## 2 Bioactive Compounds  
### Lycopene  
Lycopene is synthesized by plants and microorganisms as a common natural pigment [28]. It is chemically characterized by a highly unsaturated hydrocarbon chain containing 11 conjugated and 2 unconjugated double bonds [29]. Lycopene is found in red fruits and vegetables such as carrots, watermelon, grapefruit, apricot, pink guava, and papaya [30].  
Findings from epidemiological studies have suggested the possibility that lycopene can prevent the emergence of cancer cells as well as their progression, with numerous reports shedding light on the molecular mechanisms underlying these effects. A meta-analysis showed that 57 out of 72 studies reported an inverse correlation between lycopene consumption and the risk of diverse cancer types including prostate, breast, colon, and lung cancer [31]. In 2019, [PERSON] et al. demonstrated that lycopene induced apoptosis in gastric cancer cells by inhibiting the nuclear translocation of \(\beta\)-catenin and expression of predominant cancer cell survival genes [32]. In this study, lycopene increased DNA fragmentation and the Bax/Bcl-2 ratio, reducing viability of the AGS cells. Lycopene-mediated ROS reductions also decreased activation of the EGFR/Ras/ERK and p38 MAPK pathways, thereby sequentially attenuating NF-kB mediated COX-2 expression via attenuation of the DNA-binding activity of NF-kB p65/p50 [33]. An in vivo study supported these in vitro anti-gastric cancer findings. [PERSON] et al. demonstrated that tumor weight was significantly decreased in gastric cancers in nude mice following lycopene treatment, while suggesting that LC3-1 and ERK were involved in the effect [34]. In addition, lycopene reduced the viability of the pancreatic cancer cell line PANC-1 via a similar mechanism of action [35]. In that study, lycopene induced apoptosis of PANC-1 cells by decreasing ROS levels, consequently abrogating NF-kB activity and the expression of its target genes such as cLAP1, cLAP2, and survivin. MicroRNA (miR)-let-7f was also involved in suppression of the prostate cancer cells. [PERSON] et al. demonstrated that lycopene up-regulated miR-let-7f-1 expression and induced the down-regulation of AKT2 in PC3 cells through gain- and loss-of-function experiments [36]. In n-nitrosomethylbenzylamine (NMBzA)-induced esophageal cancer in F344 rats, lycopene intervention (25 mg/kg/day) for 25 weeks not only significantly reduced inflammatory cytokines by suppressing NF-kB and COX-2, but also enhanced apoptotic cytokine expression by increasing PPAR and caspase-3 activity [37]. Another two studies showed that lycopene enhanced expression of the pro-apoptotic protein BAX, while suppressing the anti-apoptotic protein Bcl-2 in ovarian [38], oral [39], and breast cancers [40]. Furthermore, lycopene improved the efficacy of anti-PD-1 treatment, a cancer immunotherapy. In mice injected with Lewis lung carcinoma cells, the combination of lycopene and anti-PD-1 agent reduced tumor volume and weight to a greater extent than either lycopene or anti-PD-1 alone [41]. As well as inducing cellular apoptosis, the combination elevated the levels of IL-1 and IFN-\(\gamma\) in the spleen of the LCC bearing mice, consequently diminishing PD-1 expression by activating JAK and increasing phosphorylation of AKT. These studies suggest that lycopene could be used as a nutraceutical or as a potential adjuvant to anti-cancer drugs to synergistically improve their efficacy.