Розмарин и рак Rosmarinus officinalis & cancer Научные исследования

Discussion

Several advantages warrant the use of rosemary extracts, and specifically supercritical extracts, instead of their isolated components in cancer treatment. On the one hand, the obtaining of rosemary extracts is much less expensive than the isolation of its compounds. Moreover, supercritical rosemary extracts do not contain chemical residues, which would entail harmful effects. Indeed, supercritical fluid rosemary extract has been recognized as a healthy component by the European Food Safety Authority (EFSA), and is currently used as an antioxidant food additive [28]. On the other hand, as we have demonstrated in this work the combination of carnosol and carnosic acid exerts a higher effect than the sum of their effects separately. Jordan et al. recently reported the relationship between the carnosic acid and carnosol content of RE's with their antimicrobial and antioxidant activities [19]. They found that the two diterpenes equally affected to the antioxidant activity, whereas antimicrobial effect was higher when the carnosolcarnosic acid ratio increased. Future studies are warranted in order to determine the specific carnosolcarnosic acid ratio needed to achieve the highest antitumor effect. Moreover, additional rosemary components (e.g. volatile compounds) further increase the antiproliferative effect of RE, thus contributing to the higher antitumor activity of the extract in comparison to the effect of the combination of its main components (carnosic acid and carnosol).

In order to test the efficacy of RE in vivo, several RE's were orally administered to mouse colon cancer xenografts. Previous animal studies found in the literature showed the preventive effect or rosemary extract in vivo in several tumor types. In our experiment, since the tumor cells are already in the organism at the time of treatment, we demonstrate the inhibitory effect of rosemary extract on tumor progression in vivo. The activities of the three RE's assayed (RE-3, RE-4 and RE-5) resulted very similar at the end of the experiment despite cell viability in vitro experiments showed the lesser efficacy of RE-3. However, the effect of RE-3 began later than those of RE-4 and RE-5. One explanation could be the saturation of the absorption mechanisms of rosemary active components in the bowel, but more experiments are needed to address this issue.

Rosemary and their components were reported to modulate glutathione metabolism [20], Nfr2-dependent pathway [21], AMPK and PPAR pathways [22], among others, as well as apoptosis-related genes [17]. However, the antitumor mechanism of action is not completely understood. In this study, we observed the up-regulation of GCNT3 by RE, and the correlation of this up-regulation with its antitumor efficacy. The rosemary component responsible for this modulation is carnosic acid. Since GCNT3 has been previously reported to possess tumor suppressor activities in colon cancer [27], it is up-regulated by several chemotherapeutic drugs and its overexpression correlates with a better outcome of colon cancer patients (González-Vallinas M et al., submitted for publication) we propose that GCNT3 may be a key molecule in the antitumor action of rosemary.

The finding that miR-15b, which was reported to target GCNT3 by in silico analysis, correlated with the antitumor effect of rosemary and can be found in mouse plasma, provides a potential suitable biomarker to monitor the in vivo response to RE. In addition, miR-15b has been recently proposed as potential biomarker for colorectal cancer since it has been found up-regulated in colorectal cancer patients, which suggests a relevant role of this miRNA in the progression of the disease [29]. The determination of the circulating miRNAs is a non-invasive and relatively accessible method which could be useful in order to discriminate the responder and non-responder individuals during the treatment. Future work should be directed both to analyze the functional role of these molecules in the action of this agent, and to investigate their clinical value as potential molecular biomarkers.