# Gastrointestinall Tumors: Phytochemical and Drug Combinations Targeting the Hallmarks of Cancer
## 2 Anticancer Effects of Phytochemicals Used Alone and in Combination with Anticancer Drugs
### Liver Cancer  
The antiproliferative effects of EGCG were studied in liver cancer both in vitro and in vivo. EGCG in combination with sorafenib inhibited cell growth both in liver cancer cell lines and xenografted mice, specifically targeting the glycolytic pathway [98]. Interestingly, it was shown that the combined treatments of DOX + EGCG and DOX + Epicatechin-3-gallate (ECG) exerted significant cytotoxic effects in both BEL-7404 and BEL-7404/DOX hepatocellular carcinoma cells, through the reduction of \(MDR1\) and HIF-1\(\alpha\) levels [99]. Furthermore, the combination of DOX and these phytochemicals reduced tumor volume in in vivo models [99]. Interestingly, a combination of EGCG and 5-FU increased the antitumor effects of 5-FU in Hep3B cells, through the modulation of Akt, COX-2, Prostaglandin E2 (PGE2) levels [100]. Moreover, it was shown that the combined treatment with Y6 (EGCG-derivative) and DOX in liver cancer cells BEL-7404/DOX reduced P-gp activity, leading to a 10 fold decrease of DOX IC\({}_{50}\) value, and remarkably induced the apoptotic process [101]. Importantly, it was shown that the combination of bevacizumab and curcumin in an in vivo model of liver cancer was able to inhibit VEGF/Vascular endothelial growth factor receptor (VEGFR)/K-ras signaling pathways [102]. Interestingly, the curcumin-derived compound EF24 enhanced the anticancer effects of sorafenib by inhibiting MDR mechanisms through the modulation of Von Hippel-Lindau (VHL) and HIF-1\(\alpha\), in liver cancer in vitro and in vivo models [103]. Interestingly, genistein shows synergistic behavior with well-known anticancer drugs, such as adriamycin, docetaxel and tamoxifen, suggesting \begin{table}
\begin{tabular}{c c c c} \hline \hline
**Phytochemical-Drug** & **Molecular Mechanisms** & **Molecular Targets** & **References** \\ \hline Berberine+5-FU & Proliferation inhibition & Survivin; STAT3 & [72] \\ \hline Curcumin+Oxaliplatin & Apoptosis induction & Caspase 9; Wnt/\(\beta\)-catenin & [92] \\ Curcumin+5-FU & Inhibition of pro-survival mechanisms & Caspase 3; Bcl-2; ERK1/2 & \\ \hline Resveratrol+DOX & Resensitizing cancer cells to DOX effects & PTEN; Akt & [93] \\  & Reduction of metastasis capacity & & \\ \hline EGCG+5-FU & Proliferation inhibition & P-gp; VEGF; \(MDR1\) & [94] \\  & Resensitizing cancer cells to 5-FU effects & & \\ \hline EGCG+Docetaxel & Reduction of tumor volume & Ki-67; VEGF & [95] \\ \hline Mithramycin A+Bevacizumab & Angiogenesis inhibition & Sp1; VEGF & [96] \\  & Reduction of metastasis capacity & & \\ \hline \hline \end{tabular}
\end{table} 
Table 2: Gastric cancer targets. a potential role in combinational anticancer therapy [104]. Importantly, it was shown that the combination of TRAIL and genistein was able to increase the apoptosis induction rate in Hep3B liver cancer cells [105]. In addition, it was demonstrated that the use of arsenic trioxide (ATO) and genistein led to the reduction of the proliferation rate and to the induction of the apoptotic process in liver cancer cells, exerted through the inhibition of Akt and NF-kB [106]. Moreover, the combination of this phytochemical (50 ug genistein/g) with ATO reduced both tumor growth and angiogenesis in a xenograft mouse model [106]. Importantly, [PERSON] et al. [107] studied the in vivo anticancer effects of a combination of resveratrol and 5-FU against Hepatoma 22 transplanted Balb/c mice xenografts, demonstrating the S phase arrest of Hepatoma 22 cells and the resveratrol-mediated enhancement of the anti-tumor effect of 5-FU in this xenograft model [107]. Regarding the phytochemicals of cruciferous vegetables, the anticancer effects of indole-3 carbined were studied in combination with sorafenib in liver cancer cells HepG2 and Huh-7, showing that this association potentiated apoptosis and decreased angiogenesis process, especially in HepG2 cells, through the modulation of the levels of EMT markers and NADPH oxidase 1 (NOXI) [108].