Potential Cancer Therapeutics Research Articles

Effect of Interferon-Beta (IFN-β) on tumor suppressor and apoptotic markers in hepatocellular carcinoma cell line

IFN-β (Rebif) is a drug with valuable cancer therapeutic potential as it mediates anti-proliferation and apoptosis induction. Therefore, this study aimed to evaluate the anti-proliferation of IFN-β through assessing gene expression of p53 and caspase-3 in hepatocellular carcinoma cell (HCC) line (HepG2). The 50% inhibition viability concentration (IC50) of IFN-β was calculated by cytotoxicity assay, and it was tested on normal cell line (Vero). After treating HepG2 cells with IFN-β, p53 and caspase-3 expression was analyzed, at time intervals of 2, 4, 6, and 24 hrs, by real-time PCR, histopathology and immunohistochemistry. IC50 of IFN-β was 420 µg/ml, which wasn't cytotoxic on normal cells. P53 expression was gradually up-regulated by time, and then, it was decreased after 24 hrs incubation. However, no expression of caspase-3 was detected compared to cell control. Histopathologically, cells degeneration was remarkable after 24 hrs while no change was noticed in control. Immunohistochemical analysis revealed a decline of p53 and caspase-3 expression in treated cells with IFN-β, after 24 hrs, to 30% compared to cell control (50% and 60%, respectively). IFN-β has the potential to be utilized as a suppressor of HCC proliferation and inducer of malignant cells apoptosis.

Mouse models of thyroid cancer: Bridging pathogenesis and novel therapeutics.

Due to a global increase in the incidence of thyroid cancer, numerous novel mouse models were established to reveal thyroid cancer pathogenesis and test promising therapeutic strategies, necessitating a comprehensive review of translational medicine that covers (i) the role of mouse models in the research of thyroid cancer pathogenesis, and (ii) preclinical testing of potential anti-thyroid cancer therapeutics. The present review article aims to: (i) describe the current approaches for mouse modeling of thyroid cancer, (ii) provide insight into the biology and genetics of thyroid cancers, and (iii) offer guidance on the use of mouse models for testing potential therapeutics in preclinical settings. Based on research with mouse models of thyroid cancer pathogenesis involving the RTK, RAS/RAF/MEK/ERK, PI3K/AKT/mTOR, SRC, and JAK-STAT signaling pathways, inhibitors of VEGFR, MEK, mTOR, SRC, and STAT3 have been developed as anti-thyroid cancer drugs for "bench-to-bedside" translation. In the future, mouse models of thyroid cancer will be designed to be ''humanized" and "patient-like," offering opportunities to: (i) investigate the pathogenesis of thyroid cancer through target screening based on the CRISPR/Cas system, (ii) test drugs based on new mouse models, and (iii) explore the underlying mechanisms based on multi-omics.

76P - Proton-sensitizing effect of small molecule inhibitor of P300 histone acetyltransferase C646 in human pancreatic cancer cells

BackgroundHistone acetylation plays an important role in regulating the chromatin structure and is tightly regulated by histone acetyltransferases (HAT) and histone deacetylases (HDAC). Recent studies have demonstrated that several chromatin-regulating proteins can modulate cellular responses to other cytotoxic modalities including ionizing radiation and chemotherapeutic drugs. Even though histone acetylation is one of the key mechanisms of epigenetic regulation, relatively little is known about the cancer therapeutic potential of HAT inhibitors. This is in stark contrast to the well-studied effects of HDAC inhibitors. In this study, we investigated the proton beam-sensitizing effect of C646, a selective small molecule inhibitor of p300 histone acetyltransferase in human pancreatic cancer cells. MethodsCell viability assay (CCK-8; Dojindo), Clonogenic survival assay, Cell cycle analysis (PI staining). Annexin V-FITC and PI staining, γ-H2AX foci, Western blot, BxPC-3 Xenograft tumor model, TUNEL assay. ResultsAsPC-1, BxPC-3 and Mia-paca2 cells exhibited increase in radiosensitivity when exposed to C646 at all doses of proton beam tested. C646 pre-treatment induce led to increase of sub-G1 population and abolishment of G2/M arrest. Flow cytometry analysis with annexin V staining and Western blot analysis showed that The pre-treatment with C646 significantly enhanced proton-induced apoptotic cell death through the down-regulation of anti-apoptotic molecules. Our in vivo results demonstrate synergistic effects of combination therapy with C646 and proton beam. In BxPC-3 xenograft tumor model, C646 pre-treatment increased proton-induced tumor growth inhibition and apoptotic cell death in tumor tissues. In addition, the combination treatment of C646 with proton beam increased DNA damage and decreased activation of DNA repair pathway compared with proton alone. ConclusionsOur results suggest that the C646 may increase proton- induced apoptosis through the modulation of various pro- and anti- apoptotic molecules in human pancreatic cancer cells. These results provide proof of principle that the inhibition of histone acetylation by HATis can be exploited to develop new proton-sensitizer. Legal entity responsible for the studyThe authors. FundingNational Research Foundation of Korea (NRF). DisclosureAll authors have declared no conflicts of interest.

Postdoc perspective: Finding the right mentor matters

Adorned in a blue gown with black velvet panels, seated alongside fellow scholars, I peered into the crowd of proud friends and families of the graduates. I couldn’t find the face of the one who encouraged and congratulated me at every ascension throughout my academic endeavors—my mother, who was diagnosed with stage 4 colon cancer during my doctoral program; she passed shortly after her diagnosis. Although it was difficult to continue in her absence, I managed to earn a PhD in organic chemistry in what became a callous environment. I realized that the ephemeral excitement of synthesizing potential cancer therapeutics was gone, and I questioned whether to continue doing the research that had left me overwhelmingly empty and exhausted. I was later offered a postdoc position by a compassionate female scientist with a contagious fervor for biomedical research, and I joined her newly established academic glycobiology lab. I chose a

Statins as Potential Therapeutics for Lung Cancer: Molecular Mechanisms and Clinical Outcomes.

Lung cancer is the most common cancer worldwide. It also has the highest malignancy-associated mortality rate. Treatment options are limited by cancer and tumor heterogeneity, resistance to treatment options, and an advanced stage at time of diagnosis, all of which are common. Statins are a class of lipid-lowering medications that have been studied for their antitumor effects in various types of cancers. Multiple mechanisms have been proposed to explain their observed off-target effects. Most of these hypotheses focus largely on statin-induced upregulation of proapoptotic signaling pathways and mediators, and the downregulation of antineoplastic factors secondary to statin use. Preclinical and clinical studies support their use for conferring a mortality benefit and improving treatment effect in some chemotherapy-resistant subtypes of lung cancer. However, their exact mechanism of action, class-dependent effect, dose-dependent effect, potential use as adjuvant chemotherapeutics, and markers of statin-sensitivity in specific lung cancer subtypes remain areas of ongoing investigation. Herein, we review the latest literature pertinent to the role statins can play in the management of lung cancers.

Electrochemical Detection of Circulating Tumor Cells Based on DNA Generated Electrochemical Current and Rolling Circle Amplification

Circulating tumor cells (CTCs) are important indicators for tumor diagnosis and tumor metastasis. However, the extremely low levels of CTCs in peripheral blood challenges the precise detection of CTCs. Herein, we report DNA generated electrochemical current combined with rolling circle amplification (RCA) as well as magnetic nanospheres for highly efficient magnetic capture and ultrasensitive detection of CTCs. The antiepithelial cell adhesion molecule (EpCAM) antibody-modified magnetic nanospheres were used to capture and enrich CTCs. The following binding of an aptamer onto the CTC surface and the subsequent RCA assembled a significant amount of DNA molecules onto the electrode. The reaction of the DNA molecules with molybdate can then form redox molybdophosphate and produce an electrochemical current. Using the breast cancer cell MCF-7 as a model, the sensor displays good performances toward detection of MCF-7 that was spiked into peripheral blood. The signal amplification strategy integrated with a magnetic nanosphere platform exhibits good performance in the efficient capture and detection of CTCs, which may find wide potential in cancer diagnostics and therapeutics.

Role of the Exosome in Ovarian Cancer Progression and Its Potential as a Therapeutic Target.

Peritoneal dissemination is a distinct form of metastasis in ovarian cancer that precedes hematogenic or lymphatic metastasis. Exosomes are extracellular vesicles of 30–150 nm in diameter secreted by different cell types and internalized by target cells. There is emerging evidence that exosomes facilitate the peritoneal dissemination of ovarian cancer by mediating intercellular communication between cancer cells and the tumor microenvironment through the transfer of nucleic acids, proteins, and lipids. Furthermore, therapeutic applications of exosomes as drug cargo delivery are attracting research interest because exosomes are stabilized in circulation. This review highlights the functions of exosomes in each process of the peritoneal dissemination of ovarian cancer and discusses their potential for cancer therapeutics.

RIBOTACs: Small Molecules Target RNA for Degradation

Selective RNA degradation is a powerful strategy to combat diseases or study specific RNA function. In this issue of Cell Chemical Biology, Costales etal. (2019) develop a small molecule that mediates selective RNA degradation with the potential for cancer therapeutics.

The Mini-Organo: A rapid high-throughput 3D coculture organotypic assay for oncology screening and drug development.

BackgroundThe use of in vitro cell cultures is a powerful tool for obtaining key insights into the behaviour and response of cells to interventions in normal and disease situations. Unlike in vivo settings, in vitro experiments allow a fine‐tuned control of a range of microenvironmental elements independently within an isolated setting. The recent expansion in the use of three‐dimensional (3D) in vitro assays has created a number of representative tools to study cell behaviour in a more physiologically 3D relevant microenvironment. Complex 3D in vitro models that can recapitulate human tissue biology are essential for understanding the pathophysiology of disease.AimThe development of the 3D coculture collagen contraction and invasion assay, the “organotypic assay,” has been widely adopted as a powerful approach to bridge the gap between standard two‐dimensional tissue culture and in vivo mouse models. In the cancer setting, these assays can then be used to dissect how stromal cells, such as cancer‐associated fibroblasts (CAFs), drive extracellular matrix (ECM) remodelling to alter cancer cell behaviour and response to intervention. However, to date, many of the published organotypic protocols are low‐throughput, time‐consuming (up to several weeks), and work‐intensive with often limited scalability. Our aim was to develop a fast, high‐throughput, scalable 3D organotypic assay for use in oncology screening and drug development.Methods and resultsHere, we describe a modified 96‐well organotypic assay, the “Mini‐Organo,” which can be easily completed within 5 days. We demonstrate its application in a wide range of mouse and human cancer biology approaches including evaluation of stromal cell 3D ECM remodelling, 3D cancer cell invasion, and the assessment of efficacy of potential anticancer therapeutic targets. Furthermore, the organotypic assay described is highly amenable to customisation using different cell types under diverse experimental conditions.ConclusionsThe Mini‐Organo high‐throughput 3D organotypic assay allows the rapid screening of potential cancer therapeutics in human and mouse models in a time‐efficient manner.

Enhancing the cytotoxic efficacy of combined effect of doxorubicin and Cyclosporin encapsulated photoluminescent graphene dotted mesoporous nanoparticles against lung cancer cell-specific drug targeting for the nursing care of cancer patients

In recent years, biological nanomedicine-based biomaterials have an extreme attention for biomedical uses, herein we examined a novel kind advance of photoluminescent Graphene quandum dots encapsulated mesoporous nanoparticles (GND@MSNs) encapsulated by well-known anticancer drugs Doxorubicin (DOX) and Cyclosporin (CsA) for lung carcinoma. Electron microscopic technique exhibit the nanostructure and spherical morphology of GND@MSNs+DOX+CsA with mean size ≈110 nm. Moreover, Dynamic Light Scattering (DLS) exposed that blended GND@MSNs+DOX+CsA nanoparticles were highly stable with extremely negatively charged nanoparticles. Raman investigation was done on the all naturally dynamic nanoparticles containing shed graphene to survey the blend condition of the graphene inside the silica mesoporous nanoparticles. GND@MSNs+DOX+CsA provided an outstanding anti-cancer efficiency against the lung cancer cell lines (i.e., A549 and HEL-299). MTT assay monitored that GND@MSNs, GND@MSNs+DOX and GND@MSNs+DOX+CsA have a robust toxicity behaviour on the A549 and HEL-299 model lung cancer cell lines. Additionally, investigation of the cell death was found on AO-EB, Hoechst 33452 staining and flowcytometry techniques. Furthermore, the DNA damage were confirmed by cell cycle arrest and comet assay. Hence, we suggesting that these GND@MSNs+DOX+CsA could be applied as auspicious drug vesicles for novel lung cancer therapeutic potential and new openings to solve the complexity of lung cancer in the care of cancer patients.

Binding of quinazolinones to c-KIT G-quadruplex; an interplay between hydrogen bonding and π-π stacking

Stabilization of G-quadruplex structures in the c-KIT promoter with the aid of ligands has become an area of great interest in potential cancer therapeutics. Understanding the binding process between ligands and G-quadruplex is essential for a discovery of selective ligands with high binding affinity to G-quadruplex. In the present work, binding mechanisms of 4-quinazolinones to c-KIT G-quadruplex were investigated theoretically by means of molecular dynamics (MD) simulations. To explore the binding affinity of ligands, binding free energy calculations were performed using the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method. We demonstrate that the key interactions in G-quadruplex-ligand complexes are π-π stacking and hydrogen bond interactions. However, neither of these two interactions alone determines the stability of the G-quadruplex-ligand complexes; rather, it is the result of an intricate interplay between the two. To further examine the nature of the binding, a free energy decomposition analysis at residue level was carried out. The results clearly demonstrate the crucial roles of two hot spot residues (DG4 and DG8) for the binding of ligands to c-KIT G-quadruplex, and highlight the importance of the planar aromatic moiety of ligands in G-quadruplex stabilization via π-π stacking interactions. Our study can assist in the design of new derivatives of 4-quinazolinone with high binding affinity for c-KIT G-quadruplex.

Abstract 548: Evaluation of novel SIRP antibodies as potential cancer therapeutics

Abstract Targeting immune checkpoints of adaptive immunity has shown great therapeutic efficacy in oncology, but in a limited fraction of patients. Innate immune cells represent the most abundant immune cell types in many solid tumors and are often linked to a poor prognosis. SIRPα is expressed by innate immune cells and its interaction with CD47, expressed by most tumor cells, is an important immune checkpoint of the innate response, involved in the regulation of phagocytosis by macrophages, dendritic cells and neutrophils. Recently, first generation agents targeting CD47 (CD47 antibodies and SIRPα-Fc fusion proteins) have shown promise in clinical trials, but they have also experienced hematological toxicities such as anemia or thrombocytopenia. Consequently, we have previously reported on the development of AO-176, a next generation anti-CD47 antibody that not only blocks the CD47/SIRPα interaction and induces phagocytosis, but also preferentially binds tumor versus normal cells (including RBCs where it binds negligibly) and directly kills tumor cells via a programmed cell death type III and an immunogenic cell death process. Here we report the discovery of novel anti-SIRP antibodies that recognize either SIRPα selectively or SIRPα/γ. These antibodies are being evaluated for their ability to induce phagocytosis of tumor cells - we have identified antibodies that induce phagocytosis of tumor cells alone and in combination with Rituxan. The ability of our anti-SIRP antibodies to induce immunomodulatory activities in a variety of ex vivo cultured immune cells expressing either SIRPα or SIRPα/γ is also under investigation and will be presented. Citation Format: Ronald R. Hiebsch, Myriam N. Bouchlaka, Benjamin J. Capoccia, Michael J. Donio, Prabir Chakraborty, W. Casey Wilson, Robyn J. Puro, Daniel S. Pereira. Evaluation of novel SIRP antibodies as potential cancer therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 548.

Abstract 1997: The Rac inhibitors HV-107 and HV-118 as potential therapeutics for metastatic breast cancer

Abstract Breast cancer is the first cause of death in women globally. Metastatic breast cancer is stimated to affect more than a quarter of million of women in the US. Due to the lack of effective treatment, metastasis remains the main cause of breast cancer mortality. Therefore, it is imperative to develop novel effective strategies against metastasis. A promising target for anti-metastatic therapy is the Rho GTPase Rac because it plays a key role in metastatic cancer progression by regulating cellular processes such as adhesion, migration, proliferation and survival. Our group developed Ehop-016, a small molecule that inhibits Rac in metastatic breast cancer cells with an IC50=1µM and significantly reduces tumor growth, angiogenesis, and metastasis in a mouse model of metastatic breast cancer. However, its relative bioavailability is moderate and should be improved. Therefore, to find a compound with increased potency and bioavailability, we tested several Ehop-016 derivatives. Using Rac pulldown assays we show that HV-107 and HV-118 inhibit Rac activation by 60% in MDA-MB-231 and MDA-MB-435 metastatic breast cancer cells at 100 and 250nM, respectively. MTT assays show HV-107 (at ≥500nM) and HV-118 (at ≥50nM) significantly inhibit metastatic breast cancer cell viability, while showing minimal toxicity towards non-cancerous cells. Cell cycle analysis by flow cytometry demonstrates a G2-M arrest and a prominent sub-G1 population, indicative of cell death, in metastatic breast cancer cells treated with HV-107 (1000 nM) and HV-118 (100 nM). To evaluate apoptosis as a potential cell death mechanism, we measured caspase 3 activity. Our results show HV-107 and HV-118 significantly induce caspase 3 activity by approximately 1.6-fold at 1000 and 100nM, respectively in metastatic breast cancer cells. Therefore, these Rac inhibitors affect cell viability by inhibiting cell cycle progression and inducing apoptosis. Finally, we tested HV-118 (at 1mg/kg BW) in a mouse model of metastatic breast cancer and found a 30% reduction in tumor growth and a 90% inhibition in metastasis. Taken together, our results indicate HV-107 and HV-118 have potential as anti-breast cancer metastasis therapeutics. This study was supported by awards from the Susan Komen for the Cure, NIH/NIMHHD U54MD008149, and the Puerto Rico Science and Technology Trust to SD; NIH/NCRR R25GM061838 to UPR MSC; NIH/NIMHHD RCMI 8G12MD007583RCMI, Title V PPOHA 031M10505 and Title V Cooperative P031S130068 from U.S. Department of Education to UCC; and and PRINBRE (NIH/NIGMS P20GM103475-13) Sub-Award to LCP. Citation Format: Grace E. Velez, Cornelis Vlaar, Eliud Hernandez, Anibal Valentin, Linette Castillo-Pichardo, Suranganie Dharmawardhane. The Rac inhibitors HV-107 and HV-118 as potential therapeutics for metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1997.

Abstract 5173: Development of a novel tunable synthetic 3D hydrogel platform for the study of tumor and stromal cell interactions

Abstract Numerous cancer cell models exist used to investigate disease mechanisms and to screen potential cancer therapeutics. Roughly 90% of promising preclinical drugs fail to result in efficacious human treatments. Traditional two-dimensional (2D) tissue culture models lack realistic complexity, while animal models are expensive, time consuming, and too frequently fail to reflect human tumor biology. Recently, three-dimensional (3D) cell culture models are a new method to generate new drug candidates before moving to expensive and time-consuming animal models. We have developed a biochemically defined hydrogel platform formed by mixing various polymers with chemical crosslinkers with enhanced functionality. The hydrogel system employs one of two types of backbone polymers: a synthetic non-degradable polyvinyl alcohol (PVA) or an enzymatically-degradable dextran. Both polymers are functionalized either with fast or slow thiol-reactive groups. Crosslinkers consist of either PEG non-cell-degradable or a CD cell-degradable crosslinkers containing peptide sequences that create cleavage sites for matrix metalloproteases (MMPs) that allow cell migration. The technology provides mechanical and biochemical cues to investigate both morphological and physiological properties of cells in a 3D environment. The hydrogel allows precise control over hydrogel stiffness, gelation speed, cell migration and allows cell recovery for downstream applications. Here, we demonstrate the utility of this hydrogel platform to grow epithelial, fibroblast and tumor cells in 3D cell cultures with high cell viabilities and functionalities. Furthermore, we have constructed a 3D tumor/stromal cell co-culture using the hydrogel to model the dynamic tumor cell microenvironment. This technology will allow the creation of more accurate 3D cancer cell models for basic research and drug discovery applications. Note: This abstract was not presented at the meeting. Citation Format: Hsu-Kun Wang, Vi Chu, Nick Asbrock. Development of a novel tunable synthetic 3D hydrogel platform for the study of tumor and stromal cell interactions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5173.

γδ T cells: pleiotropic immune effectors with therapeutic potential in cancer.

The potential of cancer immunotherapy relies on the mobilization of immune cells capable of producing antitumour cytokines and effectively killing tumour cells. These are major attributes of γδ T cells, a lymphoid lineage that is often underestimated despite its major role in tumour immune surveillance, which has been established in a variety of preclinical cancer models. This situation notwithstanding, in particular instances the tumour microenvironment seemingly mobilizes γδ T cells with immunosuppressive or tumour-promoting functions, thus emphasizing the importance of regulating γδ T cell responses in order to realize their translation into effective cancer immunotherapies. In this Review we outline both seminal work and recent advances in our understanding of how γδ T cells participate in tumour immunity and how their functions are regulated in experimental models of cancer. We also discuss the current strategies aimed at maximizing the therapeutic potential of human γδ T cells, on the eve of their exploration in cancer clinical trials that may position them as key players in cancer immunotherapy.

Cysteine Cathepsin Protease Inhibition: An update on its Diagnostic, Prognostic and Therapeutic Potential in Cancer.

In keeping with recent developments in basic research; the importance of the Cathepsins as targets in cancer therapy have taken on increasing importance and given rise to a number of key areas of interest in the clinical setting. In keeping with driving basic research in this area in a translational direction; recent findings have given rise to a number of exciting developments in the areas of cancer diagnosis; prognosis and therapeutic development. As a fast-moving area of research; the focus of this review brings together the latest findings and highlights the translational significance of these developments.

C-terminal BRE inhibits cellular proliferation and increases sensitivity to chemotherapeutic drugs of MLL-AF9 acute myeloid leukemia cells

BRE (Brain and Reproductive Organ-Expressed) is an anti-apoptotic protein and a core component of DNA-repair BRCA1-A complex. Microarray-detected high BRE gene expression has been found to be associated with better patient survival in AML (acute myeloid leukemia) with MLL-AF9 translocation, and radiotherapy-treated non-familial breast cancer. A recent finding suggests that the high BRE gene expression in MLL-AF9 AML could be attributed to the additional expression of a transcript variant encoding a novel C-terminal BRE isoform. Using THP-1 as the MLL-AF9 AML cell model, we found that ectopic expression of the C-terminal BRE, which could not form an intact BRCA1-A complex, indeed increased cellular sensitivity to chemotherapeutic drugs and inhibited cell proliferation, while the complete opposite was achieved by the ectopic expression of full-length BRE. Our findings suggest that the C-terminal BRE-encoding transcript could be responsible for better patient survival and may have therapeutic potential for cancer.

Bumetanide-Derived Aquaporin 1 Inhibitors, AqB013 and AqB050 Inhibit Tube Formation of Endothelial Cells through Induction of Apoptosis and Impaired Migration In Vitro.

AqB013 and AqB050 compounds inhibit aquaporin 1 (AQP1), a dual water and ion channel implicated in tumour angiogenesis. We tested AqB013 and AqB050 either as monotherapy or in combination on tube formation of murine endothelial cells (2H-11 and 3B-11) and human umbilical vascular endothelial cells (HUVECs). The mechanism underlying their anti-tubulogenic effect was explored by examining cell viability, induction of apoptosis and migration using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay, Annexin V/propidium iodide apoptosis assay and scratch wound assay. Tube formation of all the cell lines was inhibited by AqB013, AqB050 and the combination of the two compounds. The inhibition of 2H-11 and 3B-11 was frequently accompanied by impaired migration, whereas that of HUVEC treated with AqB050 and the combination was associated with reduced cell viability due to apoptosis. AqB013 and AqB050 exhibited an anti-tubulogenic effect through inhibition of AQP1-mediated cell migration and induction of apoptosis. Together with previously reported anti-tumour cell effect of AqB013 and AqB050, our findings support further evaluation of these compounds as potential cancer therapeutics.

Studying the Role of Zinc (Zn2+) in Cellular Transitions Under Acidic Conditions

The maintenance of ionic homeostasis is critical for cell metabolism, cell growth, and cell survival. It has been shown that pH and zinc dyshomeostases are linked to pathophysiological conditions such as cancerous mutations, urinary diseases, gastric infections, and ischemia. In particular, we observed that there were concentration increases of intracellular free zinc after acidic treatments. We further hypothesize that zinc may be a mediator for the acidic treatment‐induced cellular changes. A spindle shape or fibroblast‐like shape has been used as an indicator of decreased cell‐to‐cell adhesion, increased cellular motility, and an increased possibility of metastasis in cancer. Our preliminary experiments showed that the accumulation of spindle cells occurred after acidic treatments and that zinc chelation reduced the accumulation, indicating the role of Zn2+ in the accumulation of spindle cells. Spindle cell accumulation is a sign for cancer cell synchronizations at a particular phase in cell cycle, which provide windows for potential cancer therapeutics that target cell cycles. Our preliminary experiments showed that acidic treatments enhanced the expression of vimentin, which was attenuated by an application of zinc chelator, suggesting that zinc plays an important role in cellular transitions under acidic conditions. The significance of this research is to provide a novel mechanism that zinc may be a mediator in acidic treatment‐induced cellular changes. Acidic environment is seen in physiological condition such as gastric ulcer, and in abnormal conditions such as ischemia and cancer. It will be interesting to see how zinc is involved in these processes.Support or Funding InformationThanks to the Osteopathic Heritage Foundations, Graduate Assistantship Program at Ohio University Heritage College of Osteopathic Medicine for supporting graduate student Yuli Hu.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Dioscin inhibits intimal hyperplasia in rat carotid artery balloon injury model through inhibition of the MAPK-FoxM1 pathway

Vascular smooth muscle cell (VSMC) proliferation and migration are crucial events in the pathological course of atherosclerosis and restenosis after percutaneous coronary intervention (PCI). Dioscin has been shown to exhibit powerful cardiovascular protective effects and potent therapeutic potential in cancer owing to the inhibition of cell proliferation and migration. However, its effects on arterial wall hypertrophy-related diseases caused by VSMC proliferation and migration remain unclear. In this study, we investigated the effects of dioscin on intimal hyperplasia after balloon injury in vivo, its effects on VSMC proliferation and migration in vitro, and the mechanisms underlying these effects. Results showed that dioscin treatment significantly inhibited VSMC proliferation and intimal thickening after balloon injury. In cultured VSMCs, treatment with dioscin significantly decreased fetal bovine serum or platelet-derived growth factor-induced cell proliferation and migration. Moreover, dioscin inhibited the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and expression of Forkhead box M1 (FoxM1) and its downstream target genes. FoxM1 knockdown with shRNA partially counteracted the inhibitory effects of dioscin on cell proliferation and migration. In conclusion, we demonstrated that dioscin attenuated neointima formation in response to balloon injury by suppressing VSMC proliferation and migration through MAPK-FoxM1 pathway. Our data suggested that dioscin might be a potential therapeutic agent for atherosclerosis and restenosis after PCI.