Entry #: 24
Date: 25 November 2017
Section: Phenolic extracts
Topic: Phenolic extracts and breast cancer
Type: Original Paper

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OliveNetTM Journal Club

Expert review of literature related to olives and olive oil

D. Elizabeth McCord, Nancy B. Ray and Tom C. Karagiannis

Title

Crude phenolic extracts from extra virgin olive oil circumvent de novo breast cancer resistance to HER1/HER2-targeting drugs by inducing GADD45-sensed cellular stress, G2/M arrest and hyperacetylation of histone H3

Author(s)

Olivera-Ferraros et al

Citation / Year

(1) / 2011

Keywords

Extra-virgin olive oil, phenolic extracts, olive polyphenols, breast cancer, HER-2 positive breast cancer, acquired resistance, trastuzumab

Summary

Over the past decade, antibody-based cancer therapies have emerged as a new targeted approach to cancer therapy. A prime example is Herceptin™ (trastuzumab) which was approved by the US Food and Drug Administration, for the treatment of advanced HER2 positive breast in 1998 (the first for a solid tumor) (2-4). Despite clinical success in many cases, it was recognized that approximately 15% of women with HER2 positive breast cancer are resistant to trastuzumab (5-7). The current study represents an important early examination of the ability of crude phenolic extracts from extra-virgin olive oil in a cell culture model, HER2-gene amplified JMIT-1 cells, which exhibits cross-resistance to HER1/HER2 targeted antibodies and tyrosine kinase inhibitors. Although this study represents a simple in vitro model in a single cell line, the breadth of the crude olive extracts examined and the detailed series of molecular studies performed define the importance of this work in the field.

Key points and implications

A total of 14 different phenolic extracts from single varieties of Spanish extra-virgin olive oils (Hojiblanca [2], Picual [5], Cornezuelo [1], Manzanilla [1], Gutamanta [1], Agrosegura [1], Mosteroli [1], Arbequisur [2]). The composition of the extracts including total phenolic content, secoiridoids, phenolics alcohols, lignans and flavones, was determined and stock and working solution were prepared in ethanol. Firstly, cells were treated with different concentrations of the phenolic extracts to determine reduction in cell viability. Although a concentration-dependent decease in cell viability was observed for all of the extracts, a strong correlation between IC50 (concentration required to reduce viability to 50%), and phenolic index was observed. Specifically, a higher presence of complex phenolic secoiridoids compared to lignans was associated growth inhibition of JMIT-1 cells. Using human microarray-based, genome-wide analysis it was shown that extra-virgin olive oil extracts regulated canonical cancer-related signalling pathways including those associated with p53 signalling and the cell cycle. The effects on the cell cycle were further evaluated using conventional flow cytometric analysis indicating, G2/M arrest following treatment with phenolic-rich extracts. The ability of phenolic extracts to induce DNA double-strand breaks was evaluated using γH2AX as an epigenetic marker, and the findings indicated the appearance of discrete foci and pan-nuclear staining (indicative of DNA damage) with the phenolic-rich extract. Finally, the secoiridoid-rich extract induced hyperacetylation of lysine 18 on histone 3, an epigenetic mechanism which has been widely investigated and shown to be dysregulated in a wide-range of cancers. Overall, the findings of this study highlight that olive-derived phenolics may have the ability to circumvent resistance by producing anticancer effects via alternative pathways. It was an early that has motivated much further research in the filed over the past few years.

Related publications

  1. C. Oliveras-Ferraros et al., Crude phenolic extracts from extra virgin olive oil circumvent de novo breast cancer resistance to HER1/HER2-targeting drugs by inducing GADD45-sensed cellular stress, G2/M arrest and hyperacetylation of Histone H3. International journal of oncology 38, 1533-1547 (2011).
  2. R. Nahta, F. J. Esteva, Herceptin: mechanisms of action and resistance. Cancer letters 232, 123-138 (2006).
  3. S. J. Nass, H. A. Hahm, N. E. Davidson, Breast cancer biology blossoms in the clinic. Nature medicine 4, 761-762 (1998).
  4. J. Baselga, L. Norton, J. Albanell, Y. M. Kim, J. Mendelsohn, Recombinant humanized anti-HER2 antibody (Herceptin) enhances the antitumor activity of paclitaxel and doxorubicin against HER2/neu overexpressing human breast cancer xenografts. Cancer research 58, 2825-2831 (1998).
  5. R. Nahta, D. Yu, M. C. Hung, G. N. Hortobagyi, F. J. Esteva, Mechanisms of disease: understanding resistance to HER2-targeted therapy in human breast cancer. Nature clinical practice. Oncology 3, 269-280 (2006).
  6. N. L. Spector, K. L. Blackwell, Understanding the mechanisms behind trastuzumab therapy for human epidermal growth factor receptor 2-positive breast cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 27, 5838-5847 (2009).
  7. G. N. Hortobagyi, Trastuzumab in the treatment of breast cancer. The New England journal of medicine 353, 1734-1736 (2005).