## 5 Pancreatic Cancer
This effect was also demonstrated in tumors derived from BxPC3 induced in mice, where it was observed that the combination of GEM and the extract was capable of significantly inhibiting proliferation [69]. Emodin is an anthraquinone isolated from the roots of rheumatic palm leaves currently used as a laxative treatment. This natural compound has been investigated in PC as a possible inhibitor of drug resistance in pancreatic tumor cells. Thus, co-treatment with GEM and emodin was capable of significantly inhibiting the proliferation of tumor cells in two-dimensional cultures of the Bxpc-3 line in a dose dependent-manner with respect to individual treatments, as well as increasing significantly the apoptosis rate of these gemcitabine resistant cells with the combined treatment. This effect was related to the ability of emodin to inhibit the expression and activity of certain membrane protein markers involved in drug resistance and survival and apoptosis signaling proteins, such as NF-kB, involved in upregulation of MDR-1 mRNA expression and ABC transporter protein superfamily, survivin and XIAP (X-linked inhibitor of apoptosis), within an upregulation of the expression of Caspase-3 and 9 observing that co-treatment with this compound and GEM produced the greatest decrease in the expression of these proteins [70]. A different protein that has been implicated in resistance is heat shock protein 27 (HSP27). A study using an enzyme-treated asparagus extract (ETAS) determined that this extract reduced the expression of the HSP27 protein, both in its basal and phosphorylated versions, in a pancreatic tumor line resistant to GEM (KLM1-R). Therefore, the use of this extract could improve the effect of GEM due to the decrease in the expression of molecular pathways that confer resistance to it [71]. A ginseng isolated from Panax ginseng (Rg3) has been shown to have antitumor potential in various tumors. Its treatment was characterized in PC, observing how this compound suppressed the growth of two tumor lines resistant to the drug GEM: Panc-1/GEM and SW1990/GEM. Furthermore, it was shown that this antitumor effect was due to this compound being capable of increasing the expression of an lncRNA (CASC2) and the PTEN gene, this PTEN-mediated signaling being involved in the significant suppression of tumor growth that was observed in the cell lines and in an in vivo assay carried out in mice with the Panc-1/GEM line [72]. A distinct natural compound extracted from Garcinia yunnanensis, Oblongifolin C (OC), has been shown to be effective in sensitizing PC cells to GEM. To achieve this, OC triggers proteasome-mediated degradation of the Src protein and negatively regulates the MAPK pathway. This deregulation of Src, a protein related to resistance phenomena, allows GEM to have a greater effect on MIA PaCa-2 and Capan-1 GEM-resistant cell lines. An in vivo assay with tumors generated from the MIA PaCa-2-GEM-resistant line confirmed that the combination of OC and GEM decreased the weight and volume of the tumors generated [73]. On the other hand, a compound isolated from the fungus Chaetomium sp. called chaetospirolactone is capable of sensitizing PC cells to tumor necrosis factor-related ligand (TRAIL) therapy in the PANC-1 and AsPC-1 tumor lines, showing a decrease in the cell proliferation and migration of the lines and an increase in apoptosis. In addition, in vivo tests in mice proved that the combination of the compound and TRAIL therapy decreased the size of the tumors generated [74]. Besides all these natural compounds usually extracted from plants, a medical formula used in China for the treatment of PC called Qingyihuaji (QYHJ) has also been shown to be effective against resistance to GEM. This formulation is generated from five herbs of Chinese origin: Herba Scutellariae barabatae, Herba Hedyotdis, Rhiza Arisematis erubescentis, Herba seu Radix Gynostematis pentaphylli, and Fructus Amomi Rotundus.