The substitution inert platinum agent [Pt(1 S,2 S-diaminocyclohexane)(5,6-dimethyl-1,10-phenanthroline)]2+ (56MeSS, 5) is a potent cytotoxic metallodrug. In contrast to conventional cisplatin or oxaliplatin, the mechanism of action (MoA) of 5 is fundamentally different. However, details of the mechanism by which the 5,6-dimethyl-1,10-phenanthroline ligand contributes to the cytotoxicity of 5 and its derivatives have not been sufficiently clarified so far. Here, we show that 5 and its Pt(IV) derivatives exhibit an intriguing potency in the triple-negative breast cancer cells MDA-MB-231. Moreover, we show that the Pt(IV) derivatives of 5 act by multimodal MoA resulting in the global biological effects, that is, they damage nuclear DNA, reduce the mitochondrial membrane potential, induce the epigenetic processes, and last but not least, the data provide evidence that changes in the organization of cytoskeleton networks are functionally important for 5 and its derivatives, in contrast to clinically used platinum cytostatics, to kill cancer cells.
- MeSH
- aktiny antagonisté a inhibitory MeSH
- antitumorózní látky chemická syntéza metabolismus farmakologie MeSH
- CHO buňky MeSH
- Cricetulus MeSH
- cytoskelet účinky léků MeSH
- DNA nádorová účinky léků MeSH
- epigeneze genetická účinky léků MeSH
- křečci praví MeSH
- léky antitumorózní - screeningové testy MeSH
- lidé MeSH
- ligandy MeSH
- mikrotubuly účinky léků MeSH
- modulátory tubulinu farmakologie MeSH
- nádorové buněčné linie MeSH
- organoplatinové sloučeniny chemická syntéza metabolismus farmakologie MeSH
- triple-negativní karcinom prsu farmakoterapie MeSH
- zvířata MeSH
- Check Tag
- křečci praví MeSH
- lidé MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
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
- antitumorózní látky * farmakokinetika farmakologie 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
- regulace genové exprese u nádorů účinky léků MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The molecular and cellular mechanisms of enhanced toxic effects in tumor cells of the Pt(IV) derivatives of antitumor oxaliplatin containing axial dichloroacetate (DCA) ligands were investigated. DCA ligands were chosen because DCA has shown great potential as an apoptosis sensitizer and anticancer agent reverting the Wartburg effect. In addition, DCA reverses mitochondrial changes in a wide range of cancers, promoting tumor cell apoptosis in a mitochondrial-dependent pathway. We demonstrate that (i) the transformation of oxaliplatin to its Pt(IV) derivatives containing axial DCA ligands markedly enhances toxicity in cancer cells and helps overcome inherent and acquired resistance to cisplatin and oxaliplatin; (ii) a significant fraction of the intact molecules of DCA conjugates with Pt(IV) derivative of oxaliplatin accumulates in cancer cells where it releases free DCA; (iii) mechanism of biological action of the Pt(IV) derivatives of oxaliplatin containing DCA ligands is connected with the effects of DCA released in cancer cells from the Pt(IV) prodrugs on mitochondria and metabolism of glucose; (iv) treatments with the Pt(IV) derivatives of oxaliplatin containing DCA ligands activate an autophagic response in human colorectal cancer cells; (v) the toxic effects in cancer cells of the Pt(IV) derivatives of oxaliplatin containing DCA ligands can be potentiated if cells are treated with these prodrugs in combination with 5-fluorouracil. These properties of the Pt(IV) derivatives of oxaliplatin containing DCA ligands provide opportunities for further development of new platinum-based agents with the capability of killing cancer cells resistant to conventional antitumor platinum drugs used in the clinic.
Substitutionally inert Pt(IV) prodrugs, combining bioactive axial ligands with Pt(IV) derivatives of antitumor Pt(II) compounds, represent a new generation of anticancer drugs. The rationale behind these prodrugs is to release, by reductive elimination inside the cancer cell, an active Pt(II) drug which binds nuclear DNA as well as bioactive ligands that may potentiate toxic effects of the Pt(II) drugs by an independent pathway. Platinum prodrugs, such as Pt(IV) derivatives of cisplatin containing axial valproic acid (VPA) ligands, destroy cancer cells with greater efficacy than conventional cisplatin. These axial ligands were chosen because VPA inhibits histone deacetylase (HDAC) activity, thereby decondensing chromatin and subsequently increasing the accessibility of DNA within chromatin to DNA-binding agents. We examined the mechanism of cytotoxic activity of Pt(IV) derivatives of cisplatin with VPA axial ligands. Particular attention was paid to the role of the VPA ligand in these Pt(IV) prodrugs in the mechanism underlying their toxic effects in human ovarian tumor cells. We demonstrate that (i) treatment of the cells with these prodrugs resulted in enhanced histone H3 acetylation and decondensation of heterochromatin markedly more effectively than free VPA; (ii) of the total Pt inside the cells, a considerably higher fraction of Pt from the Pt(IV)-VPA conjugates is bound to DNA than from the conjugates with biologically inactive ligands. The results indicate that the enhanced cytotoxicity of the Pt(IV)-VPA conjugates is a consequence of several processes involving enhanced cellular accumulation, downregulation of HDACs and yet other biochemical processes (not involving HDACs) which may potentiate antitumor effects.
- MeSH
- acetylace MeSH
- epigeneze genetická * MeSH
- glutathion metabolismus MeSH
- histondeacetylasy metabolismus MeSH
- histony metabolismus MeSH
- kyselina valproová chemie metabolismus MeSH
- lidé MeSH
- magnetická rezonanční spektroskopie MeSH
- nádorové buněčné linie MeSH
- nádory vaječníků genetika metabolismus patologie MeSH
- organoplatinové sloučeniny chemie metabolismus MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
We report new anticancer prodrugs, platinum(IV) derivatives of oxaliplatin conjugated with valproic acid (VPA), a well-known drug having histone deacetylase inhibitory activity. Like most platinum(IV) derivatives, the cytotoxicity of the conjugates was lower in cell culture than that of oxaliplatin, but greater than those of its Pt(IV) derivative containing biologically inactive axial ligands in several cancer cell lines. Notably, these conjugates display activity in both cisplatin sensitive- and resistant tumor cells capable of both markedly enhanced accumulation in tumor cells and acting in a dual threat manner, concurrently targeting histone deacetylase and genomic DNA. These results demonstrate the dual targeting strategy to be a valuable route to pursue in the design of platinum agents which may be more effective in cancer types that are typically resistant to therapy by conventional cisplatin. Moreover, platinum(IV) derivatives containing VPA axial ligands seem to be promising dual-targeting candidates for additional preclinical studies.
- MeSH
- antitumorózní látky chemie farmakologie MeSH
- inhibitory histondeacetylas chemie farmakologie MeSH
- lidé MeSH
- ligandy MeSH
- magnetická rezonanční spektroskopie MeSH
- nádorové buněčné linie MeSH
- organoplatinové sloučeniny chemie farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
