin forms preferentially monofunctional adducts with DNA.•The monofunctional DNA adducts can be recognized by HMGB1 proteins.•The kinetics of hydrolysis and reaction with GMP of ampyplatin have been studied.