The heterocyclic ruthenium(III) complex KP1019 (FFC14A) causes DNA damage and oxidative stress in colorectal tumor cells

Characterization of the binding sites of the anticancer ruthenium(III) complexes KP1019 and KP1339 on human serum albumin via competition studies

“…Chart 1 KP1019 shows remarkable antineoplastic activity against a wide number of preclinical tumor models, including cisplatin resistant colorectal tumors and some primary explanted human tumors [2,6,11,12]. Although the pharmacological target for antitumor ruthenium compounds has not been unequivocally identified, it is unlikely that their modes of action are similar to that of cisplatin [7].…”

“…The selective tumor targeting can be realized by the enhanced permeability and retention effect of the tumor tissue, and by the overexpression of transferrin receptors on cancer cells [16]. A further reason for their selectivity is the insufficient formation of new blood vessels in rapidly growing tumors that results in a more reductive environment as compared to normal tissue and facilitates Ru(III) reduction to Ru(II) ("activation by reduction" hypothesis) [17][18][19] and therefore ligand exchange and coordination towards biological targets such as DNA or proteins [7,12,20]. Therefore, reactions of anticancer metallodrugs with proteins are of considerable interest as these interactions might feature processes that are crucial for the biodistribution, the toxicity and even the mechanism of action of this important group of anticancer agents.…”

Redox-active and DNA-binding coordination complexes of clotrimazole

“…Hence, it is of great importance to understand in detail the DNA binding properties of novel metal complexes and their possible relationship to cytotoxicity in tumor cells since this may provide grounds for establishing new structure-pharmacological activity relationships. In the studies presented herein, we demonstrate that the antitumor mechanism of mononuclear Cu 2+ , Co 2+ , Zn 2+ , and Ni 2+ complexes of the biologically active ligand clotrimazole (clotri) of the forms [M(clotri)2Cl2]·nH2O (1)(2)(3)(4), [M(clotri)2Br2]·nH2O (5,6), and [M(clotri)3NO3]NO3·nH2O (9,11) and [M(clotri)3(NO3)2] (10) previously studied by us [17], involves not only oxidative DNA damage with generation of ROS but also specific DNA interactions.…”

“…The less electrochemically accessible Co 3+/2+ potentials (0.512 V for the cobalt chloride complex 2 and only an oxidation potential of 0.977 V for the cobalt bromide complex 6) lie outside the biological window for hydroxyl radical generation, so these complexes may be less likely to cause cellular damage by ROS formation. Unsurprisingly, the redox inactive Zn 2+ complexes were found to be the least cytotoxic [9]. Correlation of the cellular toxicity results with the electrochemical redox potentials for these complexes suggest that some of these compounds may cause cell death by generating ROS.…”

“…In this respect, metal complexes are promising as a new generation of anticancer drugs for effective oxidant therapy; their anticancer activity may involve direct oxidative DNAdamage [7,8,9] and/or interference in the redox signaling pathways in cancer cells by novel mechanisms [10,11,12]. In particular, distortions of the DNA structure induced by metalbased anticancer agents often correlate with anticancer activity [13,14,15].…”