Antitumor activity of binuclear copper (II) complexess with S-isoalkyl derivatives of thiosalicylic acid

[J. D. Dimitrijević]

88 listova

Brojni neželjeni efekti terapije tumora lekovima koji sadrže platinu uslovili su dizajniranje novih potencijalnih terapeutika u kojima je platina zamenjena drugim prelaznim metalom. Bakar se zahvaljujući aktivnim sistemima transporta u većoj koncentraciji nalazi u tumorskim nego u zdravim ćelijama, pa postoji mogućnost da kompleksi bakra sa odgovarajućim ligandom imaju selektivniju citotoksičnost, što je uticalo na razvoj različitih serija kompleksa bakra u cilju pronalaženja potencijalnog selektivnijeg hemoterapeutika. Cilj ove studije je karakterizacija sintetisanih binuklearnih kompleksa bakra(II) sa S-izoalkil derivatima tiosalicilne kiseline i analiza antitumorskog efekta sintetisanih kompleksa. Kompleksi su sintetisani, a njihova struktura je opisana na osnovu elementalne mikroanalize i potvrđena na osnovu infracrvene i nuklearno-magnetno-rezonancione spektroskopije i rendgenske strukturne analize. Binuklearni kompleksi bakra(II) sa S-izoalkil derivatima tiosalicilne kiseline pokazuju citotoksički efekat na ćelijama mišjeg karcinoma kolona i pluća, kao i humanog kolorektalnog i adenokarcinoma pluća in vitro, indukuju apoptozu ćelija mišjeg Lewis karcinoma pluća i zaustavljaju tumorske ćelije u G2/M fazi ćelijskog ciklusa. Binuklearni kompleks bakra(II) sa S-izoamil derivatom tiosalicilne kiseline značajno smanjuje ekspresiju inflamacijskih molekula, pro-IL-1β, TNF-α, ICAM-1 i VCAM-1, u tkivu primarnog heterotopskog mišjeg karcinoma kolona što je praćeno značajnom redukcijom rasta tumora kao i smanjenjem incidence, veličine i broja metastaza u plućima i jetri. Rezultati ove studije ukazuju da binuklearni kompleks bakra(II) sa S-izoamil derivatom tiosalicilne kiseline, pokazuju antitumorski efekat in vitro, kao i značajan efekat in vivo u modelu karcinoma kolona miša.

Numerous side effects of platinum based chemotherapy caused the design of new therapeutics with platinum replaced by another transition metal. Concentration of copper is higher in cancer than in normal cells implying the possibility that copper complexes with the appropriate ligand could have more selective cytotoxicity. This led to the development of different series of copper complexes in order to find a potential more selective chemotherapeutics. The aim of this study is to characterize the synthesized binuclear complexes of copper(II) with S-isoalkyl derivatives of thiosalicylic acid and to analyze their antitumor effect. The complexes were synthesized, and their structure was described on the basis of elemental microanalysis, confirmed on the basis of infrared and nuclear-magneticresonance spectroscopy and X-ray structural analysis. Binuclear complexes of copper(II) with S-isoalkyl derivatives of thiosalicylic acid show a cytotoxic effect on mouse colon lung carcinoma cells, as well as human colorectal and lung adenocarcinoma cells in vitro, induce apoptosis of mouse lung carcinoma cells and arrest tumor cells in G2/M phase of the cell cycle. Binuclear complex of copper(II) with S-isoamyl derivative of thiosalicylic acid significantly reduces the expression of inflammatory molecules, pro-IL-1β, TNF-α, ICAM-1 and VCAM-1, in tissue of primary heterotopic murine colon cancer, which is accompanied by a significantly reduced tumor growth and the incidence, size and number of lung and liver metastases. The results of this study indicate that the dinuclear complex of copper(II) with the S-isoamyl derivative of thiosalicylic acid, exert the antitumor effect in vitro, as well as significant antitumor effect in vivo in the model of mouse heterotopic primary colon cancer.

binuklearni kompleksi bakra(II), karcinom kolona, ST26 ćelije, citotoksičnost, antitumorska aktivnost, inflamacija

binuclear copper(II) complexes, colon cancer, CT26 cells, cytotoxicity, antitumor activity, inflammation

616.348-006-08:577(043.3)

Maligni tumori -Terapija

Tekst