We present the anticancer properties of cis, cis, trans-[Pt(IV)(NH3)2Cl2(OA)2] [Pt(IV)diOA] (OA = octanoato), Pt(IV) derivative of cisplatin containing two OA units appended to the axial positions of a six-coordinate Pt(IV) center. Our results demonstrate that Pt(IV)diOA is a potent cytotoxic agent against many cancer cell lines (the IC50 values are approximately two orders of magnitude lower than those of clinically used cisplatin or Pt(IV) derivatives with biologically inactive axial ligands). Importantly, Pt(IV)diOA overcomes resistance to cisplatin, is significantly more potent than its branched Pt(IV) valproato isomer and exhibits promising in vivo antitumor activity. The potency of Pt(IV)diOA is a consequence of several factors including enhanced cellular accumulation correlating with enhanced DNA platination and cytotoxicity. Pt(IV)diOA induces DNA hypermethylation and reduces mitochondrial membrane potential in cancer cells at levels markedly lower than the IC50 value of free OA suggesting the synergistic action of platinum and OA moieties. Collectively, the remarkable antitumor effects of Pt(IV)diOA are a consequence of the enhanced cellular uptake which makes it possible to simultaneously accumulate high levels of both cisplatin and OA in cells. The simultaneous dual action of cisplatin and OA by different mechanisms in tumor cells may result in a markedly enhanced and unique antitumor effects of Pt(IV) prodrugs.

• MeSH
• cisplatina * analogy a deriváty   farmakokinetika   farmakologie   MeSH
• DNA nádorová metabolismus   MeSH
• epigeneze genetická účinky léků   MeSH
• lidé MeSH
• metylace DNA účinky léků   MeSH
• nádorové buněčné linie MeSH
• nádory vaječníků * farmakoterapie   metabolismus   patologie   MeSH
• protinádorové látky * farmakokinetika   farmakologie   MeSH
• regulace genové exprese u nádorů účinky léků   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cisplatina * MeSH
• DNA nádorová MeSH
• protinádorové látky * MeSH

Halogenido and carboxylato Ru(II) half-sandwich complexes of the general composition [Ru(η⁶-p-cym)(dpa)X]PF₆ (1-5) were prepared and thoroughly characterized with various techniques (e.g., mass spectrometry, NMR spectroscopy and X-ray analysis); dpa = 2,2'-dipyridylamine; p-cym = p-cymene; X = Cl- (for 1), Br- (for 2), I- (for 3), valproate(1-) (for 4) or 4-phenylbutyrate(1-) (for 5). A single-crystal X-ray analysis showed a pseudo-octahedral piano-stool geometry of [Ru(η⁶-p-cym)(dpa)I]PF₆ (3), with a η⁶-coordinated p-cymene, bidentate N-donor dpa ligand and iodido ligand coordinated to the Ru(II) atom. The results of the ¹H-NMR solution behaviour studies proved that the complexes 1-5 hydrolyse were in the mixture of solvents used (10% MeOD-d₄/90% D₂O). Complexes 1-5 were in vitro inactive against the A2780 human ovarian carcinoma cell line, up to the highest tested concentration (IC50 > 100 μM).

• Klíčová slova
• 2,2′-dipyridylamine, X-ray structure, half-sandwich, in vitro cytotoxicity, ruthenium, solution behaviour,
• MeSH
• glutathion chemie   MeSH
• krystalografie rentgenová MeSH
• lidé MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• nádory farmakoterapie   MeSH
• protinádorové látky chemická syntéza   chemie   MeSH
• protonová magnetická rezonanční spektroskopie MeSH
• racionální návrh léčiv * MeSH
• rozpouštědla chemická syntéza   chemie   MeSH
• ruthenium chemie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• glutathion MeSH
• protinádorové látky MeSH
• rozpouštědla MeSH
• ruthenium MeSH

Our study demonstrates that Pt(iv) derivative of cisplatin, with two axial PhB ligands, ctc-[Pt(NH3)2(PhB)2Cl2], is a very potent cytotoxic agent against many different human cancer cell lines and is up to 100 fold more potent than cisplatin, and significantly more potent than the Pt(iv) derivatives of cisplatin with either two hydroxido, two acetato or two valproato ligands. The high potency of this compound (and some others) is due to several factors including enhanced internalization, probably driven by "synergistic accumulation" of both the Pt moiety and the phenylbutyrate, that correlates with enhanced DNA binding and cytotoxicity. ctc-[Pt(NH3)2(PhB)2Cl2] inhibits 60-70% HDAC activity in cancer cells, at levels below the IC50 values of PhB, suggesting synergism between Pt and PhB. Mechanistically, ctc-[Pt(NH3)2(PhB)2Cl2] induces activation of caspases (3 and 9) triggering apoptotic signaling via the mitochondrial pathway. Data also suggest that the antiproliferative effect of ctc-[Pt(NH3)2(PhB)2Cl2] may not depend of p53. Pt(iv) derivatives of cisplatin with either two axial PhB or valproate ligands are more potent than their oxaliplatin analogs. ctc-[Pt(NH3)2(PhB)2Cl2] is significantly more potent than its valproate analog ctc-[Pt(NH3)2(VPA)2Cl2]. These compounds combine multiple effects such as efficient uptake of both Pt and PhB with DNA binding, HDAC inhibition and activation of caspases to effectively kill cancer cells.

• Publikační typ
• časopisecké články MeSH