Pancreatic ductal adenocarcinoma (PDAC) has one of the highest mortality rates among all cancer types. Its delayed diagnosis precludes curative resection, thus most of the current therapies against PDAC are based on chemo- and radiotherapy. Unfortunately, these strategies are insufficient to improve its poor prognosis. Despite the advances made in chemotherapy (e.g. nab-paclitaxel and gemcitabine), many patients with PDAC are unable to benefit from them due to the rapid development of drug resistance. Currently, more than 165 genes have been found to be implicated in drug resistance of pancreatic tumors, including different integrins, mucins, NF-κB, RAS and CXCR4. Moreover, drug resistance in PDAC is thought to be mediated by the modulation of miRNAs (e.g. miRNA-21, miRNA-145 and miRNA-155), which regulate genes that participate in cell proliferation, invasion and metastasis. Finally, cancer stem cells are intimately related to drug resistance in PDAC due to their ability to overexpress ABC genes -involved in drug transport-, and enzymes such as aldehyde dehydrogenases -implicated in cellular drug metabolism- and poly (ADP-ribose) polymerases -involved in drug-induced DNA damage repair. Understanding the mechanisms involved in drug resistance will contribute to the development of efficient therapeutic strategies and to improve the prognosis of patients with PDAC.

The development of drug resistance is one of the main causes of cancer treatment failure. This phenomenon occurs very frequently in different types of cancer, including colon and pancreatic cancers. However, the underlying molecular mechanisms are not fully understood. In recent years, nanomedicine has improved the delivery and efficacy of drugs, and has decreased their side effects. In addition, it has allowed to design drugs capable of avoiding certain resistance mechanisms of tumors. In this article, we review the main resistance mechanisms in colon and pancreatic cancers, along with the most relevant strategies offered by nanodrugs to overcome this obstacle. These strategies include the inhibition of efflux pumps, the use of specific targets, the development of nanomedicines affecting the environment of cancer-specific tissues, the modulation of DNA repair mechanisms or RNA (miRNA), and specific approaches to damage cancer stem cells, among others. This review aims to illustrate how advanced nanoformulations, including polymeric conjugates, micelles, dendrimers, liposomes, metallic and carbon-based nanoparticles, are allowing to overcome one of the main limitations in the treatment of colon and pancreatic cancers. The future development of nanomedicine opens new horizons for cancer treatment.

Moringa oleifera, Tropaeolum tuberosum and Annona cherimola are medicinal plants traditionally used in Ecuador. However, their therapeutic properties are not completely known. We analyzed chromatographically ethanolic extracts of the seeds of M. oleifera, A. cherimola and the tubers of T. tuberosum; all presented a high content of polyphenols. The extract of A. cherimola showed the highest antioxidant activity and M. oleifera had the highest capacity to enhance the activity of detoxifying enzymes such as glutathione S-transferase and quinone oxidoreductase. The antitumor effect of these extracts was evaluated in vitro with colorectal cancer (CRC) cell lines T84, HCT-15, SW480 and HT-29, as well as with cancer stem cells (CSCs). A. cherimola and M. oleifera extracts presented the lowest IC₅₀ in T-84 and HCT-15 (resistant) cells, respectively, as well as the highest level of inhibition of proliferation in multicellular tumor spheroids of HCT-15 cells. The inhibitory effect on CSCs is noteworthy because in vivo, these cells are often responsible for cancer recurrences and resistance to chemotherapy. Moreover, all extracts showed a synergistic activity with 5-Fu. The antiproliferative mechanism of the extracts was related to overexpression of caspases 9, 8 and 3 and increased production of reactive oxygen species. In addition, we observed cell death by autophagy in M. oleifera and T. tuberosum extracts. Therefore, these ethanolic extracts are excellent candidates for future molecular analysis of the presence of bioactive compounds and in vivo studies which could improve colon cancer therapy.

Lung cancer is the most common cancer in the world and several miRNAs are associated with it. MiRNA sponges are presented as tools to inhibit miRNAs. We designed a system to capture miRNAs based on circular RNAs (circRNA). To demonstrate its usefulness, we chose miR-21, which is upregulated and implicated in lung cancer. We constructed a miR-21 sponge and inserted it into a vector that facilitates circular RNA production (Circ-21) to study its effect on growth, colony formation, and migration in lung cancer cell lines and multicellular tumor spheroids (MTS). Circ-21 induced a significant and time-dependent decrease in the growth of A549 and LL2 cells, but not in L132 cells. Furthermore, A549 and LL2 cells transfected with Circ-21 showed a lower number of colonies and migration than L132. Similar findings were seen in A549 and LL2 Circ-21 MTS, which showed a significant decrease in volume growth, but not in L132 Circ-21 MTS. Based on this, the miR-21 circular sponge may suppress the processes of tumorigenesis and progression. Therefore, our system based on circular sponges seems to be effective, as a tool for the capture of other miRNAs.

Sodium selenite acts by depleting enzymes that protect against cellular oxidative stress. To determine its effect alone or in combination with gemcitabine (GMZ) in pancreatic cancer, we used PANC-1 and Pan02 cell lines and C57BL mice bearing a Pan02-generated tumor. Our results demonstrated a significant inhibition of pancreatic cancer cell viability with the use of sodium selenite alone and a synergistic effect when associated with GMZ. The molecular mechanisms of the antitumor effect of sodium selenite alone involved apoptosis-inducing factor (AIF) and the expression of phospho-p38 in the combined therapy. In addition, sodium selenite alone and in association with GMZ significantly decreased the migration capacity and colony-forming ability, reduced tumor activity in multicellular tumor spheroids (MTS) and decreased sphere formation of cancer stem cells. In vivo studies demonstrated that combined therapy not only inhibited tumor growth (65%) compared to the untreated group but also relative to sodium selenite or GMZ used as monotherapy (up to 40%), increasing mice survival. These results were supported by the analysis of C57BL/6 albino mice bearing a Pan02-generated tumor, using the IVIS system. In conclusion, our results showed that sodium selenite is a potential agent for the improvement in the treatment of pancreatic cancer and should be considered for future human clinical trials.

Euphorbia lathyris seeds have been used to treat various medical conditions. We previously reported that ethanolic extract from the defatted seed of Euphorbia lathyris (EE) (variety S3201) possesses a potent in vitro antitumor activity against colon cancer (CRC) cell lines. However, the effects of EE on CRC in vivo models and its possible preventive activity have not been elucidated. The aim of this study is to develop an in vivo study to corroborate its efficacy. For this purpose, two tumor induction models have been developed. In orthotopic xenograft model, it has been shown that EE reduces tumor size without hematological toxicity. The ethanolic extract induced an intense apoptosis in tumors mediated by caspase 3. Using the Azoxymethane/Dextran Sulfate Sodium model, a reduction of dysplastic polyps has been demonstrated, showing its preventive power. Furthermore, EE promoted the presence of an eubiotic microbiotal environment in the mucosa of the colon and induced an increase in antioxidant enzyme activity. This fact was accompanied by a modulation of cytokine expression that could be related to its protective mechanism. Therefore, although further experiments will be necessary to determine its applicability in the treatment of CRC, ES could be a new prevention strategy as well as treatment for this type of tumor, being a powerful candidate for future clinical trials.