# Antitumor Effects of _Cannabis sativa_ Bioactive Compounds on Colorectal Carcinogenesis
## 3 Bioactive Compounds in the Prevention and Treatment of Colorectal Cancer
### Effects of Terpenes on CRC
Additionally, \(\beta\)-caryophyllene-oxide and \(\alpha\)-humulene were shown to improve the antiproliferative effects of 5-fluorouracil and oxaliplatin in CACO-2 and SW620 cell lines [79]. D-limonene is another terpene found in cannabis that has been claimed to exhibit antitumor effects in CRC. In particular, in a study by [PERSON] and coworkers, the authors described that D-limonene caused a reduction in the viability of colon cancer cells (LS174T) in a dose-dependent manner (0.4-3.2 mmol/L) [80], through apoptosis induction. This event was mediated through the activation of caspase-3, -9, and PARP cleavage, the increase in Bcl-2-like protein 4 (Bax) protein and cytosol cytochrome \(c\) from mitochondria, thedecrease in Bcl-2 protein, and the suppression of the PI3K/Akt pathway. Additionally, [PERSON] et al. [81] verified that the treatment of AOM-induced F344 rats with D-limonene, at 0.5%, significantly reduced (_p_ < 0.001) the number of ACF when compared to cancer animals (157.2 \(\pm\) 28.2 vs. 234.6 \(\pm\) 63.2, respectively), a type of precancerous lesions, in the colon of rats administrated with AOM, suggesting that D-limonene may have chemopre potential in CRC. Although less studied, there is some evidence that other terpen found in _C. sativa_ may hold the potential for fighting CRC. In this regard, myrcene was reported to be cytotoxic against colon cancer cells (HT-29) at concentrations higher than 200 \(\mu\)g/mL [82]. \(\alpha\)-pinene also proved to inhibit tumor growth in Balb/c mice allografted with colon cancer CT-26 cells via NK cell activation [83]. Geraniol, in addition to increasing the cytotoxicity of 5-fluorouracil treatment in CACO-2 cells (geraniol, 400 \(\mu\)M and 5-fluorouracilacil, 5 \(\mu\)M) [84], reduced 53% of the tumor volume in Swiss nu/nu female mice with TC118 colorectal tumor grafts obtained from patients with CRC (geraniol, 150 mg/kg and 5-fluorouracilacil, 20 mg/kg) [85]. Linalool was found to significantly reduce the growth, migration, and invasion of colon cancer cells (HCT116 and SW480) and increase cell death, an effect probably mediated by the Akt/mTOR and Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 signaling pathways [86]. Compared with the effects of cannabinoids, several results were similar in different CRC cell lines and animal models. The antiproliferative and pro-apoptotic effects of BCP on HCT116 cells were also observed for CBD, CBG, CBDV, CBL, and CBGV. The decrease in cell growth in HT29 was induced by myrcene, CBD, and THC. In addition, limonene led to a decrease in ACF, as did CBD in a chemically induced AOM animal model. However, linalool, in addition to the anticancer mechanisms induced by cannabinoids in the SW480 cell line, also led to a reduction in cancer cell invasion and migration. Additionally, D-limonene reduced the viability of colon cancer cells (LS174T), not demonstrated for cannabinoids. Despite studies claiming promising potential options for the treatment of CRC, it is necessary to note that most of the studies to date have been conducted in vitro, and more research, including in vivo studies, is needed to fully understand the potential benefits of terpen in the treatment of CRC alone or combined with other drugs. Furthermore, the interactions between terpen and cannabinoids should be further studied for a better understanding of their effects on CRC, i.e., whether their interaction enhances or counteracts the effects of the plant on this type of cancer.