Olive oil's bitter principle reverses acquired autoresistance to trastuzumab (Herceptin™) in HER2-overexpressing breast cancer cells

[Background] A low incidence of breast cancer in the Mediterranean basin suggests that a high consumption of Extra Virgin Olive Oil (EVOO) might confer this benefit. While the anti-HER2 oncogene effects of the main ω-9 fatty acid present in EVOO triacylglycerols (i.e., oleic acid) have been recently described, the anti-breast cancer activities of EVOO non-glyceridic constituents -which consist of at least 30 phenolic compounds-, remained to be evaluated. [Methods] Semi-preparative HPLC was used to isolate EVOO polyphenols (i.e., tyrosol, hydroxytyrosol, oleuropein). Both the anti-proliferative and the pro-apoptotic effects of EVOO phenolics were evaluated by using MTT-based quantification of metabolically viable cells and ELISA-based detection of histone-associated DNA fragments, respectively. The nature of the interaction between oleuropein aglycone and the anti-HER2 monoclonal antibody trastuzumab (Herceptin™) was mathematically evaluated by the dose-oriented isobologram technique. HER2-specific ELISAs were employed to quantitatively assess both the basal cleavage of the HER2 extracellular domain (ECD) and the expression level of total HER2. The activation status of HER2 was evaluated by immunoblotting procedures using a monoclonal antibody specifically recognizing the tyrosine phosphorylated (Phosphor-Tyr1248) form of HER2. [Results] Among EVOO polyphenols tested, oleuropein aglycone was the most potent EVOO phenolic in decreasing breast cancer cell viability. HER2 gene-amplified SKBR3 cells were ~5-times more sensitive to oleuropein aglycone than HER2-negative MCF-7 cells. Retroviral infection of the HER2 oncogene in MCF-7 cells resulted in a "SKBR3-assimilated" phenotype of hypersensitivity to oleuropein aglycone. An up to 50-fold increase in the efficacy of trastuzumab occurred in the presence of oleuropein aglycone. A preclinical model of acquired autoresistance to trastuzumab (SKBR3/Tzb100 cells) completely recovered trastuzumab sensitivity (> 1,000-fold sensitization) when co-cultured in the presence of oleuropein aglycone. Indeed, the nature of the interaction between oleuropein aglycone and trastuzumab was found to be strongly synergistic in Tzb-resistant SKBR3/Tzb100 cells. Mechanistically, oleuropein aglycone treatment significantly reduced HER2 ECD cleavage and subsequent HER2 auto-phosphorylation, while it dramatically enhanced Tzb-induced down-regulation of HER2 expression. [Conclusion] Olive oil's bitter principle (i.e., oleuropein aglycone) is among the first examples of how selected nutrients from an EVOO-rich "Mediterranean diet" directly regulate HER2-driven breast cancer disease.JAM is the recipient of a Basic, Clinical and Translational Research Award (BCTR0600894) from the Susan G. Komen Breast Cancer Foundation (Texas, USA). This work was also supported by the Instituto de Salud Carlos III (Ministerio de Sanidad y Consumo, Fondo de Investigación Sanitaria -FIS-, Spain, Grants CP05-00090 and PI06-0778 to JAM, and Grant RD06-0020-0028 to JAM, RC and JB)

Recent advances in systemic therapy: Advances in systemic therapy for HER2-positive metastatic breast cancer

Human epidermal growth factor receptor (HER)2 over-expression is associated with a shortened disease-free interval and poor survival. Although the addition of trastuzumab to chemotherapy in the first-line setting has improved response rates, progression-free survival, and overall survival, response rates declined when trastuzumab was used beyond the first-line setting because of multiple mechanisms of resistance. Studies have demonstrated the clinical utility of continuing trastuzumab beyond progression, and further trials to explore this concept are ongoing. New tyrosine kinase inhibitors, monoclonal antibodies, PTEN (phosphatase and tensin homolog) pathway regulators, HER2 antibody-drug conjugates, and inhibitors of heat shock protein-90 are being evaluated to determine whether they may have a role to play in treating trastuzumab-resistant metastatic breast cancer

Human–animal cytoplasmic hybrid embryos, mitochondria, and an energetic debate

Scientists are seeking permission to generate human embryonic stem cells to study disease by introducing human genetic material into an animal oocyte. this has raised ethical questions that centre on whether the entities being generated are actually human. the answer to these questions will determine how this area of research will be regulated and whether such work will be legal. the function of the extra-nuclear mitochondrial genome lies at the heart of these issues and forms the focus of this commentary

PROTECTIVE EFFECTS OF GINKGO BILOBA EXTRACT AGAINST CISPLATIN OTOTOXICITY

Cisplatin is one of the most common agents employed in standard treatments of a variety of malignant tumors. However, its clinical application is limited because of serious and sometimes irreversible side effects, that include ototoxicity. Upon cisplatin treatment, several areas of the cochlea are damaged, including outer hair cells in the organ of Corti, spiral ganglion and the stria vascularis. Notwithstanding extensive research, the presently available treatments to prevent ototoxicity are scarcely effective. Cisplatin is thought to interfere with production of endogenous antioxidants that protect inner ear against reactive oxygen species (ROS). Outer hair cells are the most sensitive to ROS damage which can lead to apoptosis: strategies of chemoprevention include the administration of antioxidants to protect hair cells at an early stage in the ototoxic pathways. In this study we evaluated the protective effect of a nutraceutical product compounds with antioxidant activity (ACUVAL®, Scharper Healthcare, Italy). Ginkgo biloba is known for antioxidant properties and for this reason we tested by cytofluorimetry the otoprotective effects of a Ginkgo biloba extract (Ginkgoselect®) against cisplatin-induced toxicity in a mouse inner ear cell line (OCk3). The results support the hypothesis that the pre-treatment with Ginkgo biloba extract (50-100 µg/ml) is able to protect OCk3 against cisplatin-induced toxicity. We are presently investigating the effects of the same extract in rat inner ear organ cultures