Abstract
We analyzed antitumor effects of a series of curcumin analogues. Some of them were obtained by reaction of substitution involving the two phenolic OH groups of curcumin while the analogues with a substituent at C-4 was prepared following an original procedure that regards the condensation of benzenesulfenic acid onto the nucleophilic central carbon of the curcumin skeleton. We analyzed cytotoxic effects of such derivatives on two TNBC (triple negative breast cancer) cell lines, SUM 149 and MDA-MB-231, but only three of them showed an IC50 in a lower micromolar range with respect to curcumin. We also focused on these three derivatives that in both cell lines exhibited a higher or at least equivalent pro-apoptotic effect than curcumin. The analysis of molecular mechanisms of action of the curcumin derivatives under study has highlighted that they decreased NF-κB transcriptional factor activity, and consequently the expression of some NF-κB targets. Our data confirmed once again that curcumin may represent a very good lead compound to design analogues with higher antitumor capacities and able to overcome drug resistance with respect to conventional ones, even in tumors difficult to treat as TNBC.
Highlights
Cancer can be described as uncontrolled DNA replication and cell division, evasion from programmed cell death, breaking through normal tissue boundaries and invasion to new sites in the body
Extensive structure-activity studies have shown that the phenolic OHs and the α,β-unsaturated di-keto groups are essential for the antioxidant properties exerted by curcumin and the α,β-unsaturated di-keto moiety, in particular, is a key for its anticancer activity
It is believed that the poor bioavailability and stability of curcumin in physiological media depend on these groups [36,37]
Summary
Cancer can be described as uncontrolled DNA replication and cell division, evasion from programmed cell death, breaking through normal tissue boundaries and invasion to new sites in the body. The most promising anti-cancer therapies combine agents with different molecular mechanisms such as specific drugs and chemo- or radiotherapies, resulting in a better efficacy and longer survival [1] In this scenario, polyphenols are to be considered molecules with antitumor action because of their capacity to interfere with a large number of pathways that in the neoplastic cell are simultaneously deregulated. We have chosen to study these molecules on TNBC cell line models because TNBC represents one of the most aggressive malignant neoplasms, characterized by molecular aspects as the lack of the respective receptor targets, that limit therapeutic possibility because it does not respond to conventional hormonal interventions Another peculiar characteristic is the over-expression and hyperactivation of the transcription factor NF-κB, of which curcumin is an inhibitor [34,35]
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