Cynaropicrin Increases [Ca] and Ciliary Beat Frequency in Human Airway Epithelial Cells by Inhibiting SERCA.

Mucociliary clearance (MCC) is a host defense mechanism of the respiratory system. Beating cilia plays a crucial role in the MCC process and ciliary beat frequency (CBF) is activated by several factors including elevations of the intracellular cAMP concentration ([cAMP]), intracellular Ca concentration ([Ca]), and intracellular pH (pH). In this study, we investigated whether an artichoke-extracted component cynaropicrin could be a beneficial compound for improving MCC.

Compound #41 Targets Acute Myelogenous Leukemia by Inhibiting the Wnt/β-catenin Signaling Pathway.

Background/aim: Aberrant activation of the Wnt/β-catenin signaling pathway contributes to the pathogenesis of acute myelogenous leukemia (AML). Thus, targeting this pathway offers a promising therapeutic strategy against AML. Here, we synthesized a novel dipeptide-type inhibitor of the Wnt/β-catenin signaling pathway, compound #41, and explored its anti-tumor effects on AML cells.

Occurrence of respiratory and urinary tract infections in patients treated with docetaxel compared with afatinib based on a health insurance claims database in Japan.

Background: The relative occurrence of infection in patients treated with cytotoxic chemotherapeutic drugs and molecularly targeted drugs is unclear.

Aim: To compare the occurrence of respiratory and urinary tract infections in patients treated for lung cancer with docetaxel versus afatinib and to predict the occurrence of the respiratory and urinary tract infections.

Method: Data on patients who received docetaxel or afatinib were obtained from a health insurance claims database.

POLD1 Is Required for Cell Cycle Progression by Overcoming DNA Damage in Malignant Pleural Mesothelioma.

Background/aim: The prognosis of patients with malignant pleural mesothelioma (MPM) remains poor due to lack of effective therapeutic targets. DNA damage caused by long-time exposure to asbestos fibers has been associated with the development of MPM, with mutations at genes encoding DNA damage repair (DDR)-related molecules frequently expressed in patients with MPM. The present study was designed to identify novel therapeutic targets in MPM using large public databases, such as The Cancer Genome Atlas (TCGA) and Genotype Tissue Expression project (GTEx) focused on DDR pathways.

Linderapyrone analogue LPD-01 as a cancer treatment agent by targeting importin7.

The Wnt/β-catenin signaling pathway plays important roles in several cancer cells, including cell proliferation and development. We previously succeeded in synthesizing a small molecule compound inhibiting the Wnt/β-catenin signaling pathway, named LPD-01 (1), and 1 inhibited the growth of human colorectal cancer (HT-29) cells. In this study, we revealed that 1 inhibits the growth of HT-29 cells stronger than that of another human colorectal cancer (SW480) cells.

Depletion of Induces Cell Cycle Arrest in Pancreatic Cancer Cells.

Background/aim: Pancreatic cancer is one of the most lethal malignant cancers worldwide and the seventh most common cause of cancer-related death in both sexes. Herein, we analyzed open access data and discovered that expression of a gene called deoxynucleotidyltransferase terminal-interacting protein 2 (DNTTIP2) is linked to prognosis of pancreatic ductal adenocarcinoma (PDAC). We then elucidated the role of DNTTIP2 in the proliferation of pancreatic cancer cells in vitro.

Targeting acidic pre-metastatic niche in lungs by pH low insertion peptide and its utility for anti-metastatic therapy.

Dysregulated extracellular pH, the universal feature of tumor, works as an evolutional force to drive dissemination of tumor cells. It is well-established that tumor acidity is associated with tumor growth and metastasis. However, the pH of pre-metastatic niche remains unclear.

Exosome-Hijacking Drug Delivery System with Branched Arginine Linker Effectively Deliver Antisense Oligonucleotides into Lung Adenocarcinoma Cells.

Exosomes are a type of extracellular vesicles that contain diverse molecules and are present in our body fluids. They play a crucial role in transporting materials and transmitting signals between cells. Currently, there have been numerous reports on the use of exosomes in drug delivery systems (DDS).

Hypoxia-adapted Multiple Myeloma Stem Cells Resist γδ-T-Cell-mediated Killing by Modulating the Mevalonate Pathway.

Background/aim: The prognosis of patients with multiple myeloma (MM) has recently improved due to the emergence of new molecular targeting agents. However, MM remains incurable because MM stem cells are resistant to these agents. Therefore, it is essential to develop strategies to eradicate MM stem cells.

7,8-Dihydroxy-3-(4'-hydroxyphenyl)coumarin inhibits invasion and migration of osteosarcoma cells.

Advances in pharmacy and medicine have led to the development of many anti-cancer and molecular targeted agents; however, there are few agents capable of suppressing metastasis. To prevent cancer recurrence, it is essential to develop novel agents for inhibiting metastasis. Coumarin-based compounds have multiple pharmacological activities including anti-cancer effects.

Successful Incorporation of Exosome-Capturing Antibody-siRNA Complexes into Multiple Myeloma Cells and Suppression of Targeted mRNA Transcripts.

Nucleic acid medicines have been developed as new therapeutic agents against various diseases; however, targeted delivery of these reagents into cancer cells, particularly hematologic cancer cells, via systemic administration is limited by the lack of efficient and cell-specific delivery systems. We previously demonstrated that monoclonal antibody (mAb)-oligonucleotide complexes targeting exosomal microRNAs with linear oligo-D-arginine (Arg) linkers were transferred into solid cancer cells and inhibited exosomal miRNA functions. In this study, we developed exosome-capturing anti-CD63 mAb-conjugated small interfering RNAs (siRNAs) with branched Arg linkers and investigated their effects on multiple myeloma (MM) cells.

The CDK4/6-UCHL5-BRD4 axis confers resistance to BET inhibitors in MLL-rearranged leukemia cells by suppressing BRD4 protein degradation.

Among acute leukemias, mixed-lineage leukemia-rearranged (MLL-r) leukemia is associated with poor prognosis. Bromodomain and extra-terminal inhibitors (BETi) are promising agents for treatment of hematological malignancies; however, the mechanisms underlying sensitivity to BETi and biomarkers to predict sensitivity are yet to be clarified. Here, we established OTX015-resistant MLL-r cell lines (OTX015-R cells) and used them to explore therapeutic targets in BETi-resistant MLL-r leukemia.

Expression level of BTN3A1 on the surface of CD14 monocytes is a potential predictor of γδ T cell expansion efficiency.

Human γδ T cells expressing Vγ9Vδ2 T cell receptors exert a robust response to pathogens and malignant cells. These cells are activated by BTN3A1, which is expressed by pathogen-derived phosphoantigens (pAgs) or host-derived pAgs that accumulate in transformed cells or in cells exposed to aminobisphosphonates. Activated Vδ2 (+) T cells exert multiple effector functions; therefore, they are a promising candidate for immunotherapy.

Strategies to Improve the Antitumor Effect of γδ T Cell Immunotherapy for Clinical Application.

Human γδ T cells show potent cytotoxicity against various types of cancer cells in a major histocompatibility complex unrestricted manner. Phosphoantigens and nitrogen-containing bisphosphonates (N-bis) stimulate γδ T cells via interaction between the γδ T cell receptor (TCR) and butyrophilin subfamily 3 member A1 (BTN3A1) expressed on target cells. γδ T cell immunotherapy is classified as either in vivo or ex vivo according to the method of activation.

Human Vγ9Vδ2 T cells exert anti-tumor activity independently of PD-L1 expression in tumor cells.

Human γδ T cells expressing Vγ9Vδ2 T cell receptors play a crucial role in the innate immune system and have an attracted interest as effector cells in adoptive cellular immunotherapy. However, the efficacy of adoptive cellular immunotherapy for the treatment of tumors requires overcoming the immunosuppressive microenvironment. αβ T cell inhibition in the tumor microenvironment is associated with programmed death-ligand 1 (PD-L1) expression level.

Linderapyrone: A Wnt signal inhibitor isolated from Lindera umbellata.

Linderapyrone, a Wnt signal inhibitor was isolated from the methanolic extract of the stems and twigs of Lindera umbellata together with epi-(-)-linderol A. Linderapyrone inhibited TCF/β-catenin transcriptional activity that was evaluated using cell-based TOPFlash luciferase assay system. To evaluate the structure-activity relationship and mechanism, we synthesized linderapyrone and its derivatives from piperitone.

Plasma membrane anchored nanosensor for quantifying endogenous production of HO in living cells.

Hydrogen peroxide (HO) is one of the main second messengers involved in signaling pathways controlling cell metabolism. During tumorigenesis HO is generated on the extracellular space by membrane-associated NADPH oxidases and superoxide dismutase to stimulate cell proliferation and preservation of the transformed state. Accordingly, a characteristic feature of malignant cells is overproduction of HO in the extracellular milieu and the subsequent absorption in the cytosol.

γ-Glutamylcyclotransferase, a novel regulator of HIF-1α expression, triggers aerobic glycolysis.

Metabolic reprogramming leading to aerobic glycolysis, termed the "Warburg effect," is a critical property of cancer cells. However, the precise mechanisms underlying this phenomenon are not fully understood. A growing body of evidence indicates that γ-glutamylcyclotransferase (GGCT), an enzyme involved in glutathione homeostasis that is highly expressed in many types of cancer, represents a promising therapeutic target.

A novel dipeptide type inhibitor of the Wnt/β-catenin pathway suppresses proliferation of acute myelogenous leukemia cells.

The Wnt/β-catenin pathway is an attractive target for the treatment of acute myelogenous leukemia (AML), since aberrant activation of the Wnt/β-catenin pathway contributes to carcinogenesis in various types of cancers including AML. Screening of an in-house compound library, constructed at Kyoto Pharmaceutical University, identified a novel compound designated "31" that was found to be an inhibitor of the Wnt/β-catenin pathway. The compound inhibited T-cell factor (TCF) activity in a TCF firefly luciferase-reporter assay and suppressed the proliferation of several human AML cell lines in a dose-dependent manner.

Sphere-derived Prostate Cancer Stem Cells Are Resistant to γδ T Cell Cytotoxicity.

Background/aim: γδ T cells mediate cytotoxicity against prostate cancer (PCa) cells in vitro; however, the clinical efficacy of γδ T cell-targeted immunotherapy for recurrent and metastatic PCa is unsatisfactory. We hypothesized that the resistance of recurrent and metastatic PCa to γδ T cells is related to the presence of prostate cancer stem cells (PCSCs), and we examined their relationship.

Materials And Methods: PCa spheres (prostaspheres) were generated from five PCa cell lines, and their susceptibility to cytotoxicity by γδ T cells was investigated.

Factors Associated with Dose Modification of Lenalidomide Plus Dexamethasone Therapy in Multiple Myeloma.

Long-term combination treatment with lenalidomide and low-dose dexamethasone is important to achieve a curative effect in patients with multiple myeloma (MM). In this study, the plasma concentration of lenalidomide was measured at 3 h after oral administration, when the drug is in the elimination phase and can be easily measured in outpatients, to identify factors that may lead to the discontinuation of this combination therapy. Patients were assigned to continuation or discontinuation of therapy groups, and the baseline characteristics of patients, lenalidomide concentration, and concentration/dose (C/D) ratios reflecting oral clearance were compared between the two groups.

Development of Antibody-Oligonucleotide Complexes for Targeting Exosomal MicroRNA.

MicroRNAs in exosomes (exosomal miRNAs) are considered as significant targets for cancer therapy. Anti-miR oligonucleotides are often used for the functional inhibition of miRNAs; however, there are no studies regarding the regulation of exosomal miRNA functions. In this study, we attempted to develop a novel drug delivery system using anti-exosome antibody-anti-miR oligonucleotide complexes (ExomiR-Tracker) to hijack exosomes to carry anti-miR oligonucleotides inside exosome-recipient cells.

Cytotoxic activities of sesquiterpenoids from the aerial parts of Petasites japonicus against cancer stem cells.

From the methanolic extract of the aerial parts of Petasites japonicus, six new eremophilane-type sesquiterpenoids, petasitesterpenes I-VI were isolated together with eight known compounds including S-japonin and eremophilenolide. The chemical structures of the isolated new compounds were elucidated based on chemical/physicochemical evidence. For petasitesterpenes I and II, the absolute configurations were established by comparison of experimental and predicted electronic circular dichroism (ECD) data.