# Resveratrol: A Review on the Biological Activity and Applications
## 3 Antitumor Properties
### Leukemia and Lymphoma  
RSV has been determined to inhibit carcinogenesis in murine models. Besides its chemopretive action, it also induces apoptotic cell death in human leukemia cells, exhibiting specific involvement of the cluster of differentiation (CD)95-CD95L system in the antitumor activity of RSV and emphasizing the chemotherapeutic ability of this natural compound [28]. It is a significant inhibitor of ribonucleotide reductase and DNA synthesis in mammalian cells, with possible utilizations as an antiproliferative and chemopretive factor [27; 29].  
Studies demonstrate that RSV can inhibit every step of multistage carcinogenesis by reducing the viability and DNA synthesis ability of promyelocytic leukemia cells, inducing apoptotic cell death, and decreasing the expression of anti-apoptotic B-cell lymphoma-2 (Bcl-2) [30]. In the concentration spectrum of 20 \(\upmu\)M and higher, it blocked the S-phase and caused apoptosis in the T-cell acute lymphoblastic leukemia (T-ALL), insufficient in functional p53 and p16 [31]. Other studies had the same results in human histiocytic lymphoma cells, indicating that RSV is an important cell cycle blocker in addition to being a chemopretive agent [27; 32].  
In the case of acute monocytic leukemia, researchers have shown that RSV inhibits the growth of Tohoku Hospital Pediatrics-1 (THP-1) cells by inducing apoptosis, independent of the Fas/FasL signaling pathway and has no toxic effect on differentiated THP-1 cells [33]. Other data established that RSV and its correspondent, piceatannol, are powerful generators of apoptosis in BJAB Burkitt-like lymphoma cells, with a median effective dose of 25 \(\upmu\)M, autonomous of the CD95/Fas signaling cascade [34].  
\(t\)RSV, \(\epsilon\)-viniferin, and vineatrol induced apoptosis in chronic leukemic B cells by activating caspase-3, reducing the mitochondrial transmembrane potential, and inhibiting both the expressions of the Bcl-2 anti-apoptotic protein and the inducible nitric oxide synthase (iNOS) [35; 36]. Some studies suggest the involvement of apoptosis signal-regulating kinase 1/c-Jun N-terminal kinase (JNK) signaling in the regulation of FasL expression and following apoptosis induced by RSV in leukemia cells [37].  
The inhibitory effect on hydrogen peroxide (H\({}_{2}\)O\({}_{2}\))-induced apoptosis is attributed to the antioxidant property of RSV, which, in small concentrations, can inhibit death signaling in human leukemia cells via nicotinamide adenine dinucleotide phosphate reduced-form (NADPH) oxidase-dependent increase in intracellular superoxide that stops mitochondrial H\({}_{2}\)O\({}_{2}\) synthesis [36; 38].  
Researchers determined that RSV has the ability to sensitize cancer cells to X-irradiation. The study involved cervix carcinoma, chronic myeloid leukemia, and multiple myeloma and demonstrated that the addition of RSV alone induced apoptosis and inhibited cell growth, while concomitant treatment with either RSV or X-irradiation caused a synergical reaction [39].  
A plasma membrane receptor for RSV has been discovered near the arginine-glycine-aspartate recognition site on integrin \(\alpha\)v\(\beta\)3 that participates in the proapoptotic mechanism of RSV in tumor cells, along with stimulating the intranuclear COX-2 accumulation, correlated to the activation of p53 [40].  
The possible antitumor actions of RSV against the natural killer (NK) cell malignancies, especially aggressive NK cell leukemias and lymphomas, include strong G0/G1 cell cycle blockage and substantial cell proliferation and apoptosis restriction. Furthermore, RSV caused synergistic activity on the apoptotic and antiproliferative effects of L-asparaginase against cancer cells [41].  
RSV's effectiveness varies among different human cancer cells, showing greater potential to induce cell death in leukemic cells than in solid tumor cells by inhibiting Akt activation through Ras downregulation [42].