## 2 Bioactive Compounds
### \(\beta\)-Carotene  
\(\beta\)-carotene is a major source of vitamin A and is a key member of the carotenoid family [54]. It is a strongly red-orange colored pigment that is common in the human diet. \(\beta\)-carotene is derived from carotenes, which are terpenids, synthesized biochemically from 8 isoprene units harboring 40 carbon atoms. It is primarily found in carrots, apricots, paprika, and chili powder [55]. In patients with various types of cancer, \(\beta\)-carotene levels in the serum are inversely associated with tumor development [56; 57]. In 2020, a study presented the first evidence suggesting that \(\beta\)-carotene regulates the tumor microenvironment through IL-6/STAT3-mediated inhibition of M2 macrophage polarization and fibroblast activation [58]. \(\beta\)-carotene also controls the self-renewal capacity of colon cancer stem cells via epigenetic regulation [59]. In one particular study, a miRNA sequencing array analysis showed that \(\beta\)-carotene regulates miRNA expression associated with histone acetylation; Histone H3 and H4 acetylation status were elevated following \(\beta\)-carotene treatment in colon cancer stem cells. Additionally, DNMT mRNA expression was also down-regulated, consequently reducing global DNA methylation. Additional studies have shown the effect of \(\beta\)-carotene on cancer cell stemness, indicating that \(\beta\)-carotene not only reduces cell growth and induces differentiation of neuronal cells through increasing ERK phosphorylation, but can also inhibit the self-renewal property of cancer stem cells by reducing drosophila delta-like 1 homolog (DLK1), a predominant stem cell marker [60]. Another study supported these findings, demonstrating the anti-stemness properties of \(\beta\)-carotene using a xenograft model [61]. In this study, mice were supplemented with \(\beta\)-carotene for 3 weeks, before receiving a subcutaneous injection of SK-N-BE(2)C neuroblastoma cells. Both tumor growth and incidence were significantly suppressed in the group administrated with \(\beta\)-carotene compared to those in the control group. \(\beta\)-carotene repressed cancer stem cell markers including Oct 3/4 and DLK1. In addition, \(\beta\)-carotene controls cancer development and progression via regulation of various anti-cancer mechanisms. For example, it can trigger apoptosis by inhibiting the caveolin-1-mediated AKT/NF-kB signaling pathway in human esophagael squamous cell carcinoma cells [62]. In breast cancer cells, \(\beta\)-carotene blocks the activation of AKT and ERK1/2, which is mediated by an intracellular growth signaling cascade, and decreases levels of the antioxidant enzyme SOD-2 via down-regulation of its transactivation factor (Nrf-2), thereby suppressing cancer cell survival [63]. In AGS cells (a human stomach cancer cell line), \(\beta\)-carotene induced apoptosis via reduction of Ku70/80, which plays a critical role in DNA double-strand break repair [64], and inhibited MMP-10-mediated cell invasion by suppressing the H. pylori-induced up-regulation of MAPKs and AP-1 [64]. The combination of 5-fluorouracilacil and \(\beta\)-carotene was shown to impart greater tumor inhibition in a human esophageal carcinoma cell-xenografted mouse model [65]. The study demonstrated that the combined treatment synergistically down-regulated the expression of Cav-1, p-AKT, p-NF-kB, and mTOR to a greater extent than 5-FU alone. The combination of \(\beta\)-carotene and chemotherapeutic agents remarkably attenuated toxicity in P-glycoprotein-overexpressing and multi-drug resistance cancer cells [66]. By targeting cancer stem cells, \(\beta\)-carotene can also resensitize cells to the anti-cancer drug cisplatin [60].