# Gastrointestinall Tumors: Phytochemical and Drug Combinations Targeting the Hallmarks of Cancer
## 2 Anticancer Effects of Phytochemicals Used Alone and in Combination with Anticancer Drugs  
Phytochemicals can be found in grains, vegetables, fruits and several foods [33]. Many phytochemicals, like genistein and resveratrol, were combined with different antitumor drugs for their synergistic anticancer effects against various forms of cancer [33]. Synergy effect is broadly defined as the interaction or cooperation of two or more substances to produce a combined effect greater than the sum of their individual effects [34]. Combinational treatment with phytochemicals and anticancer drugs can suppress cancer recurrence and reduce the resistance of tumor cells to chemotherapeutic agents [35]. Interestingly, green beet and red beetroot have been described as vegetables rich in phytochemicals with anticancer effects, like vitexin-2-\(O\)-xyloside, apigenin, betacyanins, betaxanthus, which possess antitumor properties against colon, liver and bladder cancers [36]. These phytochemicals are able to downregulate pro-survival genes _BIRC5_, catenin beta-1 (_CTNNB1_), _HIF1A_, _VEGFA_ and to inhibit the multidrug resistance mechanisms of tumor cells [36]. Phytochemicals extracted from green beet and red beet target several proteins, which have been identified either as tumor suppressors, like Bax, FS-7-associated surface antigen (Fas), p53, Bcl-2-associated agonist of cell death (Bad), TRAIL, or as oncoprotein, like Bcl-2, Cyclooxygenase-2 (COX-2), Survivin, \(\beta\)-catenin, HIF1\(\alpha\), VEGF [36]. Importantly, the chemopreentive and antitumor properties of several other phytochemicals, like curcumin, resveratrol, sulforaphane and piperine have been demonstrated. The chemopreentive action of curcumin and its synergistic effects, when combined with other phytochemicals (like quercetin) and antitumor drugs (like tamoxifen and 5-fluorouracil(5-FU)) against several cancers, have already been described [37]. Curcumin can reverse the drug resistance to doxorubicin (DOX) or paclitaxel by directly inhibiting the expression of P-gp in cancer cells [38,39]. Resveratrol is also able to reverse drug resistance in cancer cells by directly affecting the efflux pumps. Importantly, co-administration of DOX with resveratrol led to the reversal of drug resistance in various cancer cell lines, as a result of the downregulation of Multidrug resistance-associated protein 1 (MRP1) and the reduced expression of P-gp [40]. Interestingly, it was shown that sulforaphane re-sensitized [PERSON] esophageal adenocarcinoma cells to the effects of the drug paclitaxel [41]. Importantly, piperine has been extensively used to enhance the oral bioavailability of various drugs as it significantly inhibits the expression of Cytochrome P450 (CYP3A4) and P-gp [42]. Bioavailability of anticancer drugs enhanced by piperine includes docetaxel, etoposide and 5-FU [43,44,45]. In the following sections, we describe the antitumor properties and biological effects of several combinations of phytochemicals and anticancer drugs against gastrointestinal tumors: colon cancer, gastric cancer, liver cancer, pancreatic cancer.