Selective cytotoxicity of cyclometalated gold(III) complexes on Caco-2 cells is mediated by G2/M cell cycle arrest

Abstract

New cyclometalated gold(III) complexes with a general structure [Au(C^N)(SR)2] or [Au(C^N)Cl(SR)] where C^N is biphenyl ligands such as 2-(p-tolyl)pyridinate (tpy), 2-phenylpyridinate (ppy) and 2-benzylpyridinate (bzp) (SR = Spym, S(Me)2pym, 2-thiouracil and thiourea); and also with ethynyl moieties of the type [Au(C^N)(C≡C-Ar)2] (Ar = p-toluene and 2-pyridine) have been synthesized. All of them have been characterized, including X-ray studies of complex [Au(bzp)Cl(Spym)], and these studies have permitted to elucidate that leaving chloride ligand is trans located to CAr atom. After the full characterization, physicochemical properties were measured by evaluating drug-likeness water solubility and cell permeability (partition coefficient). All these experiments pointed that our complexes present adequate properties to be used as anticancer drugs. Although not all the complexes showed antiproliferative effects on Caco-2 cells, those that did, were more cytotoxic than cisplatin, and complex [Au(tpy)Cl(2-Thiouracil)] is even more active than auranofin. In addition to this effectiveness, not evidence of cytotoxic effects was observed on considered normal cells (with the exception of [Au(bzp)Cl(2-Thiouracil)]. Further mechanistic studies were performed using these selective complexes, showing cell cycle arrest on the G2/M phase, a proapoptotic behaviour and also the modification of some genes involved in tumorigenesis. Thus, as a result of this investigation, we present a new family of seventeen cyclometalated complexes, being six of them selective and possible candidates to be used against colon cancer.

Sulfonamide-Derived Dithiocarbamate Gold(I) Complexes Induce the Apoptosis of Colon Cancer Cells by the Activation of Caspase 3 and Redox Imbalance

“…Apoptosis processes are usually accompanied by alterations in the cell cycle, and previous studies have suggested that gold-complex-treated cells may arrest the cell cycle in some of its phases [ 59 , 70 , 71 , 72 ]. Flow cytometry analysis showed that after 48h (complex 1 ) or 72 h (complex 8 ) of incubation time, both derivatives significantly increased the number of cells arrested in the G1 phase, with a slight decrease in the S phase ( Figure 4 ).…”

Gold(I) Complexes Bearing Alkylated 1,3,5-Triaza-7-phosphaadamantane Ligands as Thermoresponsive Anticancer Agents in Human Colon Cells

“…Apoptosis events frequently are accompanied by cell cycle disturbances and previous studies with gold complexes suggested that treated cells may stop progression through cell cycle phases [ 18 , 50 , 51 ] at different checkpoints along them.…”

Carnosic Acid Encapsulated in Albumin Nanoparticles Induces Apoptosis in Breast and Colorectal Cancer Cells

“…The molecular mechanisms triggering the cytotoxicity and apoptotic action of CA-BSA-NPs were investigated using cell cycle arrest analyses. The data showed the capability of CA-BSA-NPs to stimulate G2-phase cell cycle arrest on the treated cells [41,42].…”