# 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 berberine, in combination with DOX, 5-FU, CPT or taxol, in in vitro models of colon, gastric and pancreatic cancer, induced the intrinsic apoptosis, increased apoptosis inducing factor (AIF) levels, decreased Interleukin 6 (IL6) and STAT3 levels and inhibited Janus kinase (JAK)/STAT and MAPK/ERK prosurvival pathways [69, 70, 71, 72, 73]. Importantly, it was shown that the combination of cetuximab and tectochrysin in HCT116 and SW480 tumor cells decreased the expression of p-EGFR and COX-2 and, in addition, inhibited NF-kB and Activator protein-1 (AP-1), inducing the death of tumor cells [74]. Interestingly, the effect of a combination of repiment-4-ol and cetuximab was analyzed in Kirsten rat sarcoma virus (KRAS) mutated HCT116 cells and also in an in vivo mouse model, showing that this combined treatment remarkably reduced tumor growth (80-90%) and also tumor volume (62%) [75]. Importantly, cascicin has been demonstrated to potentiate Tumor necrosis factor (TNF)-related apoptosis in colon cancer cells through downregulation of survival proteins such as Bcl-2, B-cell lymphoma extra large (Bcl-xL), survivin, X-linked inhibitor of apoptosis protein (XIAP) and cellular FLICE-like inhibitory protein (cFLIP) and upregulation of DR5 [76]. Interestingly, it was shown that the use of a combination of \(\beta\)-Sesquiphellandrene and thalidomide in HCT116 cells decreased the levels of anti-apoptotic proteins cFLIP, Bcl-xL, Bcl-2, cellular inhibitor of apoptosis protein 1 (c-IAP1) and survivin [77]. Furthermore, the antitumor effects of the phytochemical \(\beta\)-caryophyllene and the anticancer drug paclitaxel were studied in DLD-1 colorectal cancer cells, showing a synergistic inhibition of proliferation rate of tumor cells and an accumulation of the chemotherapeutic agent inside the cancer cells [78]. In addition, \(\beta\)-caryophyllene and \(\beta\)-caryophyllene oxide chemosensitized Caco-2 tumor cells to the effects of DOX [79]. The authors indicated that these phytochemicals inhibited the MDR mechanisms of the tumor cells, enhancing DOX antiproliferative effects [79]. Interestingly, it was shown that Mistleto extract, in combination with DOX, paclitaxel, cisplatin,oxifluidine or cyclohexamide, in experimental models of colon, liver, pancreatic and gastric cancer induced the apoptotic process and an increase of ROS levels [80; 81; 82]. Importantly, it was shown that a combination of irinotecan and panaxadiol decreased HCT116 proliferation rate through the activation of apoptosis and an increase of cleaved caspase 9 and caspase 3 levels [83]. Interestingly, it was shown that Vitamin D (which can be found in several foods, like cheese, meat, eggs and fish) exerts chemopre effects in several solid tumors, in particular in colorectal cancer [84]. In vitro studies indicated that vitamin D is able to reduce the proliferation of colorectal cancer cells through the induction of the apoptotic process, the block of the cell cycle in G1 phase and the angiogenesis inhibition [85; 86; 87; 88]. Noteworthy, the inhibitory effects of 25-hydroxy vitamin D3 (1,25(OH)\({}_{2}\)D3) on cell proliferation and apoptosis are underlined by the findings that this molecule promotes sensitivity to the chemotherapeutic agent 5-FU by down-regulating the expression of the anti-apoptotic protein survivin and of thymidylate synthase, a key enzyme in the biosynthetic pathway of DNA [84]. Furthermore, studies on different colon carcinoma cell lines showed that 1,25(OH)\({}_{2}\)D3 may promote apoptosis by the up-regulation of the pro-apoptotic protein Bcl-2 homologous antagonist/killer 1 (BAK1) and the down-regulation of the nuclear anti-apoptotic protein Bcl-2-associated athanogene 1 (BAG1) [88].