No abstract

A long history of research has pursued the use of embryonic factors isolated during cell differentiation processes for the express purpose of transforming cancer cells back to healthy phenotypes. Recent results have clarified that the substances present at different stages of cell differentiation-which we call stem cell differentiation stage factors (SCDSFs)-are proteins with low molecular weight and nucleic acids that regulate genomic expression. The present review summarizes how these substances, taken at different stages of cellular maturation, are able to retard proliferation of many human tumor cell lines and thereby reprogram cancer cells to healthy phenotypes. The model presented here is a quantum field theory (QFT) model in which SCDSFs are able to trigger symmetry breaking processes during cancer development. These symmetry breaking processes, which lie at the root of many phenomena in elementary particle physics and condensed matter physics, govern the phase transitions of totipotent cells to higher degrees of diversity and order, resulting in cell differentiation. In cancers, which share many genomic and metabolic similarities with embryonic stem cells, stimulated redifferentiation often signifies the phenotypic reversion back to health and nonproliferation. In addition to acting on key components of the cellular cycle, SCDSFs are able to reprogram cancer cells by delicately influencing the cancer microenvironment, modulating the electrochemistry and thus the collective electrodynamic behaviors between dipole networks in biomacromolecules and the interstitial water field. Coherent effects in biological water, which are derived from a dissipative QFT framework, may offer new diagnostic and therapeutic targets at a systemic level, before tumor instantiation occurs in specific tissues or organs. Thus, by including the environment as an essential component of our model, we may push the prevailing paradigm of mutation-driven oncogenesis toward a closer description of reality.

Several diet-derived compounds have been reported to exert antioxidant, anti-proliferative and anti-angiogenic effects in numerous cancers and could be beneficial in cancer prevention. Olive oil production involves the generation of an aqueous phase defined as olive mill wastewater (OMWW), a polluting effluent rich in soluble polyphenols. Here, we assessed the cancer preventive properties exerted by a purified extract of OMWW (A009) for its activity on lung cancer cell lines. Hydroxytyrosol, the most abundant polyphenol present in our A009 extracts, was used as reference molecule in the assays performed. Extracts from OMWW from two different olive oil cultivars were used. We found that the A009 extracts limit lung cancer cell proliferation in a dose and time dependent manner. These effects were associated with the induction of apoptosis. A009 extracts were effective in inhibiting adhesion capabilities on a fibronectin layer accompanied with a reduction in their ability to generate invasive sprouts in a Matrigel layer. The production of chemokine CXCL12 and CXCR4 receptor were reduced by treatment with the extracts. Also, A009 interfered with the production of proangiogenic and pro-inflammatory VEGF, CXCL8, and CCL2 (as detected by FACS analysis) in the lung cell lines. A009 extracts were able to decrease STAT3 phosphorylation in lung cancer cells. Our results show that A009 extracts reduced activities related to tumor cell behavior in lung cancer cell lines, suggesting that they could have a potential cancer preventive role.

Epidemiological studies showed that diet can play a relevant role in reducing the risk of developing colon cancer (CC) and lower rate of CC insurgence has been observed amongst populations living within the Mediterranean basin. Olive oil, a major component of the Mediterranean diet, is an abundant source of phenolic compounds. Olive oil production is associated with the generation of waste material, termed ‘olive mill wastewaters’ (OMWW), that have been reported to be enriched in polyphenols as well. Given the beneficial activity of polyphenols on human health, we investigated whether the use of different batches of purified extracts from OMWW, termed A009, might be effective in exerting chemopreventive activities in vitro and in vivo, on CC cell lines. Cell proliferation and survival were evaluated on A009 treated cells by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, while the induction of apoptosis was assessed by flow cytometry. Further, functional studies to investigate the ability of A009 to interfere with CC cell line adhesion, migration, sprouting and invasion were performed. Finally, the ability of A009 to interfere with CT-26 CRC tumour cell growth was assessed in vivo. Purified hydroxytyrosol, the major component in the A009 extracts, was used as a control. A009 inhibited cell proliferation, migration, invasion, adhesion and sprouting of CC cells along with the release of pro-angiogenic and pro- inflammatory cytokines (VEGF, IL-8) similar to hydroxytyrosol alone. In vivo, A009 inhibited CT-26 tumour growth in a significant manner over that of hydroxytyrosol alone. Our results show that A009 extracts exert promising chemopreventive properties, suggesting that different polyphenols act synergistically, improving their single component effects in CC cell lines. Finally, our results support the idea of repositioning a waste derived material for nutraceutical employment, with environmental and industrial cost management benefits. Citation Format: Barbara Bassani, Teresa Rossi, Daniela De Stefano, Daniele Pizzichini, Paola Corradino, Antonino Bruno, Douglas M. Noonan, Adriana Albini. Chemopreventive activities of a polyphenol rich purified extract from olive oil processing on colon cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5272. doi:10.1158/1538-7445.AM2017-5272

No abstract

The presence of diverse phenolic molecules in dietary elements, has been shown to prevent the occurrence of a variety of chronic and inflammatory diseases. Olives and extra virgin oil, a basic component of mediterranean diet represent an important source of these poliphenols, including hydroxytyrosol. While the strong antioxidant potential of these molecules has extensively investigated, their anti-angiogenic and chemopreventive activities remain unknown. Here we assessed the anti-angiogenic and chemopreventive activities exerted by an extracts from olive mill wastewaters (OMWWs), termed A009, which represent a waste product from olive oil industry, in vitro and in vivo on endothelial and different tumour cell lines, as compared with hydroxytyrosol alone The ability of A009 to affect cell proliferation and survival was evaluated on human umbelical endothelial vein cells (HUVECs), six different tumor cell lines, MCF-7 and MDA-MB-231 (breast), HT-29 and HCT-116 (colon) PC-3 and DU-145 (prostate) and the murine CT26 CRC cells by MTT assay, while the induction of apoptosis and reactive oxygen species (ROS) were assessed by flow cytometry. Functional studies evaluated the capacity of OMWWs to interfere with endothelial cell tube formation, migration and invasion by morphogenesis and Boyden chamber assays, respectively. Finally, the inhibition of angiogenesis and tumor cell growth was evaluated in vivo, by the matrigel sponge assay and tumor xenograft. The A009 extract was able to inhibit both HUVECs and tumor cell lines growth in a dose dependent manner, exerting a stronger inhibitory effect as compared to the pure hydroxytyrosol alone. This effect was directly associated with the induction of apoptosis and ROS on HUVECs. HT-29 anc HCT-116 CRC cell lines exposed to A009 decreased thei ability to release VEGF and IL-8. Functional studies of HUVECs exposed to A009 demostrated impaired migratory and invasive abilities as far as reduced capability to form capillary-lile-structure in a dose dependent manner. Finally, A009s interfered with angiogenesis and CT26 tumor cell growth in vivo. Our results suggest that the polyphenol enriched extracts from olive oil processing (OMWWs) A009, show promising angio-preventive and chemo-preventive potentials. In particular, our data demonstrate that a pool of specific polyphenols are characterized by stronger anti-angiogenic/anti-tumor properties compared to hydroxytyrosol alone, a well known polyphenol with anti-tumor activity. Citation Format: Adriana Albini, Antonino Bruno, Barbara Bassani, Nicoletta Macrì, Francesca Caudano, Paola Corradino, Teresa Rossi, Douglas M. Noonan. Chemopreventive and angiopreventive activity of a purified polyphenol-rich extract from olive mill wastewaters. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5262.

The olive mill wastewater polyphenol extracts exhibit chemopreventive properties in lung cancer cell lines, acting on the CXCR4/CXCL12 axis. Lung cancer still is a leading cause of cancer death worldwide. Although avoidance of tobacco use and smoking cessation will have the greatest impact on lung cancer development, (chemo)prevention could prove to be very effective, particularly in high risk individuals. Diverse diet-derived compounds have been reported to exert antioxidant, anti-proliferative and anti-angiogenic effects. Olive oil production involves the generation of an aqueous phase, defined as olive mill wastewater (OMWW), a polluting effluent rich in soluble polyphenols. We established a polyphenol rich, purified extract, from OMWW, that we termed A009. The effect of A009 on cell proliferation was determined by the crystal violet assay, while induction of apoptosis was measured by flow cytometry. The ability of the A009 to regulate the cell migration/invasion axis CXCR4/CXL12 and the production of pro angiogenic factors (VEGF, CXCL8, CCL2), was investigated by flow cytometry. The sprouting assay on Matrigel was used to functional verify the ability of A009 to limit invasive properties. Hydroxytyrosol, the most abundant polyphenols present in our A009, was used as reference molecules in all the assays performed. We found that the A009 limit A549 and H1560 cell proliferation, in a dose and time dependent manner. These effects were associated with induction of apoptosis at 24 and 48 hours of treatment, that was higher in H1650, as compared to A549 cells. The A009 extracts were effective in inhibiting the production of CXCR4 and CXCL12 in both the A549 and H1650 cells, accompanied with reduction in H1650 cell capability to generate invasive sprouts. in a Matrigel layer. Finally, A009 interfere with the production of VEGF, CXCL8 and CCL2 in both the A549 and H1650 cells. Our preliminary results suggest that A009 exhibit promising preventing and interceptive properties on lung cancer cell lines in vitro. Citation Format: Matteo Gallazzi, Marco Festa, Clementina Sansone, Paola Corradino, Douglas Noonan, Adriana Albini. The CXCR4/CXCL12 axis is a target of a polyphenol extract from olive oil processing with potential cancer prevention and interception activities [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 18.