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Additional Hydroxyl group on CT6 (3,4-dihydroxy-5,7-dimethoxyflavone), a flavone extracted from Chromolaena Tacotana potentially confers additional activity against pancreatic cancer as compared to CT7 (4-hydroxy-5,7-dimethoxyflavone) Parker Wade1, Miranda Green1, April Weaver1, Omri Coke1, Ruben D. Torrenegra2, and Victoria Palau1 1Department of Pharmaceutical Sciences, College of Pharmacy, East Tennessee State University, Johnson City, TN. 2Department of Chemistry, Universidad de Ciencias Aplicadas y Ambientales, Bogota, Colombia and Pancreatic cancer is one of the deadliest types of cancers, with a mortality rate of about 95%. This high mortality rate signifies there is a need for further research into finding treatment options for those affected by pancreatic cancer. Recent studies have found cytotoxic effects on cancerous cells elicited from compounds, such as flavones, in plants indigenous to Western South America, specifically Colombia. The flavones 3,4-dihydroxy-5,7-dimethoxyflavone (CT6) and 4-hydroxy-5,7-dimethoxyflavone (CT7) were isolated from Chromolaena Tacotana, member of the asteraceae family. The molecular structures of the flavones differ only by an additional hydroxyl group on CT6. Both of these compounds were tested on MIA PaCa2 and Panc28 pancreatic cancer cells at concentrations ranging from 5μM to 80μM. Cell viability after dosing of CT6 and CT7 was determined using MTT and spectrophotometry analysis. MIA PaCa2 is more poorly differentiated than Panc28. CT6 conferred greater activity on both cell lines compared to CT7. Percent cell viability of the Panc28 cell line reached a low of 35.55% (p=0.0001) with CT6, compared to 84.25% (p=0.0275) with CT7. Percent cell viability of the MIA PaCa2 cell line reached a low of 46.72% (p=0.000001)with CT6. However, CT7 showed no significant difference, with percent cell viability reaching 103.73% (p=0.5605) when compared to the control for this cell line. While CT6 exerted cytotoxic activity on both Panc28 and MIA PaCa2, CT6 had significantly more cytotoxic activity on Panc28, which could be related to the greater differentiation status of this cell line. More in depth studies will need to be conducted to determine the exact reasons for greater activity of CT6 on Panc28 cells. This could be due to the compound’s target, mitochondrial activity of the cell lines, and the minor structural differences between the two compounds.

Thrombotic events are known to be associated with various cancers and recent research has implicated parts of the coagulation systemin promoting cancer progression. In particular, thrombin has been studied for its mitogenic effects in 2D cultures as well as in cancer progression in vivo in animal models however, conflicting results exist. Studies of proliferation in response to thrombin stimulation, of pancreatic cancer cells or pancreatic cancer-associated fibroblasts (CAFs) in vitro, that utilize a3D culture platform are significantly limited. In this study, PDAC cancer cells and cancer-associated fibroblast (CAF) cells were exposed to thrombin using a microfluidic device that mimics in vivo conditions. The cells used herein were cultured in a microfluid device, suspended inside of a 3D collagen matrix, and exposed to daily stimulation of 1 U/mL of thrombin in serum-free media for one hour. The findings of this study are that there is no statistically significant effect, promotive or inhibitory, on the proliferation of the cells used in this study, these results were unexpected. At the end of this paper, a review of potential reasons as to why no significant effect was seen on the cells is presented.

Background: Pancreatic ductal adenocarcinoma (PDAC), one of the fourth most lethal malig-nancies in the world, has a less than 5% five-year relative overall survival rate. Thus, there is a great need for novel therapies. PDAC is characterized as a stroma rich malignancy, composed of a large amount of extracellular matrix and pancreatic stellate cells. Accordingly, cell-matrix adhesion is crucial for cancer cell survival, invasion, and therapy resistance. We embarked on a high-throughput assay to identify the function of 117 focal adhesion proteins (FAP) in PDAC cell radiochemoresistance. Material and methods: We generated and performed a 3D tumoroid high-throughput esiRNA-based screening assay (3DHT-esiRNAs) in PDAC cell cultures (established and PDC) grown in laminin-rich extracellular matrix (IrECM). In addition to characterizing the β8 integrin expres-sion, distribution, and co-localization with other cellular organelles, such as Golgi apparatus, we also performed 3D tumoroid formation assay, sphere formation assay, type I collagen-based 3D invasion assay, and 2D clonogenic survival assay following esiRNA-mediated knockdown, 6 Gy x-ray irradiation and gemcitabine treatment. Image analysis was performed to determine Pearson's correlation coefficient, vesicle distribution and expression patterns upon irradiation or gemcitabine treatment by Fiji software (NIH). Immunoprecipitation-mass spectrometry (IP-MS) was performed to investigate the interactome of β8 integrin in the normal versus 6 Gy x-ray irradiation group. Inhibitor screen was conducted following 6 Gy x-ray irradi-ation or gemcitabine treatment to identify pathways involved in changes of β8 integrin localiza-tion upon treatment Autophagy flux was detected by monitoring LC3B puncta. Results: We identified a series of novel targets, including β8 integrin and PINCH1. Intriguingly, depletion of either β8 integrin or PINCH1 both showed radiosensitizing effect, with β8 integrin knockdown exerting a more profound radiosensitizing effect in a panel of PDAC cell lines. Without cytotoxicity, β8 integrin depletion evoked radiochemosensitization in PDAC, PDCs cell lines, and reduced sphere formation and 3D invasion into collagen-I. Intriguingly, β8 integrin was found to be located in the perinuclear region where it co-localized with the cis-Golgi matrix protein, GM130. Upon irradiation and gemcitabine treatment, β8 integrin was translocated from the perinuclear region to the cytosol, showing a slightly increased compart-mentalization in the exosome; a process that was abrogated by treatment with cytoskeletal inhibitors (paclitaxel, latrunculin B, and colchicine) and ATP synthase inhibitors (antimycin A and oligomycin). Depletion of β8 integrin influenced the autophagy via decreasing the LC3B puncta in a microtubule independent manner. Conclusion: Our results generated in 3D lrECM PDAC cell cultures, propose that β8 integrin, but not PINCH1, is a novel determinant of PDAC radiochemoresistance. Moreover, β8 integrin, although not localized to the cell membrane to facilitate cell adhesion, has a critical role in regulating intracellular vesicle trafficking under stress conditions and autophagy flux.

Pancreatic cancer (PC) is a highly aggressive disease with unmet therapeutic needs. Recent advances in the use of oncolytic viruses (OVs) as cancer therapeutic agents bring new hope to fight the notorious disease that is PC. Although OVs have shown promising results in certain cancers, some tumors remain resistant to OV therapy due to their inherent residual antiviral mechanisms. We hypothesized that the use of OV-encoded artificial microRNAs (amiRNAs) could help target the cellular antiviral components associated with the observed OV resistance and could also sensitize neighboring tumor cells to OV therapy and small molecule inhibitors through the secretion of amiRNA-containing extracellular vesicles (EVs) from infected cells. To find such amiRNAs, a viral surrogate library encoding ~16,000 unique amiRNAs was passaged in pancreatic cancer cell lines to enrich for sequences that could enhance OV replication. An amiRNA that improves PC cell killing when expressed from an OV was identified. Target identification of this amiRNA (amiR-4) revealed ARID1A as a key player in resistance to OV therapy in pancreatic cancers. This target is of particular interest, since its downregulation acts in a synthetic lethal fashion with inhibition of the EZH2 methyltransferase. Combining VSV51-amiR-4 with a small molecule inhibitor of EZH2 enhances PC cell death. Moreover, amiR-4 is packaged in cancer cell-secreted EVs which can reach neighboring naïve cells to sensitize them to EZH2 inhibition-mediated cell death and to spread the OV-mediated tumor killing effect throughout the tumor. This data translates into tumor debulking and survival in animal models of highly aggressive PC. This work not only broadens our knowledge on the resistance of select tumors to oncolytic virotherapy and the EV-mediated bystander killing effect in OV-infected tumors, but it also establishes OVs as a novel tool to produce anti-cancer therapeutic EVs in situ to improve therapeutic gain. Ultimately, our work provides new hope for a cure to the grim disease that is PC.

Oxidative stress is a documented factor in the pathogenesis of inflammation and cancer. Vitamin E with its antioxidant properties holds promise for use in clinical practice. There are two main forms of vitamin E, tocopherols and tocotrienols. Palm oil contains almost 70% of tocotrienols. Tocotrienols exerts its antiproliferative activity against malignant cells but not on normal cells. Tocotrienols play an important role in counteracting cellular inflammatory response secondary to oxidative stress, thus exerting an anticancer property. Tocotrienols mediate function of NF-kappa B, STAT3 (signal transduction and activators), and COX-2. In addition to its role as an antioxidant and anti-inflammatory agent, tocotrienols also mediate multiple cell cycle pathways. More work needs to be done on animal models and in genetic models of pancreatic cancer to gather more data to eventually consider phase III clinical trial in human subjects.

There is emerging evidence that the oncogenic potential of hdm2 (human and/or murine double minute-2 protein) stems not only from its ability to counteract tumor suppressor p53 but also from its less understood p53-independent functions. Surprisingly, little is known about the role and regulation of hdm2 in pancreatic tumors, a large proportion (50-75%) of which contain mutant p53. In this study, we determined that hdm2 was expressed in a Ras-signaling-dependent manner in various pancreatic cancer cell lines. As p53 was mutated and inactive in these cells, the expression of hdm2 was seemingly redundant. Indeed, the proliferation and survival of cell lines such as Panc-1 and Panc-28 could be inhibited by PRIMA-1 (mutant p53 activator) but not by Nutlin-3 (inhibitor of the hdm2-p53 interaction). Unexpectedly, however, the proliferation of both cell lines was strongly inhibited by hdm2-specific RNAi. Our data also revealed cyclin D1, c-Jun and c-Myc to be novel targets of hdm2 and suggested that they might mediate hdm2's role in cellular proliferation and/or survival. We conclude from our results that hdm2 is expressed in pancreatic cancer cells as a result of activated Ras signaling, and that it regulates cellular proliferation and the expression of three novel target genes by p53-independent mechanisms.

Ethanol and n-hexane extracts obtained from the leaves and inflorescences of Gnaphalium gracile, were tested at different concentrations to evaluate their antineoplastic activities on pancreatic, colon, and prostate cancer cell lines by examining mitochondrial function. The polar extracts of both, leaves and inflorescences which contain gnaphalin, quercetin, and 3-methoxy quercetin, exhibited cytotoxicity against every cell line tested with EC50 values ranging between 20.23±1.185 µg/mL and 70.71±1.1419 µg/mL. The most remarkable values were observed in pancreatic cancer Panc 28 and androgen-dependent prostate LnCaP cells, with EC50 values of 20.23±1.185 and ˂25µg/mL, and androgen-independent prostate cancer PC-3, colon HCT-116 and pancreatic MIA PaCa cells with values ranging between 28.84±1.1766 and 34.41±1.057 µg/mL. The non-polar extract derived from leaves demonstrated significant cytotoxicity towards colon cancer HCT-116 cells, with an EC50 of 39.46±1.0617 µg/mL. However, the non-polar extract from the inflorescences did not have an appreciable effect on cell proliferation of any of the cell lines tested except for androgen-independent prostate cancer PC-3 cells with an EC50 of 62.05±1.237 µg/mL. The data obtained support the traditional use of G. gracile and suggest the polar extracts from aerial parts, as an interesting source for the development of novel antineoplastic agents.

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal malignancies because it is often diagnosed at a late disease stage and has a poor response rate to currently available treatments. Therefore, it is critical to develop new therapeutic approaches that will enhance the efficacy and reduce the toxicity of currently used therapies. Here we aimed to evaluate the therapeutic potential and mechanisms of action for piperlongumine (PL), an alkaloid from long pepper, in PDAC models. We postulated that PL causes PDAC cell death through oxidative stress and complements the therapeutic efficacy of chemotherapeutic agents in PDAC cells. First, we determined that PL is one of the most abundant alkaloids with antitumor properties in the long pepper plant. We also showed PL in combination with gemcitabine, a chemotherapy agent used to treat advanced pancreatic cancer, reduced tumor weight and volume compared to vehicle-control and individual treatments. Further, biochemical analysis, including RNA sequencing and immunohistochemistry, suggested that the antitumor activity of PL was associated with decreased cell proliferation, induction of cell cycle arrest, and oxidative stress-induced cell death. Moreover, we identified that c-Jun N-terminal kinase (JNK) inhibition blocks PL-induced cell death, translocation of Nrf2, and transcriptional activation of HMOX1 in PDAC. Finally, high-throughput drug and CRISPR screenings identified potential targets that could be used in combination with PL to treat PDAC cells. Collectively, our data suggests that cell cycle regulators in combination with PL might be an effective approach to combat pancreatic cancer. / NIH

Bakgrund: Bukspottkörtelcancer är en av de dödligaste formerna av cancer. Det kan vara av värde för sjuksköterskor att inneha kunskap om hur patienter med bukspottkörtelcancer upplever sin sjukdom, för att kunna planera en personcentrerad omvårdnad. Syfte: Syftet med studien var att belysa upplevelser hos patienter med bukspottkörtelcancer. Metod: En litteraturstudie med induktiv ansats och kritisk granskning av nio vetenskapliga artiklar utfördes. Resultat: I resultatet framkom tre kategorier: Fysisk påverkan till följd av sjukdom eller behandling, Psykisk påverkan till följd av sjukdom eller behandling samt Betydelsen av kommunikation med vårdpersonal. Resultatet visade att patienter med bukspottkörtelcancer led av fysiska och psykiska symtom. Symtomen påverkade deras sociala och vardagliga aktiviteter. Resultatet visade även att patienter med bukspottkörtelcancer var i behov av information och kommunikation med vårdpersonal. Slutsats: Studien kan bidra med kunskap om hur patienter med bukspottkörtelcancer upplever sin sjukdom på en fysisk och psykisk samt kommunikativ nivå. Ytterligare forskning kring hur patienter med bukspottkörtelcancer upplever sin sjukdom kan hjälpa sjuksköterskor att känna sig trygga med att arbeta med denna patientgrupp. Förslag på vidare forskning är att studera sambandet mellan personcentrerad vård i relation till patienter med bukspottkörtelcancer. / Background: Pancreatic cancer is one of the deadliest forms of cancer. It may be valuable for nurses to have knowledge of how patients with pancreatic cancer experience their disease, in order to be able to plan a person-centered care. Purpose: The aim of the study was to explore experiences in patients with pancreatic cancer. Method: A literature study with inductive structure and review of nine scientific articles was conducted. Result: The result revealed three categories: Physical impact as a result of illness or treatment, psychological impact as a result of illness or treatment and Importance of communication with healthcare professionals. The results showed that patients with pancreatic cancer suffered from physical and psychological symptoms. The symptoms affected their social and everyday activities. The results also showed that patients with pancreatic cancer were in need of information and communication with healthcare professionals. Conclusion: This study can contribute with knowledge about how patients with pancreatic cancer experience their disease on a physical, psychological and communicative level. Further research on how patients with pancreatic cancer experience their disease can help nurses feel safe working with this type of patients. Suggestion for further research is to study the relationship between person-centered care in connection to patients with pancreatic cancer.