## 5 Pancreatic Cancer
One of them is ericalyxin b, an ent-kaurane diterpenoid isolated from Isodon eriocalyx that has shown a synergistic effect in several pancreatic lines together with the drug GEM, decreasing the resistance of SW1990, Capan-1, Panc-1, and Capan-2 to this cytotoxic treatment. This synergy is due to this terpene activating the apoptotic caspase cascade and regulating the PDK1/AKT1/caspase axis and c-Jun N-terminal kinase (JNK) cell signaling, promoting apoptosis and facilitating cell death induced by the drug GEM [62]. Likewise, several jatrophane diterpenes were isolated from alcoholic extracts, and two compounds (apoxywellwitschene and Esolatin M) were shown to be capable of inducing apoptosis by activating caspase 3. Furthermore, they interacted with a transmembrane protein involved in drug resistance, ABCB1, and allowed the sensitization of PC cells against DOX [63]. Other monoterenes such as terpinen-4-ol have also been tested on PC lines such as MIA PaCa-2, Colo357, and Panc-1, proving that their combination with GEM exerts a significant synergistic effect on tumor lines. Furthermore, this synergistic effect is also seen with oxaliplatin and 5-FU in colorectal tumor lines [64]. On the other hand, 28 triterpenoids extracted from Momordica balsamina were evaluated in the PC cell line EPP85-181 and two drug-resistant variants thereof. In this study, it was observed that two of the extracted compounds (balsaminol F and karavoate A) were quite effective against drug-resistant lines [44]. Finally, a triterpenoid called nimbolide was encapsulated in nanoparticles, and its inhibitory effect against cancer stem cells (CSCs) derived from the MIA PaCa-2 cell line was observed due to its ability to inhibit the AKT and mTOR pathways. This inhibition triggered the mesenchymal-epithelial transition of pancreatic CSCs, losing their MDR and self-renewal properties [65]. Although curcumin and terpen are the most studied compounds, distinct natural compounds have been shown to be effective in avoiding drug resistance in PC. First, a study found that GEM-resistant cells had increased ATP production, oxygen consumption, and expression of glucose transporters. Against this, the treatment of PANC-1 and MIA-PaCa2 cell lines with bitter melon juice produced a decrease in the phosphorylation of Akt and ERK1/2, proteins that have been found to be overexpressed in resistant cell lines. This dysregulation generated a decrease in their viability, demonstrating that this natural juice was capable of acting as an effective therapy against resistant cells [66]. In addition, an ethanolic extract of oat bran (OBE) showed efficacy in pancreatic tumor cells resistant to GEM. Thus, the toxicity of this extract in MIA PaCa-2 and PANC-1 cells was analyzed, observing that it induced death in PC cells through AMPK activation and JNK downregulation. The ability to sensitize cells to GEM was due to the fact that OBE produces a reduction in the expression of RRM1/2 [67]. Moreover, coix seeds have been used in PC to increase the sensitivity of tumor cells to the drug GEM. Thus, an emulsion prepared from these seeds exerted a synergistic effect with the drug GEM, decreasing its IC50 in the BXPC-3, PANC-1, and AsPC-1 cell lines. Additionally, it was found that simultaneous treatment increased the expression of proapoptotic markers such as Bax and decreased that of antiapoptotic markers (COX-2, survivin, and Bcl-2). An in vivo study carried out on the induction of tumors of the BxPC-3 line showed that co-treatment with GEM and this emulsion significantly decreased the size of the tumors with respect to the treatments applied individually [68]. Meanwhile, extracts of these seeds increased the antitumor effect of the drug GEM, showing that they could decrease the overexpression of the ABCB1 and ABCG2 drug resistance proteins produced by the drug GEM in the PANC-1 and BxPC3 tumor cell lines.