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
Combination regiments involving platinum anticancer drugs and agents with unrelated mechanisms of action are a subject of widespread interest. Here, we show that synergistic toxic action in cancer cells of combinations of antitumor platinum drug carboplatin and effective PARP inhibitor olaparib is considerably improved if these combined drugs are encapsulated into liposomes. Notably, the formation of such nano-formulations, called OLICARB, leads to a marked enhancement of activity in human cancer cell lines (including those resistant to conventional platinum antitumor drugs) and selectivity towards tumor cells. We used immunofluorescence analysis of γH2AX expression and examined DNA damage in cancerous cells treated with the investigated compounds. We find that the synergistic toxic effects in cancer cells of both drugs used in combination, nonencapsulated or embedded in the OLICARB nanoparticles, positively correlates with DNA damage. These results also suggest that the enhancement of the toxic effects of carboplatin by olaparib in cancer cells is a consequence of an accumulation of cytotoxic lesions in DNA due to the inhibition of repair of platinated DNA augmented by the synergistic action of olaparib as an effective PARP inhibitor. Our findings also reveal that the combination of olaparib with carboplatin encapsulated in the OLICARB nanoparticles is particularly effective to inhibit the growth of 3D mammospheres. Collectively, the data provide convincing evidence that the encapsulation of carboplatin and olaparib into liposomal constructs to form the OLICARB nanoparticles may represent the viable approach for the treatment of tumors with the aim to eliminate the possible effects of acquired resistance.
- Publikační typ
- časopisecké články MeSH
Two new 1-acridin-9-yl-3-methylthiourea Au(I) DNA intercalators [Au(ACRTU)2]Cl (2) and [Au(ACRTU) (PPh3)]PF6 (3) have been prepared. Both complexes were highly active in the human ovarian carcinoma cisplatin-sensitive A2780 cell line, exhibiting IC50 values in the submicromolar range. Compounds 2 and 3 are also cytotoxic toward different phenotypes of breast cancer cell lines MDA-MB-231 (triple negative), SK-BR-3 (HER2+, ERα-, and ERβ-), and MCF-7 (ER+). Both complexes induce apoptosis through activation of caspase-3 in vitro. While inhibition of some proteins (thiol-containing enzymes) seems to be the main mechanism of action for cytotoxic gold complexes, 2 and 3 present a DNA-dependent mechanism of action. They locate in the cell nucleus according to confocal microscopy and transmission electronic microscopy. The binding to DNA resulted to be via intercalation as shown by spectroscopic methods and viscometry, exhibiting a dose-dependent response on topoisomerase I mediated DNA unwinding. In addition, 2 and 3 exhibit potent antiangiogenic effects and are also able to inhibit vasculogenic mimicry of highly invasive MDA-MB-231 cells.
- MeSH
- akridiny chemie MeSH
- antitumorózní látky chemie farmakologie MeSH
- buněčné jádro metabolismus MeSH
- inhibitory angiogeneze chemie farmakologie MeSH
- interkalátory chemie farmakologie MeSH
- invazivní růst nádoru prevence a kontrola MeSH
- lidé MeSH
- molekulární mimikry MeSH
- nádorové buněčné linie MeSH
- patologická angiogeneze farmakoterapie MeSH
- thiomočovina chemie MeSH
- zlato chemie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články 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.
