## 3 Health Benefits of Rosmarinic Acid  
### Anticancer Potential  
Several mechanisms have been proposed for RA anticancer activity (Figure 3). For instance, in rats with colon cancer, RA at the concentration of 5 mg/kg body weight (b.w.) impaired tumor formation and development, reduced lipid peroxidation by-products and pro-apoptotic proteins expression, modulated xenobiotic enzymes, and increased apoptotic proteins expression [18]. In human liver cancer cell line, HepG2, transfected with plasmid containing ARE-luciferin gene, RA predominantly enhances ARE-luciferin activity and promotes nuclear factor E2-related factor-2 (Nrf2) translocation from cytoplasm to the nucleus and also increases MRP2 and P-gp efflux activity along with intercellular ATP level [19]. A study conducted by [PERSON] et al. [20] reported that RA inhibited CCRF-CEM and CEM/ADR5000 cells in a dose-dependent pattern but caused less cytotoxicity towards normal lymphocytes. RA concurrently induced necrosis and apoptosis and stimulated MMP dysfunction activated PARP-cleavage and caspase-independent apoptosis. RA also blocked the translocation of p65 from the cytosol to the nucleus [20]. Moreover, it inhibits transcription factor hypoxia-inducible factor-1\(\alpha\) (HIF-1\(\alpha\)) expression, which affects the glycolytic pathway; meanwhile, it also suppressed glucose consumption and lactate production in colorectal cells [21]. RA also inhibits micro RNAs and pro-inflammatory cytokines and thus may suppress the Warburg effects through an inflammatory pathway involving activator of transcription-3 (STAT3) and signal transducer of interleukin (IL)-6 [22]. Furthermore, RA inhibits HL-60 promylocytic leukemia cells' growth and development and provides strong scavenging free radical effects, disturbing the balance of nuclear deoxyribonucleotide triphosphate (dNTP) levels without affecting protein levels of RR (R1, R2, p53R2) subunits, ultimately leading to apoptosis induction [23; 24]. RA application, at a concentration of 5 mg/kg b.w. during 30 weeks in 1,2-dimethyldrazin stimulated colon carcinogenesis in the rat at 20 mg/kg b.w. and significantly stopped tumor formation and proliferation. RA supplementation also reduced tumor necrosis factor-\(\alpha\) (TNF-\(\alpha\)), cyclooxygenase-2 (COX-2) and IL-6 levels, and modulated p65 expression [25]. It is also able to inhibit the release of the highly mobile group box 1 (HMGB1) and to slow down HMGB1-dependent inflammatory responses in human endothelial cells, stopping HMBG1-mediated hyperpermeability and leukocytes migration in mice [26]. RA supplementation primarily decreases aberrant cryptot foci (ACF) formation and multiplicity in rats [27]. RA inhibited APC10.1 cell growth that comes in Apc (Min) mouse model of colorectal carcinogenesis [28]. Through oral administration, RA totally prevented skin tumor cells formation in DMBA-induced mouse skin carcinogenesis and decreased lipid peroxidation byproducts levels [29]. It also inhibited human ovarian cancer A2780 cell line, disturbing the cell cycle at multiple phases and stimulating apoptosis by modifying multiple genes expression, involved in apoptosis regulation [30]. RA induced the cell cycle arrest and apoptosis in prostate cancer cell lines (PCA, PC-3, and DU145) [31]. These effects were mediated through modulation of histone deacetylases expression (HDACs), specifically HDAC2; the aberrant expression of theses enzymes is related with the onset of human cancer. In rats with 1,2 dimethylhydrazine-induced colon carcinogenesis, RA administration at dose of 2.5, 5, and 10 mg/kg b.w. led to a decrease in the number of polyps (50%), reversed oxidative markers (21%), antioxidant status (38.6%), CYP450 contents (29.4%), and PNPH activities (21.9%) [32]. RA can also inhibit adhesion, invasion, and migration of Ls 174-T human colon carcinoma cells through enhancing GSH levels and decreasing ROS levels.