# Gastrointestinall Tumors: Phytochemical and Drug Combinations Targeting the Hallmarks of Cancer
## 2 Anticancer Effects of Phytochemicals Used Alone and in Combination with Anticancer Drugs
### Gastric Cancer  
Noteworthy, it has been shown in human gastric cancer cells that the use of RNA interference techniques targeting both the poly-ubiquitin genes Ubiquitin B (_UIBB_) and Ubiquitin C (_UBC_) can remarkably decrease the proliferation rate of 23132/87 primary gastric cancer cell line, through the increase of pro-apoptotic Fas protein levels, the decrease of ubiquitinated H2A histone and oncoprotein \(\beta\)-catenin levels, the activation of caspase 3 and the induction of the apoptotic process [91]. Interestingly, it was shown that the synergistic cytotoxic effect of the combination between curcumin and oxaliplatin or 5-FU in both in vitro and in vivo gastric cancer models was exerted through the activation of the mitochondria-dependent apoptosis, where the regulation upon caspase 9 and 3, Bcl-2, ERK1/2 as well as Wingless-related integration site (WNT)/\(\beta\)-catenin played a role [92]. Importantly, by activating Phosphatase and tensin homolog (PTEN), resveratrol inhibited the activity of the Rac-alpha serine/threonine-protein kinase (AKT) signaling pathway, re-sensitizing gastric cancer cells to DOX while reducing the metastasis capacity of cancer \begin{table}
\begin{tabular}{c c c c} \hline \hline
**Plytochemical-Drug** & **Molecular Mechanisms** & **Molecular Targets** & **References** \\ \hline EGCG+5-FU & Proliferation inhibition & GRP78; NF-kB; & [59] \\  & Resensitizing cancer cells to 5-FU effects & miR-155-p; _MDR1_ & \\ \hline EGCG+5-FU & Resensitizing cancer cells to 5-FU effects & Caspase 3 & [60] \\  & Proliferation inhibition & & \\ \hline EGCG+Sodium butyrate & G2/M phase cell cycle arrest & HDAC1; DNMT1; p53; & [61] \\  & Apoptosis induction & p21; Survivin & \\ \hline Thymoquinone+Topotecan & Apoptosis induction & Caspase 3 & [62] \\  & S phase cell cycle arrest & Proliferation inhibition & \\ \hline Thymoquinone+DOX & Proliferation inhibition & Caspase 3 & [63] \\ \hline Thymoquinone+Irinotecan & Autophagic cell death induction & JNK; p38 MAPK; PI3K; & [64,65] \\  & Inhibition of metastasis process & ERK 1/2; NF-kB & \\ \hline Baialein+DOX & Apoptosis induction & Caspase 3; PCNA & [66] \\  & DNA damage induction & & \\ \hline Ellagic acid+5-FU & Apoptosis induction & Bax; Bcl-2; Caspase 3; & [67] \\  & Proliferation inhibition & PARP1 & \\ \hline Ursolic acid+Capecitabine & Inhibition of metastasis process & NF-kB; STAT3; EGFR; & [68] \\  & Reduction of tumor volume & \(\beta\)-catenin; p53; p21; & \\  & Inhibition of pro-survival mechanisms & MMP-9; VEGF; ICAM-1 & \\ \hline Berberine+DOX & Apoptosis induction & AIF; IL-6; STAT3; JAK; & [69,71,73] \\ Berberine+5-FU & Proliferation inhibition & MAPK; ERK & \\ Berberine+Taxol & Inhibition of pro-survival mechanisms & & \\ \hline Tectochryssin+Cetuximab & Proliferation inhibition & p-EGFR; COX-2; AP-1; & [74] \\  & NF-kB & & \\ \hline Terpinen-4-ol+Cetuximab & Reduction of tumor volume & KRAS & [75] \\ \hline Casticin+TNF & Apoptosis induction & Bcl-2; Bcl-xL; Survivin; & [76] \\  & XIAP; cFLIP; DR5 & & \\ \hline \(\beta\)-sesquiphellandrene+Thalidomide & Apoptosis induction & cFLIP; Bcl-xL; Bcl-2; & [77] \\  & & c-IAP1; Survivin & \\ \hline \(\beta\)-caryophyllene+Paclitaxel & Resensitizing cancer cells to paclitaxel effects & P-gp & [78] \\ \hline \(\beta\)-caryophyllene+DOX & Resensitizing cancer cells to DOX effects & P-gp & [79] \\ \hline Mistletoe extract+Gemcitabine & Apoptosis induction & Caspase 3 & [82] \\ \hline Panaxadiol+Irinotecan & Apoptosis induction & Caspase 9; Caspase 3 & [83] \\ \hline \hline \end{tabular}
\end{table} 
Table 1: _Cont._cells [93]. Interestingly, the amelioration of P-gp, as well as the inhibition towards the secretion of VEGF by EGCG contributed to the reversal of drug resistance against 5-FU in gastric cancer cell line SGC-7904/FU, exhibiting enhanced inhibitory effects both in in vitro and in vivo conditions [94].