In vitro and in vivo antitumoral effects of polyphenols or combination of polyphenols in head and neck cancer and in malignant mesothelioma

Carcinogenesis is a multistep process triggered by genetic alterations that activate different signal transduction pathways and cause the progressive transformation of a normal cell into a cancer cell. Polyphenols, such as Curcumin and Resveratrol, have the ability to modulate the activity of multiple targets involved in carcinogenesis and can be employed to inhibit the growth of cancer cells. The aim of this study was to demonstrate the in vitro and in vivo antitumoral effects of Curcumin, in the treatment of epithelial (head and neck cancer “HNC”) and mesenchimal (malignant mesothelioma “MM”) tumors, used as single compound or in combination with Resveratrol. In the 1° report we provide evidence that the combination of Resveratrol (RES) and Curcumin (CUR) enhanced CUR in vitro and in vivo antitumor activities on HNC cell lines compared to the single compound; RES potentiates the apoptotic effect and reduced the IC50 of CUR on HNC cell lines. The model of compounds interaction indicated the onset of an additive effect of the two compounds compared to the single treatment after decrease of their concentrations. RES+CUR compared to CUR increased the PARP-1 cleavage, the Bax/Bcl-2 ratio, the inhibition of ERK1 and ERK2 phosphorylation, and the expression of LC3 II simultaneously with the formation of autophagic vacuoles. RES and CUR induced cytoplasmic NF-kB accumulation. Moreover, RES+CUR in vivo administrations were safe in BALB/c mice and reduced the growth of transplanted salivary gland cancer cells (SALTO) more efficiently than CUR. In the 2° report we demonstrate the in vitro antitumoral activities of CUR on MM cell lines; CUR in vitro inhibited MM cells survival in a dose- and time-dependent manner, increased reactive oxygen species intracellular production and induced DNA damage. CUR triggered autophagic flux, but the process was then blocked and was coincident with caspase 8 activation which activates apoptosis. Moreover, CUR treatment stimulated the phosphorylation of ERK1/2 and p38 MAPK, inhibited that of p54 JNK and AKT and prevented NF-κB nuclear translocation. These findings may have important implications for the design of HNC and MM treatment using CUR as single compound or in combination with Resveratrol