A series of triple action Pt(iv) prodrugs was designed to test the hypothesis that multi-action compounds, where each bioactive moiety intervenes in several cellular processes, might be more effective than a single agent at killing cancer cells.
The substitution inert platinum agent [Pt(1S,2Sdiaminocyclohexane)(5,6-dimethyl-1,10-phenanthroline)] 2+ (56MeSS, 5) is a potent cytotoxic metallodrug. In contrast to conventional cisplatin or oxaliplatin, the mechanism of action (MoA) of 5 is fundamentally different. However, details of the mechanism by which the 5,6-dimethyl-1,10-phenanthroline ligand contributes to the cytotoxicity of 5 and its derivatives have not been sufficiently clarified so far. Here, we show that 5 and its Pt(IV) derivatives exhibit an intriguing potency in the triple-negative breast cancer cells MDA-MB-231. Moreover, we show that the Pt(IV) derivatives of 5 act by multimodal MoA resulting in the global biological effects, that is, they damage nuclear DNA, reduce the mitochondrial membrane potential, induce the epigenetic processes, and last but not least, the data provide evidence that changes in the organization of cytoskeleton networks are functionally important for 5 and its derivatives, in contrast to clinically used platinum cytostatics, to kill cancer cells.
In recent years, numerous studies have demonstrated the health benefits of polyphenols. A major portion of polyphenols in western diet are derived from coffee, which is one of the most consumed beverages in the world.It has been shown that many polyphenols gain their beneficial properties (e.g. cancer prevention) through the activation of the Nrf2/Keap1 pathway as well as their direct antioxidant activity. However, activation of Nrf2 in cancer cells might lead to resistance towards therapy through induction of phase II enzymes.In the present work we hypothesize that caffeic acid (CA), a coffee polyphenol, might act as an electrophile in addition to its nucleophilic properties and is capable of inducing the Nrf2/EpRE pathway in cancer cells.The results indicate that CA induces Nrf2 translocation into the nucleus and consequently its transcription. It has been demonstrated that generated hydrogen peroxide is involved in the induction process. It has also been found that this process is induced predominantly via the double bond in CA (Michael acceptor). However, surprisingly the presence of both nucleophilic and electrophilic moieties in CA resulted in a synergetic activation of Nrf2 and phase II enzymes.We also found that CA possesses a dual activity, although inducing GSTP1 and GSR, it inhibiting their enzymatic activity.In conclusion, the mechanism of induction of Nrf2 pathway and phase II enzymes by CA has been elucidated. The electrophilic moiety in CA is essential for the oxidation of the Keap1 protein. It should be noted that while the nucleophilic moiety (the catechol/quinone moiety) can provide scavenging ability, it cannot contribute directly to Nrf2 induction. It was found that this process may be induced by H2O2 produced by the catechol group.On the whole, it appears that CA might play a major role in the cancer cells by enhancing their resistance to treatment.
This report describes the synthesis, characterization and biological activity of a series of platinum(iv) derivatives of [Pt(1S,2S-DACH)(5,6-dimethyl-1,10-phenanthroline)] (Pt56MeSS) with non-bioactive, lipophilic and bioactive axial ligands. In an attempt to explore the anticancer activity potential of the Pt(iv) derivatives, 2D and 3D cytotoxic screening and a preliminary in vivo study were performed. The average IC values of the platinum(iv) derivatives ranged from 1.26 to 5.39 μM, compared with 1.24 μM for Pt56MeSS, suggesting that the axial ligands have a relatively minor effect on the potency of the compounds. Preliminary in vivo studies indicate that the platinum(iv) derivatives of Pt56MeSS are active in vivo and can reduce the tumor to a similar extent to cisplatin.
Cisplatin is a widely used chemotherapeutic drug showing high efficiency in the treatment of primary tumors such as ovarian, testicular and cervical cancers. The major drawback of cisplatin is tumor resistance either acquired or intrinsic. Many mechanisms are involved in the resistance, among them is the Nrf2 pathway which regulates glutathione related enzymes. Caffeic acid, a non-toxic polyphenol which is abundant in many foods modulates glutathione S-transferase (GST) and glutathione reductase (GSR) activity, these enzymes were shown to be involved in resistance of cells towards cisplatin. Caffeic acid induces the Nrf2 pathway and can also inhibit the activity of GST and GSR.Our findings demonstrate that the co-treatment of cancer cells with cisplatin and caffeic acid can enhance cisplatin cytotoxicity and increases the amount of platinum bound to nuclear DNA. However, 6 h of pre incubation with caffeic acid prior to cisplatin treatment led to acquired resistance to cisplatin and reduced DNA binding.In conclusion, the enzyme inhibitory action of caffeic acid is dominant when the two agents are co-administered leading to increased cytotoxicity, and the Nrf2 induction is dominant when the cells are treated with caffeic acid prior to cisplatin treatment leading to resistance.The use of caffeic acid as adjuvant for cisplatin should be carefully examined due to different pharmacokinetic profiles of caffeic acid and cisplatin. Thus, it is questionable if the two agents can reach the tumors at the right time frame in vivo.
The discrepancy between the in vitro cytotoxic results and the in vivo performance of Pt56MeSS prompted us to look into its interactions and those of its Pt derivatives with human serum (HS), human serum albumin (HSA), lipoproteins, and serum-supplemented cell culture media. The Pt complex, Pt56MeSS, binds noncovalently and reversibly to slow-tumbling proteins in HS and in cell culture media and interacts through the phenanthroline group with HSA, with a K value of ∼1.5×10 m. All Pt complexes were found to be stable toward reduction in HS, but those with axial carboxylate ligands, cct-[Pt(1S,2S-DACH)(5,6-dimethyl-1,10-phenantroline)(acetato) ](TFA) (Pt56MeSS(OAc) ) and cct-[Pt(1S,2S-DACH)(5,6-dimehtyl-1,10-phenantroline)(phenylbutyrato) ](TFA) (Pt56MeSS(PhB) ), were spontaneously reduced at pH 7 or higher in phosphate buffer, but not in Tris buffer (pH 8). HS also decreased the rate of reduction by ascorbate of the Pt complexes relative to the reduction rates in phosphate buffer, suggesting that for this compound class, phosphate buffer is not a good model for HS.
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