An Olive Leaf Extract Rich in Polyphenols Promotes Apoptosis in Cervical Cancer Cells by Upregulating p21Cip/WAF1 Gene Expression

Abstract

Most of the common drugs used to treat the cervical cancer, which main etiological factor is the HPV infection, cause side effects and intrinsic/acquired resistance to chemotherapy. In this study we investigated whether an olive leaf extract (OLE), rich in polyphenols, was able to exert anti-tumor effects in human cervical cancer cells (HeLa). MTT assay results showed a reduction of HeLa cells viability OLE-induced, concomitantly with a gene and protein down-regulation of Cyclin-D1 and an up-regulation of p21, triggering intrinsic apoptosis. OLE reduced NFkB nuclear translocation, which constitutive activation, stimulated by HPV-oncoproteins, promotes cancer progression and functional studies revealed that OLE activated p21Cip/WAF1 in a transcriptional-dependent-manner, by reducing the nuclear recruitment of NFkB on its responsive elements. Furthermore, OLE treatment counteracted epithelial-to-mesenchymal-transition and inhibited anchorage-dependent and -independent cell growth EGF-induced. Finally, MTT assay results revealed that OLE plus Cisplatin strengthened the reduction of cells viability Cisplatin-induced, as OLE inhibited NFkB, AkT and MAPK pathways, all involved in Cisplatin chemoresistance. In conclusion, we demonstrated that in HeLa cells OLE exerts pro-apoptotic effects, elucidating the molecular mechanism and that OLE could mitigate Cisplatin chemoresistance. Further studies are needed to explore the potential coadiuvant use of OLE for cervical cancer treatment.