CAPE synthetic derivatives as adjuvant anticancer therapy with cold atmospheric plasma.

Caffeic acid phenethyl ester (CAPE), one of the main components of honeybee propolis, is reported to have broad-spectrum biological activities, including antibacterial and anticancer effects1. Since it is reported that CAPE can be easily hydrolysed or metabolized either in vitro or in vivo2, two different novel series of CAPE derivatives were designed and synthesized. The first series has an ester linkage, whereas the second one contains an amide linkage, with different heterocyclic rings such as quinoline and isoquinoline, which are known to have both anticancer and antimicrobial effects3. The twelve synthesized compounds were administered in different concentrations (0-100 ?M) to breast (MCF-7), prostate (PC3) and oral cancer cell lines (HSC-2, CAL-27 and HOC-621) and two of them, namely MB10 and MB14, showed very promising IC50, especially toward the HSC-2 cells. Cold Atmospheric Plasmas (CAP) is a new promising therapeutic option for tumour treatment, being able to enhance the efficacy of traditional drugs. Anti-proliferative effects of the two selected compounds were investigated in combination with CAP in non-malignant oral cells (HGFs) and in the oral squamous cell carcinoma cells. Combined treatment with CAP for 30 and 60 sec at a distance of 12 mm enhanced the anti-proliferative effects with a slightly different sensitivity among the cell lines. In particular, 5 ?M MB14 combined with 30 sec CAP was the mildest treatment being effective in reducing CAL-27 and HOC-621 proliferation by 40% and 50%, respectively. More importantly, HGFs were unaffected by the combination of 30 sec CAP and 5 and 10 ?M MB14 showing selectivity for this approach.