## 5 Pancreatic Cancer
With this treatment strategy, PKC\(\beta\)I expression was significantly suppressed, as well as the protein expression levels of glycogen synthase kinase 3\(\beta\), protein kinase B, signal transducer and activator of transcription 5, ribosomal protein S6 kinase \(\beta\)-1, and proline-rich AKT, in GEM-resistant PANC cells. Evo312 treatment significantly increased G2/M phase cell populations by 21%. Treatment with Evo312 increased total cell death to almost 25% with the highest concentration of GEM-resistant PANC cells. Tumor volume was suppressed by 72.15% [82]. Another study that should be highlighted is the study developed by [PERSON] et al. GEM-resistant AsPC-1 and MIA PaCa-2 cell lines were treated with parthenolide, a sesquiterpene lactone derived from the leaves of the medicinal plant Tanacetum partheium. With this strategy, reductions of 88% and 99% in the IC50 value with parthenolide in GEM-resistant MiaPaCa-2 and AsPC-1, respectively, were achieved. In AsPC-1 GR cells, p65 activity decreased by 85.9% compared with the control, and in MIA PaCa-2 GR cells, it decreased by 47.9%. In AsPC-1 GR cells, vascular tube formation decreased by 36.6% compared with the control, and in MIA PaCa-2 GR cells, it decreased by 30.5%. In AsPC-1 GR, IL-8 secretion decreased by 39.5% and VEGF secretion by 38.2% compared with the control. In MIA PaCa-2 GR, the IL-8 secretory capacity was reduced by 57.0%, and the VEGF secretory capacity was reduced by 44.6%. Parthenolide also suppressed the expression of the multidrug-resistance-related protein MRP1 and NF-kB [83]. Chrysin, a natural bioflavonoid widely found in propolisis, honey, and blue passion flowers (Passiflora caerulea), was used to reverse GEM resistance in PANC-1, Capan-2, BxPC-3, and AsPC-1 cells. In this study, human carbonyl reductase 1 (CBR1) was inhibited, enhancing the sensitivity of PC cells to GEM and potentiating the efficacy of GEM treatment in vivo and in vitro. Cell viability was reduced by 70% with chrysin compared with the control in Panc-1 and AsPC-1. Chrysin induced autophagy through ROS generation in PANC-1 cells through autophagy-related proteins such as Beclin-1, ATG5, and LC3. The ferritin heavy polypeptide 1 (FTH1) protein level was downregulated, while the expression of NCOA4 increased along with LC3-II levels. Tumoral volume was reduced by 69% with respect to the control with the combined treatment [84]. Therefore, as can be seen, most of the therapies derived from natural compounds that have shown an effect in PC are involved in sensitizing tumor cells to GEM or in targeting therapy towards cancer stem cells, responsible in part for the significant resistance to drugs that is described in pancreatic tumors. They are summarized in Table 1.  
Among all the molecular effects of these natural products, some of the most targeted mechanisms and markers of compounds with drug resistance evasion mechanisms in PC can be highlighted (Figure 4). Figure 4: Most targeted mechanisms, markers, and molecular effects of different compounds with drug resistance evasion mechanisms in PC. \begin{table}
\begin{tabular}{c c c c c} \hline \hline
**Compound or Extract** & **Cell Lines Studied** & **Molecular Effect** & **In Vivo Study** & **Reference** \\ \hline \multirow{4}{*}{Bitter melon juice} & PANC-1 and MIA PaCa-2 & Decrease in Akt and & & [66] \\  & PANC-1 and MIA PaCa-2 & ERK1/2 phosphorylation. & & [67] \\  & PANC-1 and MIA PaCa-2 & AMPK activation. JNK and & - & [67] \\  & PANC-1 & RRM1/2 downregulation. & & [71] \\  & PANC-1 and HPAC & Decrease in HSP27 expression. & & [78] \\  & PANC-1 & HPAC & Upregulation of \(\beta\)-catenin expression. & [78] \\  & PANC-3, PANC-1, & (Bax) and downregulation of & & \\  & and AsPC-1 & antiapoptotic markers (COX-2, survivin, & \\  & and BsC-1 & and BsC-2) & & BALB/c mice bearing \\  & PANC-1 and BXPC-3 & Decrease in ABCB1 and & & BXPC-3 tumors \\  & PANC-1, ASPC-1, & ABCG2 expression. & & [69] \\  & PANC-1, ASPC-1, & Suppression of Wnt/\(\beta\)-catenin & BALB/c mice bearing & [76] \\  & PANC-1, ASPC-3, & signaling pathway.