## 3 Stomach and Esophageal Cancer  
Stomach cancer has the fifth highest incidence and fourth highest mortality [2], while esophageal cancer is seventh in incidence and fifth in mortality in men [21]. The emergence of MDR means that the treatment of these tumor types requires a new approach, such as the use of natural products alone or in combination with classical chemotherapy. Stomach cancer presents chemoresistance mediated by P-gp expression, so it is of vital importance to find a mechanism to overcome this resistance. The use of curcumin has been shown to modulate both P-gp expression and function. [PERSON] et al. carried out an in vitro study with the SNU-5 gastric carcinoma cell line and the administration of curcumin together with the drug doxorubicin (DOX). The results showed an increase in the intracellular concentration of the drug derived from the use of curcumin, thus improving the effectiveness of the drug [22]. They studied the regulatory role of curcumin in vitro in the SGC7901/VCR human gastric cancer cell line, a variant resistant to vincristine. Through this, they saw a decrease in the concentration of P-gp expression 24 h after curcumin administration and 77% increased apoptosis when vincristine and curcumin were coadministered [23]. Another joint effect of the administration of DOX together with curcumin was the downregulation of the activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-\(\kappa\)B), associated with chemoresistance in these tumors, which has been shown to occur in vitro in the SGC-7901 gastric carcinoma cell line [24]. There are some studies that, in addition to testing the effect of curcumin in vitro, also tested it in vivo. [PERSON] et al. used BGC-823 xenograft tumors, to which they administered a combination of two antitumor drugs, namely 5-fluorouracil (5 FU) and oxaliplatin with curcumin, demonstrating powerful inhibition of tumor growth [25]. Another in vivo study that relates the use of curcumin to the inhibition of the transcription factor NF-\(\kappa\)B is that of [PERSON] et al. In this study, the authors generated tumors in BALB/c nude mice by inoculating cells of the tumor line SGC-7901 treated with nanostructured lipid nanoparticles loaded with etoposide and curcumin. The results obtained showed a reduction of up to 90% in tumor size with this treatment compared with the control group [26]. Figure 1: Resistance mechanisms. (**1**) Mechanisms that expel the drug from the cytoplasm to the outside of the cell, like P-gp and the MRP family; (**2**) mechanisms that prevent the drug from killing the tumor cell, like drug degradation or inactivation, the use of antioxidants or antiapoptotic proteins, and DNA repair. The use of polyphenols is also being studied in stomach cancer, especially those found in green tea. Although there have been cohort studies that did not find any relationship between the consumption of green tea and the risk of stomach cancer [27], it is important to note that the bioavailability of polyphenols is limited when consumed orally [28]. In vitro studies using the human cell lines MKN-1, MKN-45, MKN-74, and KATO-III, inhibition of proliferation and an increase in apoptosis after treatment were observed with (-)-epigallocatechin gallate (EGCG), a polyphenol found in green tea [29]. Esophageal tumors have a poor prognosis because they spread rapidly and systemically. Standard treatment for these tumors includes chemotherapy agents such as cisplatin or 5 FU, as well as paclitaxel, the combination of cisplatin and 5 FU being the most commonly used. The most common mechanism of resistance developed by this type of tumor is the expression of ATP synthase (ATP)-binding cassette (ABC) transporter systems, mediated by the ABCG protein, recognized as an unfavorable factor in the prognosis of these tumors [30]. Flavonoids such as kaempfer can reverse this resistance, as stated in the in vitro study of [PERSON] et al., in which they established a cisplatin-resistant cell line derived from the human line HKESC-1 [31].