## 5 Pancreatic Cancer
This extract was able to inhibit tumor proliferation in a GEM-resistant line (CFPAC-1), producing apoptosis both under in vitro conditions and in tumors of the line induced in immunocompetent mice. Significant differences were observed with respect to the individual treatments of the GEM + QYHJ combination in both tumor volume and weight. Furthermore, this combination reduced the expression of Ki-67 in the removed tumors [75]. A different approach to evade resistance is to focus therapy on killing cancer stem cells. Two plant extracts derived from [PERSON] and Rauwolfia vomitoria inhibited the proliferation of cancer stem cells in vitro and in vivo, a cell population that is usually related to drug resistance. This effect could be observed when the viability of these stem cells was reduced in in vitro cultures and, subsequently, the tumorigenicity of a PANC-1 stem cell-derived tumor induced in mice was reduced [76; 77]. Another compound that has been shown to be effective against cancer stem cells is quercetin, a flavanol present in fruits and vegetables. A study revealed that this compound suppressed the proliferation, invasiveness, and expression of CSC membrane markers through the regulation of \(\beta\)-catenin expression in CSCs derived from the PANC-1 and HPAC lines. Therefore, the combination of quercetin and GEM allowed the inhibition of these cells with \"stem\" characteristics that are involved in tumor resistance processes [78]. Fucoidan, an extract from the marine brown alga Turbinaria conoides, was employed in the Panc-1, MiaPaCa-2, Panc-3.27, and BxPC-3 pancreatic cell lines, and it achieved a notable increase in the expression of cleaved caspases 3, 8, and 9 and PARP and, through that, inhibition of the NFkB signaling pathway ligated to MDR development, and activation of p53 [79]. Moreover, another natural compound that has shown relevant antitumoral MDR is aronia berry extract (ABE), with a range of natural compounds such as flavonoids, coumarins, resins, saponins, and terpenoids from Aronia Melancorapa, a species of shrub in the Rosaceae family native to eastern North America. It was employed over GEM-resistant pancreatic ductal adenocarcinoma cell lines BxPC-3 and MIA-PaCa-2 and patient-derived 3D pancreatic tumor organoids. In the Gem-R BxPC-3 cell line, the inhibitory rate improved by 52.8% compared with the GEM-only treatment. Similarly, in the Gem-R MIA-PaCa-2 cell line, under the same ratio, the inhibitory rate improved by 56.5% compared with the GEM-only treatment. The apoptosis rate improved by 18.45% and 9.2% in BxPC-3 and MIA-PaCa-2, respectively, with the combined therapy compared with the individual treatments. It was shown that the combination of ABE and GEM targeted the MYD88/NF-kB signaling pathway associated with GEM resistance through the downregulation of TLR3, MYD88, and p65 in both the Gem-R BxPC-3 and Gem-R MIA-PaCa-2 cell lines by 46.6%, 53%, and 37% and 46%, 30%, and 60%, respectively [80]. A study which employed embelin, a benzoquinone extracted from Embelia ribes, a species of plant in the family Myrsniaceae, should also be highlighted. It was tested in the PC cell lines PANC-1 and MIA PaCa-2, obtaining a reduction in cell viability with half the IC50 value in resistant PANC-1 and MIA PaCa-2 in combination with GEM compared with GEM alone. Embelin induced the upregulation of Bax, \(\gamma\)H2 AX, p53, ERK1/2, and hENT1 expression and the downregulation of Bcl-2 and RRM1, related to tumor progression and drug resistance, in comparison with the control in both the cell lines. This led to 53% and 42% decreases in cell migration in Panc1 and MIA PaCa-2, respectively, with respect to the individual treatments [81]. [PERSON] et al. employed Evo312, a derivative of evodiamine, an indolequinazolidine alkaloid found in the traditional herbal medicine Evodia rutaocarpa, in human PC cells (PANC-1) and a corresponding GEM-resistant cell line to try to evade GEM resistance.