# Gastrointestinall Tumors: Phytochemical and Drug Combinations Targeting the Hallmarks of Cancer
## 2 Anticancer Effects of Phytochemicals Used Alone and in Combination with Anticancer Drugs
### Pancreatic Cancer  
Genistein enhances the efficacy of chemotherapy mainly by inhibiting survival signals and/or enhancing apoptotic signals. It was reported that genistein pretreatment inactivated NF-kB and contributed to growth inhibition and apoptosis induced by cisplatin, docetaxel, DOX or gemcitabine in various tumor cells including prostate, breast, lung, pancreatic and ovarian cancers [116, 117]. Interestingly, genistein has been investigated as a sensitizer to gemcitabine and ellotinib in cancer cell lines and in patients with pancreatic cancer [24]. In addition, genistein was tested for its synergistic combination with gemcitabine in two murine xenografts of human pancreatic carcinoma cells (COLO357 and L3.6 pl) and this treatment led to antiproliferative effects and reduction of tumor volume [117]. Furthermore, genistein restored the sensitivity to oxaliplatin in gemcitabine-resistant pancreatic cancer cells in both in vitro and in vivo models [118]. Importantly, several flavonoids including genistein and quercetin were found to downregulate MRP1 in resistant human tumor cell lines, such as pancreatic adenocarcinoma cells Panc-l, suggesting their MDR reversal potential [119]. Regarding the use of TRAIL in antitumor therapies, the combination of EGCG and TRAIL significantly diminished the proliferation of human pancreatic cancer cell line MIA PaCa-2 and increased both cleavage of proaspase-2 and apoptosis induction [120]. Importantly, the anticancer and pro-apoptotic effects of a combination of EGCG and thymoquinone in pancreatic PANC-1 cancer cell line [121] and a combination of EGCG and celecoxib in pancreatic cancer cell line Colo357 [122] have been described. Interestingly, \begin{table}
\begin{tabular}{c c c c} \hline \hline
**Plytochemical-Drug** & **Molecular Mechanisms** & **Molecular Targets** & **References** \\ \hline Curcumin+Bevacizumab & Angiogenesis inhibition & VEGF; VEGFR; KRAS & [102] \\  & Reduction of tumor volume & & \\ \hline EF24 (Curcumin & & \\ derivative)+Sorafenib & Resensitizing cancer cells to sorafenib effects & VHL; HIF-1\(\alpha\) & [103] \\  & Proliferation inhibition & & \\ \hline Genistein+TRAIL & Proliferation inhibition & MAPK; Caspase 8 & [105] \\  & Apoptosis induction & & \\ \hline Genistein+ATO & Proliferation inhibition & Akt; NF-kB & [106] \\  & Apoptosis induction & & \\  & Angiogenesis inhibition & & \\ \hline Resveratrol+5-FU & S phase cell cycle arrest & Ki-67 & [107] \\  & Resensitizing cancer cells to 5-FU effects & & \\ \hline Indole-3-carbonl+Sorafenib & Apoptosis induction & EMT markers; NOX1 & [108] \\  & Angiogenesis inhibition & & \\ \hline Isocorydine & Apoptosis induction & IGF2 BP3 & [109] \\  & Proliferation inhibition & & \\ \hline Naringenin+DOX & Apoptosis induction & MRPs & [110] \\  & Angiogenesis inhibition & & \\ \hline Luteolin+Cisplatin & Apoptosis induction & p53; JNK & [111] \\  & Proliferation inhibition & & \\ \hline Apigenin+Paclitaxel & Proliferation inhibition & SOD; Caspase 2; MMPs; & [112] \\  & Caspase 3; PARP1 & & \\ \hline Quercetin+DOX & Resensitizing cancer cells to DOX effects & p53; Bcl-xL & [113] \\ \hline L-canavanine+Unblastine & Proliferation inhibition & P-gp & [114] \\ L-canavanine+Paclitaxel & & & \\ \hline Lectin+Sorafenib & Proliferation inhibition & Ki-67 & [115] \\  & Reduction of tumor volume & & \\ \hline \hline \end{tabular}
\end{table} 
Table 3: _Cont._the sensitization of pancreatic cancer cells for TRAIL treatment in association with benzyl isothiocyanate (extracted from cruciferous vegetables) has been demonstrated [123]. Importantly, [PERSON] et al. [124] described the anticancer effects of a combination of resveratrol and gemcitabine against both pancreatic cancer cell lines AsPC-1, MIA PaCa-2, Panc-1, Panc-28 and also MIA-PaCa-2 cells-orthotopic mice model xenografts. The authors evidenced the downregulation of NF-kB, Bcl-2, Bcl-xL, COX-2, cyclin D1, MMP-9, VEGF, proliferation marker Ki-67, the micro-vessel density marker Clusters of differentiation 31 (CD31) and ICAM-1 [124].