Histone Deacetylase Inhibitors Restore Cancer Cell Sensitivity towards T Lymphocytes Mediated Cytotoxicity in Pancreatic Cancer.

Despite medical advancements, the prognosis of pancreatic ductal adenocarcinoma (PDAC) has not improved significantly over the past 50 years. By utilising the large-scale genomic datasets available from the Australia Pancreatic Cancer Project (PACA-AU) and The Cancer Genomic Atlas Project (TCGA-PAAD), we studied the immunophenotype of PDAC in silico and identified that tumours with high cytotoxic T lymphocytes (CTL) killing activity were associated with favourable clinical outcomes. Using the STRING protein-protein interaction network analysis, the identified differentially expressed genes with low CTL killing activity were associated with TWIST/IL-6R, HDAC5, and EOMES signalling. Following Connectivity Map analysis, we identified 44 small molecules that could restore CTL sensitivity in the PDAC cells. Further high-throughput chemical library screening identified 133 inhibitors that effectively target both parental and CTL-resistant PDAC cells in vitro. Since CTL-resistant PDAC had a higher expression of histone proteins and its acetylated proteins compared to its parental cells, we further investigated the impact of histone deacetylase inhibitors (HDACi) on CTL-mediated cytotoxicity in PDAC cells in vitro, namely SW1990 and BxPC3. Further analyses revealed that givinostat and dacinostat were the two most potent HDAC inhibitors that restored CTL sensitivity in SW1990 and BxPC3 CTL-resistant cells. Through our in silico and in vitro studies, we demonstrate the novel role of HDAC inhibition in restoring CTL resistance and that combinations of HDACi with CTL may represent a promising therapeutic strategy, warranting its further detailed molecular mechanistic studies and animal studies before embarking on the clinical evaluation of these novel combined PDAC treatments.

Novel Gemcitabine-Re(I) Bisquinolinyl Complex Combinations and Formulations With Liquid Crystalline Nanoparticles for Pancreatic Cancer Photodynamic Therapy.

With less than 10% of 5-year survival rate, pancreatic ductal adenocarcinoma (PDAC) is known to be one of the most lethal types of cancer. Current literature supports that gemcitabine is the first-line treatment of PDAC. However, poor cellular penetration of gemcitabine along with the acquired and intrinsic chemoresistance of tumor against it often reduced its efficacy and hence necessitates the administration of high gemcitabine dose during chemotherapy. Photodynamic therapy (PDT), a more selective and minimally invasive treatment, may be used synergistically with gemcitabine to reduce the doses utilized and dose-related side effects. This study reports the synergistic use of Re(I) bisquinolinyl complex, a transition metal complex photosensitizer with gemcitabine against PDAC. Re(I) bisquinolinyl complex was found to act synergistically with gemcitabine against PDAC in vitro at various ratios. With the aim to enhance cellular uptake and therapeutic efficiency, the Re(I) bisquinolinyl complex and gemcitabine were encapsulated into liquid crystalline nanoparticles (LCNPs) system. The formulations were found to produce homogeneous drug-loaded LCNPs (average size: 159-173 nm, zeta potential +1.06 to -10 mV). Around 70% of gemcitabine and 90% of the Re(I) bisquinolinyl complex were found to be entrapped efficiently in the formulated LCNPs. The release rate of gemcitabine or/and the Re(I) bisquinolinyl complex loaded into LCNPs was evaluated in vitro, and the hydrophilic gemcitabine was released at a faster rate than the lipophilic Re(I) complex. LCNPs loaded with gemcitabine and Re(I) bisquinolinyl complex in a 1:1 ratio illustrated the best anti-cancer activity among the LCNP formulations (IC50 of BxPC3: 0.15 µM; IC50 of SW 1990: 0.76 µM) through apoptosis. The current findings suggest the potential use of transition metal-based photosensitizer as an adjunctive agent for gemcitabine-based chemotherapy against PDAC and the importance of nano-formulation in such application.

Targeting pancreatic cancer immune evasion by inhibiting histone deacetylases.

The immune system plays a vital role in maintaining the delicate balance between immune recognition and tumor development. Regardless, it is not uncommon that cancerous cells can intelligently acquire abilities to bypass the antitumor immune responses, thus allowing continuous tumor growth and development. Immune evasion has emerged as a significant factor contributing to the progression and immune resistance of pancreatic cancer. Compared with other cancers, pancreatic cancer has a tumor microenvironment that can resist most treatment modalities, including emerging immunotherapy. Sadly, the use of immunotherapy has yet to bring significant clinical breakthrough among pancreatic cancer patients, suggesting that pancreatic cancer has successfully evaded immunomodulation. In this review, we summarize the impact of genetic alteration and epigenetic modification (especially histone deacetylases, HDAC) on immune evasion in pancreatic cancer. HDAC overexpression significantly suppresses tumor suppressor genes, contributing to tumor growth and progression. We review the evidence on HDAC inhibitors in tumor eradication, improving T cells activation, restoring tumor immunogenicity, and modulating programmed death 1 interaction. We provide our perspective in targeting HDAC as a strategy to reverse immune evasion in pancreatic cancer.

Functional Roles of JNK and p38 MAPK Signaling in Nasopharyngeal Carcinoma.

c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) family members integrate signals that affect proliferation, differentiation, survival, and migration in a cell context- and cell type-specific way. JNK and p38 MAPK activities are found upregulated in nasopharyngeal carcinoma (NPC). Studies have shown that activation of JNK and p38 MAPK signaling can promote NPC oncogenesis by mechanisms within the cancer cells and interactions with the tumor microenvironment. They regulate multiple transcription activities and contribute to tumor-promoting processes, ranging from cell proliferation to apoptosis, inflammation, metastasis, and angiogenesis. Current literature suggests that JNK and p38 MAPK activation may exert pro-tumorigenic functions in NPC, though the underlying mechanisms are not well documented and have yet to be fully explored. Here, we aim to provide a narrative review of JNK and p38 MAPK pathways in human cancers with a primary focus on NPC. We also discuss the potential therapeutic agents that could be used to target JNK and p38 MAPK signaling in NPC, along with perspectives for future works. We aim to inspire future studies further delineating JNK and p38 MAPK signaling in NPC oncogenesis which might offer important insights for better strategies in diagnosis, prognosis, and treatment decision-making in NPC patients.

Advances in Nanomaterials Used in Co-Delivery of siRNA and Small Molecule Drugs for Cancer Treatment.

Recent advancements in nanotechnology have improved our understanding of cancer treatment and allowed the opportunity to develop novel delivery systems for cancer therapy. The biological complexities of cancer and tumour micro-environments have been shown to be highly challenging when treated with a single therapeutic approach. Current co-delivery systems which involve delivering small molecule drugs and short-interfering RNA (siRNA) have demonstrated the potential of effective suppression of tumour growth. It is worth noting that a considerable number of studies have demonstrated the synergistic effect of co-delivery systems combining siRNA and small molecule drugs, with promising results when compared to single-drug approaches. This review focuses on the recent advances in co-delivery of siRNA and small molecule drugs. The co-delivery systems are categorized based on the material classes of drug carriers. We discuss the critical properties of materials that enable co-delivery of two distinct anti-tumour agents with different properties. Key examples of co-delivery of drug/siRNA from the recent literature are highlighted and discussed. We summarize the current and emerging issues in this rapidly changing field of research in biomaterials for cancer treatments.

Monomeric, Dimeric, and Trimeric Tropane Alkaloids from Pellacalyx saccardianus.

Seven new tropane alkaloids, including five monomeric (1-5), one dimeric (6), and one trimeric (7) 3α-nortropane ester, along with two known monomeric nortropane alkaloids (8 and 9), were isolated from the leaves and bark of Pellacalyx saccardianus. Their structures, including the absolute configuration of the enantiomeric pair of (±)-6, were elucidated by comprehensive spectroscopic analyses. Alkaloids 6 and 7 showed cytotoxicity toward human pancreatic cancer cell lines (AsPC-1, BxPC3, PANC-1, and SW1990). Alkaloids 1, 4, and 9 induced a smooth muscle relaxation effect comparable to that of atropine (Emax 106.1 ± 7.5%, 97.0 ± 5.2%, 100.9 ± 1.4%, 111.7 ± 1.7%, respectively) on isolated rat tracheal rings.

Inhibition of Janus Kinase 1 synergizes docetaxel sensitivity in prostate cancer cells.

Prostate cancer (PCa) is the second most common malignancy and is the fifth leading cause of cancer mortality among men globally. Docetaxel-based therapy remains the first-line treatment for metastatic castration-resistant prostate cancer. However, dose-limiting toxicity including neutropenia, myelosuppression and neurotoxicity is the major reason for docetaxel dose reductions and fewer cycles administered, despite a recent study showing a clear survival benefit with increased total number of docetaxel cycles in PCa patients. Although previous studies have attempted to improve the efficacy and reduce docetaxel toxicity through drug combination, no drug has yet demonstrated improved overall survival in clinical trial, highlighting the challenges of improving the activity of docetaxel monotherapy in PCa. Herein, we identified 15 lethality hits for which inhibition could enhance docetaxel sensitivity in PCa cells via a high-throughput kinome-wide loss-of-function screen. Further drug-gene interactions analyses identified Janus kinase 1 (JAK1) as a viable druggable target with existing experimental inhibitors and FDA-approved drugs. We demonstrated that depletion of endogenous JAK1 enhanced docetaxel-induced apoptosis in PCa cells. Furthermore, inhibition of JAK1/2 by baricitinib and ruxolitinib synergizes docetaxel sensitivity in both androgen receptor (AR)-negative DU145 and PC3 cells, but not in the AR-positive LNCaP cells. In contrast, no synergistic effects were observed in cells treated with JAK2-specific inhibitor, fedratinib, suggesting that the synergistic effects are mainly mediated through JAK1 inhibition. In conclusion, the combination therapy with JAK1 inhibitors and docetaxel could be a useful therapeutic strategy in the treatment of prostate cancers.

Roles of Inflammasomes in Epstein-Barr Virus-Associated Nasopharyngeal Cancer.

Epstein-Barr virus (EBV) infection is recognised as one of the causative agents in most nasopharyngeal carcinoma (NPC) cases. Expression of EBV viral antigens can induce host's antiviral immune response by activating the inflammasomes to produce pro-inflammatory cytokines, such as interleukin-1ß (IL-1ß) and IL-18. These cytokines are known to be detrimental to a wide range of virus-infected cells, in which they can activate an inflammatory cell death program, called pyroptosis. However, aberrant inflammasome activation and production of its downstream cytokines lead to chronic inflammation that may contribute to various diseases, including NPC. In this review, we summarise the roles of inflammasomes during viral infection, how EBV evades inflammasome-mediated immune response, and progress into tumourigenesis. The contrasting roles of inflammasomes in cancer, as well as the current therapeutic approaches used in targeting inflammasomes, are also discussed in this review. While the inflammasomes appear to have dual roles in carcinogenesis, there are still many questions that remain unanswered. In particular, the exact molecular mechanism responsible for the regulation of the inflammasomes during carcinogenesis of EBV-associated NPC has not been explored thoroughly. Furthermore, the current practical application of inflammasome inhibitors is limited to specific tumour types, hence, further studies are warranted to discover the potential of targeting the inflammasomes for the treatment of NPC.

Parallel genome-wide RNAi screens identify lymphocyte-specific protein tyrosine kinase (LCK) as a targetable vulnerability of cell proliferation and chemoresistance in nasopharyngeal carcinoma.

Despite recent in advances in the management of nasopharyngeal carcinoma (NPC), development of targeted therapy remains challenging particularly in patients with recurrent or metastatic disease. To search for clinically relevant targets for the treatment of NPC, we carried out parallel genome-wide functional screens to identified essential genes that are required for NPC cells proliferation and cisplatin resistance. We identified lymphocyte-specific protein tyrosine kinase (LCK) as a key vulnerability of both proliferation and cisplatin resistance. Depletion of endogenous LCK or treatment of cells with LCK inhibitor induced tumor-specific cell death and synergized cisplatin sensitivity in EBV-positive C666-1 and EBV-negative SUNE1 cells. Further analyses demonstrated that LCK is regulating the proliferation and cisplatin resistance through activation of signal transducer and activator of transcription 5 (STAT5). Taken together, our study provides a molecular basis for targeting LCK and STAT5 signaling as potential druggable targets for the management of NPC.

Phosphoinositide-dependent Kinase-1 (PDPK1) regulates serum/glucocorticoid-regulated Kinase 3 (SGK3) for prostate cancer cell survival.

Prostate cancer (PCa) is the most common malignancy and is the second leading cause of cancer among men globally. Using a kinome-wide lentiviral small-hairpin RNA (shRNA) library screen, we identified phosphoinositide-dependent kinase-1 (PDPK1) as a potential mediator of cell survival in PCa cells. We showed that knock-down of endogenous human PDPK1 induced significant tumour-specific cell death in PCa cells (DU145 and PC3) but not in the normal prostate epithelial cells (RWPE-1). Further analyses revealed that PDPK1 mediates cancer cell survival predominantly via activation of serum/glucocorticoid-regulated kinase 3 (SGK3). Knock-down of endogenous PDPK1 in DU145 and PC3 cells significantly reduced SGK3 phosphorylation while ectopic expression of a constitutively active SGK3 completely abrogated the apoptosis induced by PDPK1. In contrast, no such effect was observed in SGK1 and AKT phosphorylation following PDPK1 knock-down. Importantly, PDPK1 inhibitors (GSK2334470 and BX-795) significantly reduced tumour-specific cell growth and synergized docetaxel sensitivity in PCa cells. In summary, our results demonstrated that PDPK1 mediates PCa cells' survival through SGK3 signalling and suggest that inactivation of this PDPK1-SGK3 axis may potentially serve as a novel therapeutic intervention for future treatment of PCa.

Molecular Hybrids Integrated with Benzimidazole and Pyrazole Structural Motifs: Design, Synthesis, Biological Evaluation, and Molecular Docking Studies.

Synthesis of a series of benzimidazole-ornamented pyrazoles, 6a-6j has been obtained from arylhydrazine and aralkyl ketones via a multistep synthetic strategy. Among them, a hybrid-possessing para-nitrophenyl moiety connected to a pyrazole scaffold (6a) exerted the highest anti-inflammatory activity, which is superior to the standard, diclofenac sodium. While executing the 2,2-diphenyl-1-picrylhydrazyl radical-scavenging activity, a hybrid-possessing para-bromophenyl unit integrated at the pyrazole structural motif (6i) exhibited the highest activity among the hybrids examined. Besides, evaluation of anticancer potency of the synthesized hybrids revealed that the one containing a para-fluorophenyl unit tethered at the pyrazole nucleus (6h) showed the highest activity against both the pancreatic cancer cells (SW1990 and AsPCl) investigated. Considerable binding affinity between B-cell lymphoma and the hybrid, 6h has been reflected while performing molecular docking studies (-8.65 kcal/mol). The outcomes of the investigation expose that these hybrids could be used as effective intermediates to construct more potent biological agents.

Nose to brain delivery of rotigotine loaded chitosan nanoparticles in human SH-SY5Y neuroblastoma cells and animal model of Parkinson's disease.

Rotigotine, a non-ergoline dopamine agonist, has been shown to be highly effective for the treatment of Parkinson's disease (PD). However, despite its therapeutic potential, its' clinical applications were hindered due to low aqueous solubility, first-pass metabolism and low bioavailability. Therefore, we developed rotigotine-loaded chitosan nanoparticles (RNPs) for nose-to-brain delivery and evaluated its neuronal uptake, antioxidant and neuroprotective effects using cell-based studies. The pharmacological effects of nose-to-brain delivery of the RNPs were also evaluated in an animal model of PD. The average particle size, particle size distribution and entrapment efficiency of the RNPs were found to be satisfactory. Exposure of RNPs for 24 h did not show any cytotoxicity towards SH-SY5Y human neuroblastoma cells. Furthermore, the RNPs caused a decrease in alpha-synuclein (SNCA) and an increase in tyrosine hydroxylase (TH) expression in these cells, suggestion that the exposure alleviated some of the direct neurotoxic effects of 6-OHDA. Behavioral and biochemical testing of RNPs in haloperidol-induced PD rats showed a reversal of catalepsy, akinesia and restoration of swimming ability. A decrease in lactate dehydrogenase (LDH) and an increase in catalase activities were also observed in the brain tissues. The results from the animal model of PD show that intranasally-administered RNPs enhanced brain targeting efficiency and drug bioavailability. Thus, RNPs for nose-to-brain delivery has significant potential to be developed as a treatment approach for PD.

Enantiomeric pairs of ternary copper(ii) complexes and their aldol-type condensation products: synthesis, characterization, and anticancer and epigenetic properties.

Chiral enantiomers [Cu(phen)(l-ser)(H2O)]NO31 and [Cu(phen)(d-ser)(H2O)]NO32 (ser = serinato) underwent aldol-type condensation with formaldehyde, with retention of chirality, to yield their respective enantiomeric ternary copper(ii) complexes, viz. l- and d-[Cu(phen)(OCA)(H2O)]NO3·xH2O (3 and 4; phen = 1,10-phenanthroline; OCA = oxazolidine-4-carboxylate; x = 1/2, 0-2) respectively. These chiral complexes were characterized by FTIR, elemental analysis, circular dichroism, UV-visible spectroscopy, fluorescence spectroscopy (FL), molar conductivity measurement, ESI-MS and X-ray crystallography. The crystal structures of 1 and 3 showed both the cationic complexes to have a square pyramidal geometry. These complexes were about nine fold more potent than cisplatin against metastatic MDA-MB-231 breast cancer cells, inducing apoptotic cell death via ROS generation and a massive drop in mitochondrial membrane potential. The results of monitoring EZH1, EZH2 and H3K27me3 revealed that the mode of action of 1-4 also involved the downregulation of EZH2 and it seemed to be independent of the H3K27me3 status.

Additivity vs Synergism: Investigation of the Additive Interaction of Cinnamon Bark Oil and Meropenem in Combinatory Therapy.

Combinatory therapies have been commonly applied in the clinical setting to tackle multi-drug resistant bacterial infections and these have frequently proven to be effective. Specifically, combinatory therapies resulting in synergistic interactions between antibiotics and adjuvant have been the main focus due to their effectiveness, sidelining the effects of additivity, which also lowers the minimal effective dosage of either antimicrobial agent. Thus, this study was undertaken to look at the effects of additivity between essential oils and antibiotic, via the use of cinnamon bark essential oil (CBO) and meropenem as a model for additivity. Comparisons between synergistic and additive interaction of CBO were performed in terms of the ability of CBO to disrupt bacterial membrane, via zeta potential measurement, outer membrane permeability assay and scanning electron microscopy. It has been found that the additivity interaction between CBO and meropenem showed similar membrane disruption ability when compared to those synergistic combinations which was previously reported. Hence, results based on our studies strongly suggest that additive interaction acts on a par with synergistic interaction. Therefore, further investigation in additive interaction between antibiotics and adjuvant should be performed for a more in depth understanding of the mechanism and the impacts of such interaction.