# 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
In addition, in hepatocellular carcinoma model, an isocorydine derivative decreased cancer cell proliferation and induced apoptosis, in association with sorafenib, through the modulation of the levels of Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2 BP3) [109]. Importantly, cytotoxicity of DOX to HepG2 liver cancer cells was increased in combination with naringenin [110]. This study attributes the synergistic effect of this association to its ability to modulate the activity of MRPs, promote apoptosis and inhibit angiogenesis [110]. Interestingly, [PERSON] et al. [111] demonstrated the in vitro and in vivo anticancer effects of a combination of cisplatin and lute-olin against both liver cancer cell lines HepG2 and Hep3B and colorectal cancer cells HT29 and HCT116 and also HCT116-BALB/c nude mice xenografts. The antiproliferative effects were mediated by stabilization of tumor suppressor p53, increased JNK activation and induction of apoptosis [111]. Importantly, [PERSON] et al. [112] demonstrated the antiproliferative activity of a combination of apigenin and paclitaxel against Hep3B liver cancer cells, which was exerted through inhibition of Superoxide dismutase (SOD) activity, ROS-induced activation of caspase 2 and MMPs, increased cleavage of caspase 3 and PARP1 [112]. Regarding the phytochemical quercetin, a selective antiproliferative-boosting effect of this flavonoid on DOX was observed in hepatoma cells SMMC772I with no significant cytotoxicity in normal liver cells L02 [113]. In particular, the addition of 20 uM quercetin facilitated DOX accumulation in SMMC772I cells and subsequently augmented cell apoptosis [113]. Interestingly, L-canavanine, a phytochemicalanol found in several plants of the Fabaceae family, potentiated the cytotoxicity of vinblastine and paclitaxel in hepatocarcinoma cells [114]. Importantly, [PERSON] and collaborators examined _Monoratica charantia L_. lectin effects, used at the dose of 0.5 mg/Kg combined with sorafenib (at the dose of 30 mg/kg) in xenograted mice of HepG2 cells and in liver cancer cell lines. These authors documented that _M. charantia L_. lectin enhanced the lethal effects of sorafenib both in cell and animal models, decreasing cancer cell viability by more than 3 fold and tumor weight by about 50% [115]. The molecular pathways and molecular targets modulated by the combinations of phytochemicals and anticancer drugs in liver cancer models are reported in Table 3. \begin{table}
\begin{tabular}{c c c c} \hline \hline
**Pityochemical-Drug** & **Molecular Mechanisms** & **Molecular Targets** & **References** \\ \hline EGCG+Sorafenib & Proliferation inhibition & Phosphofractokinase & [98] \\  & Inhibition of glycolytic pathway & & \\ \hline EGCG+DOX & Proliferation inhibition & P-gp; _MDR1_; HIF-1\(\alpha\) & [99] \\ ECG+DOX & Reduction of tumor volume & & \\  & Resensitizing cancer cells to DOX effects & & \\ \hline EGCG+5-FU & Resensitizing cancer cells to 5-FU effects & COX-2; PGE2; Akt & [100] \\ \hline Y6 (EGCG derivative)+DOX & Resensitizing cancer cells to DOX effects & P-gp & [101] \\  & Apoptosis induction & & \\ \hline \hline \end{tabular}
\end{table} 
Table 3: Liver cancer targets.