A Polyphenol-Rich Extract of Olive Mill Wastewater Enhances Cancer Chemotherapy Effects, While Mitigating Cardiac Toxicity

Abstract

Cardiovascular toxicity remains one of the most adverse side effects in cancer patients receiving chemotherapy. Extra-virgin olive oil (EVOO) is rich in cancer preventive polyphenols endowed with anti-inflammatory, anti-oxidant activities which could exert protective effects on heart cells. One very interesting derivative of EVOO preparation is represented by purified extracts from olive mill waste waters, (OMWW) rich in polyphenols. Here, we have investigated the anti-cancer activity, of a OMWW preparation named A009 when combined with chemotherapeutics as well as its potential cardioprotective activities, Mice bearing prostate cancer (PCa) xenografts were treated with cisplatin, alone or in combination with A009. In an in vivo model, we found synergisms of A009 and cisplatin in reduction of prostate cancer tumor weight. Hearts of mice were analyzed, and the mitochondria were studied by transmission electron microscopy. The hearts of mice co-treated with A009 extracts along with cisplatin had reduced mitochondria damage compared to the ones treated with chemotherapy alone, indicating a cardioprotective role. To confirm the in vivo results, tumor cell lines and rat cardiomyocytes were treated with cisplatin in vitro with and without A009. Another frequently used chemotherapeutic agent 5-fluorouracil (5-FU), was also tested in this assay, observing a similar effect. A009 in vitro was additive to cisplatin and 5-FU to reduce cancer cell growth, while it did not further reduced growth of rat cardiomyocytes treated with cisplatin and 5-FU. A009 cardioprotective effects towards 5-FU chemotherapy were further investigated in vitro, using cardiomyocytes freshly isolated from mice pups. A009 mitigated toxicity of the fluoropyrimidine. Our study demonstrates that the polyphenol rich purified A009 extracts enhances the effect of chemotherapy in vitro and in vivo, but mitigates chemotherpy adverse effects on heart and on isolated cardiomyocytes. Olive mill waste water extracts could therefore represent a potential candidate for cardiovascular prevention in patients undergoing cancer chemotherapy.

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

“…Based on our previous published article on the cardioprotective properties of the A009 extracts against chemotherapy-induced damages in models of prostate cancers ( 11 ), we also tested whether a similar scenario could be observed with chemotherapeutic agents used in BC treatment, such as 5-FU and Doxo. We observed that the rat cardiomyocyte cell line H9C2 exhibited less reduced cell proliferation, when co-treated with the A009 + 5-FU ( Figure 5 ) or A009 + Doxo ( Figure 6 ), both at 48 and 72 h, as compared to 5-FU or Doxo alone.…”

“…A peculiar capability of polyphenols resides in their ability to target transformed malignant cells ( 40 ) also cooperating with chemotherapeutic agents ( 11 , 40 , 41 ), while sparing healthy cells or recovering healthy cells undergoing stress conditions and cellular damages ( 42 – 44 ). Based on this evidence and on our previous published article on the cardioprotective properties of the A009 extract against chemotherapy-induced damages, in models of prostate cancers, we tested whether a cardio-oncological prevention scenario could be observed, using chemotherapeutic agents used for BC treatment, such as doxorubicin and fluoropyrimidines.…”

“…Among them, phenolic compounds have gained the attention of the scientific community, thanks to their plethora of beneficial effects on health, that include antibacterial, anti-inflammatory, and anticancer activities. Also, several preclinical studies, including those published by our research group, showed that diverse phytocompounds, while synergizing with chemotherapeutic drugs, have cardioprotective activity ( 10 , 11 ).…”

“…We previously reported that the A009 polyphenol-rich extracts, purified form OMWW, exhibit chemopreventive and angiopreventive properties, in vitro and in vivo , in different cancer types (e.g., lung, colon, and prostate cancer cells) and endothelial cells ( 11 , 24 – 27 ).…”

Olive Mill Wastewater Inhibits Growth and Proliferation of Cisplatin- and Gemcitabine-Resistant Bladder Cancer Cells In Vitro by Down-Regulating the Akt/mTOR-Signaling Pathway

“…The exceptional action of OMWW on LNCaP cells, observed only after 96 h incubation, was traced to a drastic increase in apoptosis, neither observed in DU145 nor PC3 prostate cancer, nor in lung or colon cancer cells [23]. Albini et al recently showed that OMWW enhances the effect of cisplatin chemotherapy on prostate cancer xenografts [24]. In the present investigation, we found no distinct increase of apoptotic events after OMWW exposure over a time period of 72 h. Therefore, exposure to OMWW, which inhibits bladder cancer cell growth along with reducing cell clone number and size, cannot be attributed to apoptosis.…”