New gold pincer-type complexes induce caspase-dependent apoptosis in human cancer cells in vitro

Abstract

Background / Aim. We investigated cytotoxicity of Au(III) complexes with pincer type ligands against cervical carcinoma cells (HeLa), breast cancer cells (MDA-MB-231 and 4T1) and colon carcinoma cells (HCT116 and CT26). We also examined the type and mechanism of cell death that these complexes induced in cancer cells. Methods.Cytotoxicity of Au(III) complexes was investigated by MTT assay. Apoptosis of treated cancer cells was measured by flow cytometry and applying Annexin V/7AAD staining. The expressions of active proapoptotic protein Bax, antiapoptotic protein Bcl-2 and the percentage of cells containing cleaved caspase-3 in treated cancer cells was determined by flow cytometry. Results. Complex 1 showed the most potent anti-tumor effect on HeLa cells, both compared to other two examined gold complexes and compared to cisplatin. The IC50 values on HeLa cells after 72 hours were 1.3 ± 0.4 μM, 3.4 ± 1.3 μM, 5.7 ± 0.6 μM, 26.7 ± 6.5 μM for complexes 1, 2, 3 and cisplatin, respectively. Complex 1 also exhibited highest cytotoxicity against MDA-MB-231 and HCT116 cells compared to other tested compounds. The results of Annexin V/7AAD staining showed that all three complexes induced apoptosis in treated cells. Our gold(III) complexes induced apoptosis by caspasedependent mechanism, but we did not observe that an activation of the internal pathway of apoptosis occurred in treated cancer cells. Conclusion. According to the results of our in vitro study, all three compounds and especially complex 1 are promising candidates for a new generation of anticancer drugs. Uvod. Ispitivali smo citotoksičnost Au(III) kompleksa sa ligandima tipa pincer protiv ćelija karcinoma grlića materice (HeLa), ćelija raka dojke (MDA-MB-231 i 4T1) i ćelija karcinoma kolona (HCT116 i CT26). TakoĎe smo ispitali tip i mehanizam ćelijske smrti koji su ovi kompleksi indukovani u ćelijama raka. Metode. Citotoksičnost Au(III) kompleksa je ispitivana pomoću MTT testa. Apoptoza tretiranih ćelija raka je merena protočnom citometrijom i primenom bojenja Aneksin V/7AAD. Ekspresija aktivnog proapoptotičnog proteina Bax, antiapoptotskog proteina Bcl-2 i procenat ćelija koje sadrže aktivnu kaspazu-3 u tretiranim ćelijama raka je odreĎena protočnom citometrijom. Rezultati. Kompleks 1 je pokazao najsnažniji antitumorski efekat na HeLa ćelije, kako u 4 poreĎenju sa drugim ispitivanim kompleksima zlata, tako i u poreĎenju sa cisplatinom.Vrednosti IC50 kompleksa zlata na HeLa ćelije nakon 72 sata bile su 1,3 ± 0,4 μM, 3,4 ± 1,3 μM, 5,7 ± 0,6 μM, 26,7 ± 6,5 μM za komplekse 1, 2, 3 i cisplatin. Kompleks 1 je takoĎe pokazao najvišu citotoksičnost prema MDA-MB-231 i HCT116 ćelijama u poreĎenju sa drugim testiranim jedinjenjima. Rezultati bojenja aneksinomV/7AAD pokazali su da sva tri kompleksa indukuju apoptozu u tretiranim ćelijama. Naši kompleksi zlata(III) indukovali su apoptozu mehanizmom koji je zavisio od kaspaze, ali nismo pokazali da je u tretiranim ćelijama raka došlo do aktivacije unutrašnjeg puta apoptoze. Zakljuĉak. Prema rezultatima naše in vitro studij...

Gold(III) Complexes: An Overview on Their Kinetics, Interactions With DNA/BSA, Cytotoxic Activity, and Computational Calculations

“…Consequently, results have shown the reduction of the amount of antiapoptotic protein Bcl-2 in the presence of complexes 1-3, but there was not emphasized significant reduction in the activation of Bax protein. Complexes 1-3 had a possibility to increase the amount of capsase-3 compared to untreated cells (Zarić et al, 2020). These results confirm a different influence of bulky inert tridentate nitrogen-donor ligand on activity toward different cell lines.…”

Bis-pyrazolylpyridine Complexes of Some Transition Metal Ions: Structure-Activity Relationships and Biological Activity

“…We suggested that DNA is not the primary target for selected Au(III) and Rh(III) pincer complexes. Among the complexes of various metal ions that we have described in the [42] present review, it appeared that Au(III) pincer complexes are the most potent cytotoxic agents against the studied cancer cell lines. Complex 5 showed the highest cytotoxicity with IC 50 of 0.7 µM against HCT116 cells with apoptosis being the main mechanism of complex-induced cell death.…”

“…colon carcinoma (CT26) and breast carcinoma (4T1). [34,42] We then compared the obtained IC 50 values, which are summarized in Table 4. The MTT results revealed that complexes 5-7 and cisplatin, show dose-dependent cytotoxic effects against all tested cancer cells.…”

“…Furthermore, we demonstrated that Au(III) pincer complexes showed the highest cytotoxicity with IC 50 values up to 0.7 µM for HCT116 cells, compared to analogous compounds of platinum, palladium and rhodium. [33][34][35][36]42] All studied Rh(III) complexes were investigated on human colorectal cancer HCT-116 cells using an MTT assay. [35,36] Compound M 2 L* showed the most significant effects with an IC 50 of 80.01 µM and 7.26 µM after 24 and 72 h treatment.…”

New dinuclear gold(III) complex with 1,5-naphthyridine as bridging ligand: synthesis, characterization, DNA/BSA binding studies, and anticancer activity

“…Literature data about proapoptotic mechanism of some gold derivates, also implies activation of caspase-dependent apoptosis, [51] and activation of internal pathway through affecting of mitochondrial membrane potential. [50] This result implies that molecules involved in the internal apoptotic pathway may be an important therapeutic target.…”