# Gastrointestinall Tumors: Phytochemical and Drug Combinations Targeting the Hallmarks of Cancer
## 2 Anticancer Effects of Phytochemicals Used Alone and in Combination with Anticancer Drugs
### Colon Cancer  
#### 2.1.1 Antitumor Effects of Combinations of Curcumin with Anticancer Drugs in Colon Cancer  
Extensive research has evidenced that curcumin, the main curcuminoid of turmeric (_C. longa_), is able to decrease the resistance of cancer cells to several chemotherapeutic agents, like gemcitabine, 5-FU, cisplatin and DOX in pancreas, colon, liver and gastric tumors [46]. It has been shown that curcumin can sensitize colorectal cancer cells to 5-FU [47]. Interestingly, the effects of a combination of curcumin and bevacizumab were studied in a xenograft model derived from the HT29 colorectal cancer cells [48]. Mice fed with curcumin showed high bioavailability of the phytochemical and the combination therapy induced remarkable anticancer effects [48]. In addition, curcumin effects were assayed in two different human colon adenocarcinoma cell lines (HCT-116 and HT-29) and the pancreatic cancer cell line Panc-28. Curcumin reduced the proliferation rate of tumor cells, regulating NF-kB and Signal transducer and activator of transcription 3 (STAT3) activity [49]. In addition, the combination of capecitabine and curcumin increased the apoptotic rate of HCT-116 cells from 5% of cells to about 50% of cells [49]. Interestingly, the combination of curcumin and irinotecan in LoVo cancer cells modulated the levels of several therapy biomarkers: Glutathione S-transferase Mu 5 (GSTM5), Protein disulfide isomerase (PDI), Peroxiredoxin 4 (PRDX4) [50]. Importantly, the combined use of irinotecan and curcumin in an in vivo model of rat colorectal carcinogenesis remarkably reduced the activity of P-gp (7-fold), inhibiting MDR mechanisms [51]. Furthermore, it was shown that the combined therapy with curcumin and irinotecan reduced cancer growth and activated the apoptotic process in HT-29 and LoVo colon cancer cells, through the modulation of Binding Immunoglobulin Protein (BIP) and C/EBP Homologous Protein (CHOP) levels [52]. In addition, the authors demonstrated that the anticancer effects of this phytochemical and drug combination were exerted through the modulation of ROS and the induction of endoplasmic reticulum (ER) stress pathway [52]. Interestingly, a preclinical investigation revealed that combination therapy with curcumin and dasatinib was highly effective in a colon cancer model. The combination caused over 95% regression of intestinal adenomas in Apc min/+ mice, which is linked to the reduced proliferation rate and increased apoptosis induction [53]. Importantly, it was shown that curcumin is able to resensitize colon cancer cells to the drug 5-FU in a 3D alginate tumor micro-environment, through the modulation of the levels of MMP9, NF-kB and C-X-C Motif Chemokine Receptor 4 (CXCR4) [54]. Interestingly, the addition of 25 mM hexahydrocurcumin to a dose of 5 mM 5-FU exerts a synergistic effect against the growth of HT-29 cells by significantly reducing cell viability to a greater degree than monotherapy; the combination enhanced the growth inhibition of cancer cells through the downregulation of COX-2 expression [55].