# Gastrointestinall Tumors: Phytochemical and Drug Combinations Targeting the Hallmarks of Cancer
## 2 Anticancer Effects of Phytochemicals Used Alone and in Combination with Anticancer Drugs
### Colon Cancer
#### 2.1.2 Antitumor Properties of Anticancer Drug and Phytochemical Combinations in Colon Cancer  
Importantly, it was demonstrated that resveratrol can reduce the resistance to 5-FU of colon cancer cells through the reduction of slug and vimentin protein levels [56]. Interestingly, in a rat model, the combination of 10 mg/kg resveratrol and 12 mg/kg cisplatin treatments reduced the side effects of the drug [57]. In order to increase the anticancer effects of resveratrol, [PERSON] et al. [58] studied the effects of the combined use of 15 mM resveratrol and 0.5 mM 5-FU in colon cancer HCT-116 cells. This combination led to a synergistic anticancer effect, exerted through the reduction of tumor cells proliferation rate and migration capabilities, enhancement of DNA damages, induction of the apoptotic process and block of the cell cycle in the S phase. Phosphorylation of both c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases (p38 MAPK) was increased by this combination of resveratrol and 5-FU [58]. Interestingly, it was shown that a combination of 5-FU and EGCG reduced the growth of HCT116 and DLD1 colon cancer cells, through the glucose-regulated protein 78 (GRP78)/NF-kB/miR-155-5p/MDR1 pathway inhibition [59]. Importantly, it was shown that 5-FU and EGCG co-loaded nanoparticles exhibited remarkable anti-tumor activity and pro-apoptotic efficacy in both in vitro andin vivo colon cancer models [60]. Interestingly, the combination of EGCG and sodium butyrate induced G2/M arrest in RKO and HCT-116 colon cancer cells, and G1 arrest in HT-2 cancer cell line, through the modulation of the levels of Histone deacetylase 1 (HDAC1) and DNA (cytosine-5)-methyltransferase transferase 1 (DNMT1) [61]. Interestingly, the combination of thymoquinone and topotecan inhibited the proliferation of colon cancer cells through caspases activation and induction of cell cycle arrest during the S phase [62]. Furthermore, the authors indicated that the combination of this phytochemical with the anticancer drug remarkably reduced the growth of tumor cells without involving Bax, Bcl-2 and p53 [62]. In addition, the combination of DOX and thymoquinone reduced the proliferation rate of HT-29 colon cancer cells [63]. Interestingly, several authors studied the antiproliferative effects of thymoquinone in LoVo cancer cells resistant to the chemotherapeutic agent irinotecan, showing that this natural molecule can regulate JNK and p38 pathways affecting Extracellular signal-regulated kinases 1/2 (ERK1/2), Phosphoinositide 3-kinase (PI3K) and is also able to induce the autophagic process [64, 65]. Interestingly, [PERSON] et al. [66] demonstrated that the combination of baicalein and DOX in colorectal cancer cells induced the activation of caspase 3 along with DNA fragmentation, the downregulation of proliferating cell nuclear antigen (PCNA) and growth inhibition. Importantly, 5-FU and ellagic acid remarkably inhibited the growth of colon cancer cells SW480, HT-29 and Colo320 DM. The synergism between these two molecules was exerted through the activation of the apoptotic process in HT-29 cells, where the authors described an increase of the Bax/Bcl-2 ratio, cleaved caspase 3 and cleaved Poly ADP-ribosyl polymerase 1 (PARP1), and also loss of mitochondrial membrane potential [67]. Interestingly, the effects of the combination of unsolic acid and capecitabine were studied in in vitro and in vivo models of colon cancer [68]. The combined treatment reduced tumor volume and distant metastases _in vivo_. In addition, this combination of phytochemical and anticancer drugs regulated several signaling pathways, modulating the levels of key factors such as NF-kB, STAT3, \(\beta\)-catenin, Epidermal growth factor receptor (EGFR), p53, p21, matrix metallopeptidase 9 (MMP-9), VEGF and intercellular adhesion molecule 1 (ICAM 1) [68].