AUTHOR=Benedetto Nadia , Calabrone Luana , Gutmańska Karolina , Macrì Nicoletta , Cerrito Maria Grazia , Ricotta Riccardo , Pelosi Giuseppe , Bruno Antonino , Noonan Douglas M. , Albini Adriana 

TITLE=An Olive Oil Mill Wastewater Extract Improves Chemotherapeutic Activity Against Breast Cancer Cells While Protecting From Cardiotoxicity

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=Volume 9 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2022.867867

DOI=10.3389/fcvm.2022.867867

ISSN=2297-055X

ABSTRACT=Cardiovascular toxicity in cancer patients receiving chemotherapy, remains one of the most undesirable side effects, limiting the choice of the most efficient therapeutic regimen, including combinations of different anti-cancer agents. Anthracyclines (Doxorubicin) and anti-metabolites (5-Fluorouracil (5-FU), capecitabine) are among the most known agents used in breast cancer and other neoplasms and are associated with cardiotoxic effects. Extra-virgin olive oil (EVOO) is reach in polyphenols endowed with antioxidant cardio-protective activities. Olive-oil mill waste waters (OMWW), a waste product generated by EVOO processing, has been reported to be enriched in polyphenols. Here, we investigated the activities of a polyphenol-rich water extract from OMWW, A009, in cooperation with chemotherapy on two breast cancer cell lines, BT459, MDA-MB-231 in a cardio-oncology perspective. The effects of A009 on cardiac cells was also investigated with and without chemotherapeutic agents. Cell viability was determined on BT459, MDA-MB-231 (breast cancer cells) and H9C2 (rat cardiomyocytes) cells, by MTT assay. A spheroids assay was used as a 3D in vitro model on BT459 and MDA-MB-231 cells. For in vivo studies, the murine sponge assay of angiogenesis was used as a model of breast cancer-associated vascularization. The embryo of Danio rerio (Zebrafish) was used to detect the anti- cardio- protective activities of the OMWW. We found that the A009 extract exhibited anti-angiogenic activities induced by breast cancer cell supernatants and increased T cell recruitment, in vivo. The combination of the OMWW extracts with Doxorubicin or 5-FU, limited BT459 and MDA-MB-231 cell viability and the diameter of 3D spheroids, while mitigating their toxic effects on the rat H9C2 cardiomyocytes. Cardioprotective effects were observed by the combination of OMWW extracts with Doxorubicin in Zebrafish embryos. Finally in human myocytes, we observed 5-FU induced upregulation of the inflammatory, senescence associated cytokine IL6 and of p16 genes, which was reduced by OMWW treatment. Our study demonstrates that the polyphenol rich purified OMWW extract A009 combined with cancer chemotherapy, could represent a potential candidate for cardiovascular protection in breast cancer patients, while increasing the effects of breast cancer chemotherapy.