A study, published in the journal ‘Carcinogenesis’, points out that a molecule has been discovered that, once isolated and purified, is capable of losing the functional properties that define tumor stem cells (TSC), especially the ability to restart the formation of tumors by promoting the reactivation of epigenetic cell differentiation programs.

How did you start the search for photochemicals with antitumor activity in olive oil?

Five years ago, the Metabolism and Cancer group of the ProCURE Program of the Catalan Institute of Oncology (ICO) – Institute of Biomedical Research of Girona (IDIBGI), directed by the researcher Javier Menéndez, decided to implement a multidisciplinary methodological approach, similar to which is used by pharmaceutical companies to develop a new oncological drug, in order to discover and characterize the possible existence of new molecules with antitumor activity in olive oil. “Our hypothesis was that the so-called minority fraction of olive oil, which only represents 2% of its weight, but in which there are more than 200 different compounds, could be used as a natural source of information on new chemical structures capable of inhibit molecular functions necessary for the tumor stem cells, “says this researcher.

From isolation to the atomic characterization of the molecule

Firstly, the isolation and purification of the candidate molecules was carried out by analytical chemistry techniques developed at the Functional Food Research and Development Center (CIDAF) of the University of Granada. From there, the researchers of the ProCURE Program of the ICO-IDIBGI continued with the phenotypic screenings and validation studies in cell cultures and in tumors of laboratory animals.

It was decided to use a strategy called ‘phenotypic screening’ in which compounds that are able to penetrate a cell and induce a phenotypic change of interest are directly selected. “In our case, the phenotypic change analyzed was the disappearance of functional characteristics unique to the TSC, such as its ability to tolerate the presence of oncological drugs or to generate small micro-tumors in suspension”, according to the researchers.

Once the molecule of interest was discovered with a specific and potent activity against TSC in cell cultures ‘in vitro’, a second validation stage was carried out with TSC implanted in animals ‘in vivo’. The researchers confirmed that “The exposure of TSC to certain oleosides for a few hours was sufficient to completely prevent the ability of TSC to initiate tumor formation in laboratory animals.” Finally, we proceeded to the atomic characterization of the mechanism of action of the molecules with anti- TSC activity.

Following this procedure, researchers have discovered that extra virgin olive oil contains a family of polyphenolic compounds called oleosides that are capable of simultaneously inhibiting two key proteins in metabolism (mTOR) and epigenetics (DNMT) of tumor stem cells. This dual metabolite-epigenetic mechanism is capable of promoting the loss of functional properties that define TSC, especially the ability to restart the formation of tumors, by promoting the reactivation of epigenetic cell differentiation programs.

Now we know that nature, after millions of years of evolution, has created complex chemical structures capable of attacking the molecular machinery of the TSC, promoting its normalization. From now on, this activity must be chemically copied into new more stable molecules that can be used in the clinic, “says Menéndez. Researchers of the ProCURE Program of ICO-IDIBGI have registered the international patent of these compounds as new therapies against TSC and, with the collaboration of ‘Mind the Byte’, they have already begun the design of new molecules able to chemically mimic the anti activity – TSC of the oleosides.

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