## 5 Pancreatic Cancer  
Pancreatic cancer (PC) is the fourth leading cause of cancer death in Western countries. Its incidence has increased in recent years, but its high mortality rate (greater than 90% at 5 years after diagnosis) has not been reduced. This is due to the late diagnosis of the disease, the absence of serum biomarkers that allow it to be diagnosed prematurely, and high resistance to chemotherapy and radiotherapy [55]. The currently most widespread therapies in patients in advanced stages (generally metastatic) are FOLFIRINOX (a mixture of several drugs) and gemcitabine (GEM). However, PC cells are highly resistant to GEM, so new drugs are needed to reduce this chemoresistance to try to increase the quality of life and survival of patients [56]. Research into the use of natural products to treat PC has spread in recent years. The antitumor mechanisms of these compounds are usually divided into four categories: inhibitors of metastasis and angiogenesis, proapoptotic drugs, and inhibitors of drug resistance [57]. We are going to focus on studying natural compounds that have been used to try to evade PC cell resistance (Figure 3). One of the natural products that has been most widely used in the literature as a potential antitumor treatment is curcumin. A study determined that curcumin could produce a decrease in the proliferation of several pancreatic tumor lines (BxPC3, PANC-1, MPanc-96, and MIA PaCa-2) and was also capable of synergizing its effect with GEM, reducing resistance to this antitumor drug in pancreatic tumors. This effect was studied both in in vitro and in vivo conditions, determining that curcumin might be capable of suppressing the expression of the nuclear transcription factor (NF-\(\kappa\)), involved in proliferation, survival, angiogenesis, and chemoresistance [58]. Other studies have shown that the effect of curcumin on drug resistance (specifically 5-FU) might be related to its ability to inhibit the transmembrane resistance protein MRP5. Thus, it was shown that the IC50 of 5-FU decreased significantly in the PANC-1 and Mia PaCa-2 lines after co-treatment with this drug and curcumin [59]. Otherwise, it has been shown that curcumin might carry out this sensitization through the inhibition of EZH2, a catalytic subunit of the polycomb repressive complex 2 (PRC2), present in the PRC2-PVT1-cMyc axis. This complex is related to the expression of several lncRNAs that modulate the epithelial-mesenchymal transition, a phenomenon associated with drug resistance. The combined treatment of curcumin and GEM in BxPC3 cells resistant to this drug showed that curcumin could possibly sensitize these cells. In addition, it decreased the formation of spheroids and was capable of inhibiting growth in tumors of immunosuppressed mice generated from the BxPC3 GEM-resistant cell line in combination with GEM [60]. Given the suggested efficacy of co-treatment with GEM and curcumin, an attempt was made to encapsulate both drugs in pH-sensitive PEGylated liposomes (poly(ethylene-glycol)-PEG) to try to improve the cytotoxic effect exerted. The results showed that the simultaneous treatment might increase the intracellular accumulation of GEM, and a synergistic cytotoxic effect was observed in the MIA PaCa-2 tumor line, which was especially high when both drugs were encapsulated in the same liposome [61]. Figure 3: Effects of natural compounds on drug resistance in PC. Natural compounds extracted mainly from vegetables are shown to possibly be effective against drug resistance in PC through three main routes: (1) deregulation of MDR (MDR) proteins, (2) selective treatment against pancreatic tumor stem cells, and (3) deregulation of different molecular pathways that have been related to drug resistance in PC, generally GEM. Terpenes have also been studied in recent years because of their antitumor activity.