# 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
Interestingly, [PERSON] et al. [125] described the anticancer effects of a combination of sulforaphene and gemcitabine against both pancreatic CSCs and MIA-PaCa2 cells-xenografted BALB/c nude mice. The authors described a decrease of NF-kB activity, the downregulation of Notch homolog 1 translocation-associated (NOTCH-1) and Transcription factor p65, inhibition of aldehyde dehydrogenase 1 (ALDH1) activity, decreased proliferation of the subpopulation of CSCs, reduction of the growth of xenografts and inhibition of the relapse of drug-treated cancer cells in the mouse model [125]. Furthermore, also the phytochemical cucurbitacin B potentiated the inhibitory effects of gemcitabine in pancreatic tumors, through the modulation of the levels of Bcl-xL, Bcl-2, JAK and cellular-Myelocytomatosis oncogene product (c-myc) [126]. Regarding the use of the DNA and RNA polymerase inhibitor mithramycin A, this compound was used in combination with the phytochemical benthic acid and the anticancer drug gemcitabine in xenograft mouse models of human pancreatic cancer, where the authors observed a decrease of Sp1 and VEGF levels [127]. Moreover, it was shown that the combination of toleranamic acid and mithramycin A exerted remarkable antitumor effects in an in vivo pancreatic cancer model through the decrease of Sp1 protein levels [128]. Interestingly, in an orthotopic pancreatic cancer mouse model obtained with PANC-1 cells, B-carboline in combination with gemcitabine reduced tumor burden and metastatic potential development [129]. Importantly, it was shown that red beetroot (_Beta vulgaris_) extract together with DOX induced synergistic antiproliferative effects against pancreatic PaCa-2 tumor cells [130]. The molecular pathways and molecular targets modulated by the combinations of phytochemicals and anticancer drugs in pancreatic cancer models are reported in Table 4. \begin{table}
\begin{tabular}{c c c c} \hline \hline \multicolumn{1}{c}{**Phypochemical-Drug**} & \multicolumn{1}{c}{**Molecular Mechanisms**} & \multicolumn{1}{c}{**Molecular Targets**} & \multicolumn{1}{c}{**References**} \\ \cline{1-1} \multicolumn{1}{c}{**Combinations**} & & & \\ \hline Genistein+Erlotinib & Resensitizing cancer cells to erlotinib effects & Ubiquitin; Proteasome & [24] \\ \hline Genistein+Gemcitabine & Proliferation inhibition & NF-kB & [116; 117] \\  & Reduction of tumor volume & & \\ \hline Genistein+Oxaliplatin & Resensitizing cancer cells to oxaliplatin effects & NF-kB; Ki-67 & [118] \\ \hline EGCG+TRAIL & Apoptosis induction & Caspase 2; Caspase 3 & [120] \\  & Proliferation inhibition & & \\ \hline EGCG+Celecoxib & Proliferation inhibition & IL-1 & [122] \\ \hline Benzyl isothiyanate+TRAIL & Apoptosis induction & Caspase 8; Caspase 3 & [123] \\ \hline Resveratrol+Gemcitabine & Proliferation inhibition & NF-kB; Bcl-2; Bcl-xL; & [124] \\  & Angiogenesis inhibition & COX-2; Cyclin D1; VEGF; & \\  & Reduction of tumor volume & MMP-9; Ki-67; CD31 & \\ \hline Sulforaphene+Gemcitabine & Proliferation inhibition & NF-kB; NOTCH-1; p65; & [125] \\  & Reduction of tumor volume & ALDH1 & \\  & Inhibition of CSCs growth & & \\ \hline Cucurbitacin B+Gemcitabine & Resensitizing cancer cells to gemcitabine effects & Bcl-xL; Bcl-2; JAK; c-myc & [126] \\ \hline Betulinic acid+ Mithramycin A & Proliferation inhibition & Sp1; VEGF & [127] \\  & Angiogenesis inhibition & & \\  & Reduction of metastasis capacity & & \\ \hline \hline \end{tabular}
\end{table} 
Table 4: Pancreatic cancer targets.