Improved in vitro antitumor potential of (O,O′-Diisobutyl-ethylenediamine-N,N′-di-3-propionate)tetrachloridoplatinum(IV) complex under normoxic and hypoxic conditions

• Published in: European journal of pharmacology Vol. 760; pp. 136 - 144
• Main Authors: Bulatović, Mirna, Kaluđerović, Milena R., Mojić, Marija, Zmejkovski, Bojana B., Hey-Hawkins, Evamarie, Vidaković, Melita, Grdović, Nevena, Kaluđerović, Goran N., Mijatović, Sanja, Maksimović-Ivanić, Danijela
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 05.08.2015
• Subjects: Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Apoptosis - physiology; ATP depletion; Cell Hypoxia - drug effects; Cell Hypoxia - physiology; Cell Line, Tumor; Cell Survival - drug effects; Cell Survival - physiology; Cisplatin; Dose-Response Relationship, Drug; Hypoxic conditions; Mice; Mitochondrial collapse; NIH 3T3 Cells; Oxidative stress; Platinum Compounds - chemistry; Platinum Compounds - pharmacology; Platinum(IV) complex; Oxidative stress; Hypoxic conditions; ATP depletion; Mitochondrial collapse; Platinum(IV) complex; Cisplatin; Cisplatin (PubChem CID: 441203)
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2015.04.012

(O,O′-Diisobutyl-ethylenediamine-N,N′-di-3-propionate)tetrachloridoplatinum(IV), [PtCl4(iBu2eddp)], shows an improved pharmacological profile in comparison to cisplatin. This is manifested through accelerated dying process led by necrotic cell death, reflected through mitochondrial collapse, strong ATP depletion and reactive oxygen species production. Loss of mitochondrial potential was further followed with intensive apoptosis that finalized with DNA fragmentation. Different dynamic of tumoricidal action could be partly ascribed to less affected repair mechanisms in comparison to cisplatin. Importantly, [PtCl4(iBu2eddp)] did not induce necrosis in primary fibroblasts suggesting different intracellular response of normal vs. tumor cells. This selectivity toward malignant phenotype is further confirmed by retained tumoricidal potential in hypoxic conditions, while cisplatin became completely inefficient. [Display omitted]