期刊
MOLECULES
卷 27, 期 3, 页码 -出版社
MDPI
DOI: 10.3390/molecules27030644
关键词
platinum; organometallic complexes; antiproliferative activity; drug resistance
资金
- MUR (Italian Ministry of University and Research)
- Dipartimento di Scienze del Farmaco, Universita di Padova, Progetti di Ricerca di Dipartimento PRID 2017 [DALL_SID17_02]
- Pisa University [PRA_2020_39]
Resistance to cisplatin limits its usefulness as an anticancer drug. This study describes the synthesis and characterization of two new platinum complexes and demonstrates their potential in overcoming cisplatin resistance in cancer cells. The complexes exhibited poor ability to platinate DNA but showed significant intracellular accumulation. Mechanistic studies revealed their ability to inhibit DNA relaxation and activate the apoptotic pathway. Comparison with related complexes provides insights into the resistance phenotype.
The high incidence of the resistance phenomenon represents one of the most important limitations to the clinical usefulness of cisplatin as an anticancer drug. Notwithstanding the considerable efforts to solve this problem, the circumvention of cisplatin resistance remains a challenge in the treatment of cancer. In this work, the synthesis and characterization of two trans-dichloro(triphenylarsino)(N,N-dialkylamino)platinum(II) complexes (1 and 2) were described. The trypan blue exclusion assay demonstrated an interesting antiproliferative effect for complex 1 in ovarian carcinoma-resistant cells, A2780cis. Quantitative analysis performed by ICP-AES demonstrated a scarce ability to platinate DNA, and a significant intracellular accumulation. The investigation of the mechanism of action highlighted the ability of 1 to inhibit the relaxation of supercoiled plasmid DNA mediated by topoisomerase II and to stabilize the cleavable complex. Cytofluorimetric analyses indicated the activation of the apoptotic pathway and the mitochondrial membrane depolarization. Therefore, topoisomerase II and mitochondria could represent possible intracellular targets. The biological properties of 1 and 2 were compared to those of the related trans-dichloro(triphenylphosphino)(N,N-dialkylamino)platinum(II) complexes in order to draw structure-activity relationships useful to face the resistance phenotype.
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