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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.
Acknowledgments
The authors thank Prof. Daniela Bonofiglio and Dr. Sakay who gifted p21 CIP/WAF1 construct plasmids.
Disclosure Statement
No potential conflict of interest was reported by the authors.
Authors’ Contribution
Vizza Donatella has designed the study and has performed transfection and CHIP assays. In addition, she contributed to write the manuscript.
Lupinacci Simona has performed cell viability assays and immunoblotting analysis. In addition, she contributed to design the study.
Toteda Giuseppina has performed real time PCR and soft agar assay.
Puoci Francesco prepared olive leaf extract (OLE).
Parisi Ortensia I performed the quantification of main phenolic compounds present in OLE by HPLC analysis.
De Bartolo Anna performed DNA laddering and contributed to designed the figures.
Lofaro Danilo performed the statistical analysis and designed the figures.
Scrivano Luca contributed to elaborate HPLC analysis and to write methods.
Bonofiglio Renzo contributed to write the manuscript.
La Russa Antonella performed wound-healing scratch assay and motility assay. In addition, she contributed to write materials and methods.
Bonofiglio Martina has revised the references included in the manuscript.
Perri Anna supervised the results and wrote the manuscript.