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The endocytic trafficking pathway is a highly organized cellular program responsible for the regulation of membrane components and uptake of extracellular substances. Molecules internalized into the cell through endocytosis will be sorted for degradation or recycled back to membrane, which is determined by a series of sorting events. Many receptors, enzymes, and transporters on the membrane are strictly regulated by endocytic trafficking process, and thus the endocytic pathway has a profound effect on cellular homeostasis. However, the endocytic trafficking process is typically dysregulated in cancers, which leads to the aberrant retention of receptor tyrosine kinases and immunosuppressive molecules on cell membrane, the loss of adhesion protein, as well as excessive uptake of nutrients. Therefore, hijacking endocytic trafficking pathway is an important approach for tumor cells to obtain advantages of proliferation and invasion, and to evade immune attack. Here, we summarize how dysregulated endocytic trafficking process triggers tumorigenesis and progression from the perspective of several typical cancer hallmarks. The impact of endocytic trafficking pathway to cancer therapy efficacy is also discussed. [Display omitted] [ABSTRACT FROM AUTHOR]

Comparative biological studies typically require plenty of samples to ensure full representation of the given problem. A frequently-encountered question is how many samples are sufficient for a particular study. This question is traditionally assessed using the statistical power , but it alone may not guarantee the full and reproducible discovery of features truly discriminating biological groups. Two new types of statistical criteria have thus been introduced to assess sample sufficiency from different perspectives by considering diagnostic accuracy and robustness. Due to the complementary nature of these criteria, a comprehensive evaluation based on all criteria is necessary for achieving a more accurate assessment. However, no such tool is available yet. Herein, an online tool SSizer (https://idrblab.org/ssizer/) was developed and validated to enable the assessment of the sample sufficiency for a user-input biological dataset, and three statistical criteria were adopted to achieve comprehensive and collective assessment. A sample simulation based on a user-input dataset was performed to expand the data and then determine the sample size required by the particular study. In sum, SSizer is unique for its ability to comprehensively evaluate whether the sample size is sufficient and determine the required number of samples for the user-input dataset, which, therefore, facilitates the comparative and OMIC-based biological studies. Image 1 • A key question in the current comparative biological study is how many samples are sufficient. • A novel tool was developed to comprehensively evaluate sample sufficiency using multiple criteria. • This new tool was unique in determining the required sample size for comparative biological study. • The developed tool can facilitate the current comparative biological and OMIC-based studies. [ABSTRACT FROM AUTHOR]

Abstract Idiopathic pulmonary fibrosis is a pathological result of dysfunctional repair response to tissue injury, leading to chronically impaired gas exchange and death. Macrophages are believed to be critical in this disease pathogenesis; However, the exact mechanisms remain enigmatic. Here, we demonstrated that macrophages might contribute to pulmonary fibrosis at the early stage because the aggregation of macrophages appeared earlier than epithelial-mesenchymal transition and fibrosis in mouse and rat experimental models of pulmonary fibrosis. It has been found that macrophages could promote epithelial-mesenchymal transition of alveolar epithelial cells and fibroblast migration in co-culture models between macrophages and alveolar epithelial cells/fibroblasts. Importantly, we used protein micro array to analyze the cytokines that were altered after bleomycin treatment. Only thymic stromal lymphopoietin and matrix metalloproteinase 9 were significantly increased. We further confirmed that TSLP participated in the macrophage-induced epithelial-mesenchymal transition of alveolar epithelial cells using a TSLP recombinant protein. MMP9 was also involved in macrophage-induced fibroblast migration, which can be reversed by an inhibitor of MMP9. Collectively, these findings explained the underlying mechanisms of macrophage-promoted pulmonary fibrosis. Highlights • Macrophages contribute to bleomycin-induced pulmonary fibrosis • TSLP and MMP9 may be pivotal cytokines secreted by macrophages • TSLP may induce epithelial-mesenchymal transition of alveolar epithelial cells • MMP9 is involved in macrophage-induced fibroblast migration [ABSTRACT FROM AUTHOR]

Although M2-like tumor-associated macrophages (TAMs) have been considered as a vital therapeutic target in cancer therapy due to their role in promoting tumor progression and metastasis, very few compounds have been identified to inhibit M2-like polarization of TAMs. Here, we showed that Imatinib significantly prevented macrophage M2-like polarization induced by IL-13 or IL-4 in vitro, as illustrated by reduced expression of cell surface marker CD206 and M2-like genes, including Arg1, Mgl2, Mrc1, CDH1, and CCL2. Further, the migration of lung cancer cells promoted by the conditioned medium from M2-like macrophages could be restrained by Imatinib. Mechanistically, Imatinib inhibited STAT6 phosphorylation and nuclear translocation, resulting in the macrophage M2-like polarization arrest. Furthermore, Imatinib reduced the number of metastasis of Lewis lung cancer without affecting tumor growth. Both in tumor and lung tissues, the percentage of M2-like macrophages decreased after the administration of Imatinib for one week. Taken together, these data suggest that Imatinib is able to inhibit macrophage M2-like polarization, which plays a vital role in Imatinib suppressed metastasis of Lewis lung cancer. [ABSTRACT FROM AUTHOR]

[Display omitted] • A series of dihydropyridine-based PD-L1 degraders were designed and synthesized. • Summarize the SAR of dihydropyridine derivatives for the degradation of PD-L1. • Compounds maintain PD-L1 degradation after attenuating calcium channel blockade. • F4 showed best degradation activity (66.99% @20 μM) but no calcium blocking effect. • F4- induced PD-L1 degradation strengthen the T cell-mediated killing of tumor cells. Immune checkpoint blockade (ICB) by targeting programmed cell death-1/programmed cell death ligand 1 (PD-1/PD-L1) signaling pathway is a promising strategy for tumor immunotherapy. Developing small-molecules inducing PD-L1 protein degradation has been proven as an alternative and useful approach for targeting the immunotherapy pathway. Our previous study showed that Lercanidipine could down-regulate the expression of PD-L1 protein, but its calcium influx antagonistic activity hampers further development. For attenuating the unexpected calcium channel blockade effect, a series of compounds were synthesized and evaluated through structure-activity relationship (SAR) exploration. Amongst, compound F4 exhibited a loss of calcium antagonistic activity, while the PD-L1 degradation activity can still retain. Further studies indicated that F4 degraded PD-L1 dose- and time-dependently, and may function through a lysosomal-dependent manner. Furthermore, compound F4 showed a good bioavailability value of 24.9% in mice. Moreover, the F4- induced PD-L1 degradation strengthened the T cell-mediated killing of tumor cells. Our findings show the discovery of a new PD-L1 degrader, providing a potential strategy for immunotherapy. [ABSTRACT FROM AUTHOR]

Abstract: Combretastatin A-4 (CA-4) has already entered clinical trials of solid tumors over ten years. However, the limited anticancer activity and dose-dependent toxicity restrict its clinical application. Here, we offered convincing evidence that CA-4 induced autophagy in various cancer cells, which was demonstrated by acridine orange staining of intracellular acidic vesicles, the degradation of p62, the conversion of LC3-I to LC3-II and GFP-LC3 punctate fluorescence. Interestingly, CA-4-mediated apoptotic cell death was further potentiated by pretreatment with autophagy inhibitors (3-methyladenine and bafilomycin A1) or small interfering RNAs against the autophagic genes (Atg5 and Beclin 1). The enhanced anticancer activity of CA-4 and 3-MA was further confirmed in the SGC-7901 xenograft tumor model. These findings suggested that CA-4-elicited autophagic response played a protective role that impeded the eventual cell death while autophagy inhibition was expected to improve chemotherapeutic efficacy of CA-4. Meanwhile, CA-4 treatment led to phosphorylation/activation of JNK and JNK-dependent phosphorylation of Bcl-2. Importantly, JNK inhibitor or JNK siRNA inhibited autophagy but promoted CA-4-induced apoptosis, indicating a key requirement of JNK-Bcl-2 pathway in the activation of autophagy by CA-4. We also identified that pretreatment of Bcl-2 inhibitor (ABT-737) could significantly enhance anticancer activity of CA-4 due to inhibition of autophagy. Taken together, our data suggested that the JNK-Bcl-2 pathway was considered as the critical regulator of CA-4-induced protective autophagy and a potential drug target for chemotherapeutic combination. [Copyright &y& Elsevier]

Abstract: Dasatinib, a multitargeted inhibitor of BCR–ABL and SRC kinases, exhibits antitumor activity and extends the survival of patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL). However, some patients suffer from hepatotoxicity, which occurs through an unknown mechanism. In the present study, we found that Dasatinib could induce hepatotoxicity both in vitro and in vivo. Dasatinib reduced the cell viability of rat primary hepatocytes, induced the release of alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) in vitro, and triggered the ballooning degeneration of hepatocytes in Sprague–Dawley rats in vivo. Apoptotic markers (chromatin condensation, cleaved caspase-3 and cleaved PARP) were detected to indicate that the injury induced by Dasatinib in hepatocytes in vitro was mediated by apoptosis. This result was further validated in vivo using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assays. Here we found that Dasatinib dramatically increased the level of reactive oxygen species (ROS) in hepatocytes, reduced the intracellular glutathione (GSH) content, attenuated the activity of superoxide dismutase (SOD), generated malondialdehyde (MDA), a product of lipid peroxidation, decreased the mitochondrial membrane potential, and activated nuclear factor erythroid 2-related factor 2 (Nrf2) and mitogen-activated protein kinases (MAPK) related to oxidative stress and survival. These results confirm that oxidative stress plays a pivotal role in Dasatinib-mediated hepatotoxicity. N-acetylcysteine (NAC), a typical antioxidant, can scavenge free radicals, attenuate oxidative stress, and protect hepatocytes against Dasatinib-induced injury. Thus, relieving oxidative stress is a viable strategy for reducing Dasatinib-induced hepatotoxicity. [Copyright &y& Elsevier]

Abstract: Sunitinib, which is a multitargeted tyrosine-kinase inhibitor, exhibits antiangiogenic and antitumor activity, and extends survival of patients with metastatic renal-cell carcinoma (mRCC) and gastrointestinal stromal tumors (GIST). This molecule has also been reported to be associated with cardiotoxicity at a high frequency, but the mechanism is still unknown. In the present study, we observed that Sunitinib showed high anti-proliferative effect on H9c2 cardiac muscle cells measured by PI staining and the MTT assay. But apoptotic markers (PARP cleavage, caspase 3 cleavage and chromatin condensation) were uniformly negative in H9c2 cells after Sunitinib treatment for 48h, indicating that another cell death pathway may be involved in Sunitinib-induced cardiotoxicity. Here we found Sunitinib dramatically increased autophagic flux in H9c2 cells. Acidic vesicle fluorescence and high expression of LC3-II in H9c2 cells identified autophagy as a Sunitinib-induced process that might be associated with cytotoxicity. Furthermore, knocking down Beclin 1 by RNA-interference to block autophagy in H9c2 cells revealed that the death rate was decreased when treated with Sunitinib in comparison to control cells. These results confirmed that autophagy plays an important role in Sunitinib-mediated H9c2 cells cytotoxicity. Taken together, the data presented here strongly suggest that autophagy is associated with Sunitinib-induced cardiotoxicity, and that inhibition of autophagy constitutes a viable strategy for reducing Sunitinib-induced cardiomyocyte death thereby alleviating Sunitinib cardiotoxicity. [ABSTRACT FROM AUTHOR]

Abstract: 10-Methoxy-9-nitrocamptothecin (MONCPT), a topoisomerase I inhibitor, exhibited high anticancer activity in solid tumour xenograft animal models in our previous study. We hypothesized that this phenomenon was associated with antiangiogenesis response. In the present study, we found that MONCPT exhibited high antiproliferation action in human EA.hy926 endothelial cells and the IC50 value was 0.13±0.04μM (MTT assay). With AO/EB stain, MONCPT (50–5000nM)-mediated apoptosis was observed in EA.hy926 cells, and the similar results were shown in flow cytometry assay, the percentage of apoptotic cells induced by MONCPT (50–5000nM) was 9.2–58.5%. In Chick embryo chorioallantoic membrane (CAM) assay, MONCPT (1–5μg) resulted in a dose-dependent angiogenic inhibition. In addition, MONCPT significantly inhibited chemotactic-migration invasion on gelatin and tube formation on Matrigel of HUVECs. These results suggest that MONCPT has potential property for inhibiting angiogenesis which is involved in its antitumour activity. [Copyright &y& Elsevier]

Osteosarcoma, a highly malignant tumor, is characterized by widespread and recurrent chromosomal and genetic abnormalities. In recent years, a number of elaborated sequencing analyses have made it possible to cluster the osteosarcoma based on the identification of candidate driver genes and develop targeted therapy. Here, we reviewed recent next-generation genome sequencing studies and advances in targeted therapies for osteosarcoma based on molecular classification. First, we stratified osteosarcomas into ten molecular subtypes based on genetic changes. And we analyzed potential targeted therapies for osteosarcoma based on the identified molecular subtypes. Finally, the development of targeted therapies for osteosarcoma investigated in clinical trials were further summarized and discussed. Therefore, we indicated the importance of molecular classification on the targeted therapy for osteosarcoma. And the stratification of patients based on the genetic characteristics of osteosarcoma will help to obtain a better therapeutic response to targeted therapies, bringing us closer to the era of personalized medicine. [Display omitted] [ABSTRACT FROM AUTHOR]

Targeted therapy has become increasingly important and indispensable in cancer therapy. Cullin3-RING ligases (CRL3) serve as essential executors for regulating protein homeostasis in cancer development, highlighting that CRL3 might be promising targets in various cancer treatment. However, how to design new targeted therapies by disrupting the function of CRL3 is poorly understood. Here, we focus on the substrate adaptors of CRL3, and carry out a systematical research on the function of Kelch-like (KLHL) family proteins. We have identified twenty-four KLHL proteins with function of tumor promotion and thirteen KLHL proteins with high clinical significance on cancer therapy. Furthermore, we have clarified the novel biological function of KLHL13 as a vital factor that contributes to malignant progression in lung cancer. Taken together, our findings reveal multiple potential therapeutical targets and provide evidence for targeting CRL3 via KLHL substrate adaptors for cancer therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Thioredoxin 1 (Trx1) and telomerase play key roles in the development and progression process of most tumors, and they both are promising drug therapy targets. We have, for the first time, discovered that Trx1 and telomerase had a dual-target synergistic effect. Based on that results, we designed a series of 6-dithio-2′-deoxyguanosine analogs (named as YLS00X) and verified whether they can inhibit Trx1 and telomerase simultaneously. TrxR1/Trx1 system activity and telomerase expression were significantly inhibited by 6-dithio-2′-deoxyguanosine analogs, especially YLS004. YLS004 can also cause ROS accumulation, and induce tumor cell apoptosis. The vitro antitumor activity of 6-dithio-2′-deoxyguanosine analogs using MTT assay on 11 different human cancer cells and found that human colon cancer cells(HCT116) and melanoma cells (A375) were the most sensitive cells to 6-dithio-2′-deoxyguanosine analogs treatment and vivo xenografts models also confirmed that. The serum biochemical parameters and multiple organs HE staining results of subacute experiments indicated that YLS004 might be mildly toxic to immune organs, including the thymus, spleen, and hematopoietic system. Besides, YLS004 was rapidly metabolized in the rats' blood. Our study revealed that YLS004, a Trx1 and telomerase inhibitor, has strong anti-tumor effects to colon cancer and melanoma cells and is a promising new candidate drug. Unlabelled Image • Trx1 and telomerase have a dual-target synergistic effect. • YLS00X can inhibit Trx1 and telomerase simultaneously. • YLS00X cause ROS accumulation and induce colon cancer and melanoma cells apoptosis. [ABSTRACT FROM AUTHOR]

Liver fibrosis is a dynamic wound-healing process characterized by the net accumulation of extracellular matrix. There is no efficient antifibrotic therapy other than liver transplantation to date. Activated hepatic stellate cells (HSCs) are the major cellular source of matrix-producing myofibroblasts, playing a central role in the initiation and progression of liver fibrosis. Paracrine signals from resident and inflammatory cells such as hepatocytes, liver sinusoidal endothelial cells, hepatic macrophages, natural killer/natural killer T cells, biliary epithelial cells, hepatic progenitor cells, and platelets can directly or indirectly regulate HSC differentiation and activation. Intercellular crosstalk between HSCs and those "responded" cells has been a critical event involved in HSC activation and fibrogenesis. This review summarizes recent advancement regarding intercellular communication between HSCs and other "responded cells" during liver fibrosis and experimental models of intercellular crosstalk systems, and provides novel ideas for potential antifibrotic therapeutic strategy. [ABSTRACT FROM AUTHOR]

A characteristic feature of leukemia cells is a blockade of differentiation in cellular maturation. All-trans-retinoic acid (ATRA) has been successfully applied for the treatment of M3-type AML (APL, 10 %), but it fails to demonstrate a significant efficacy on the remaining patients with non-APL AML (90 %). Therefore, the research for strategies to extend the efficacy of ATRA-based therapy to non-APL AML is a key avenue of investigation. Here, we evaluate the synergetic effect of CDK2 inhibition and ATRA in AML both in vitro and in vivo. We have determined that both the CDK2 depletion and pharmacological inhibitor of CDK2 significantly sensitize three subtypes of AML cells (including two non-APL cells) to ATRA-induced cell differentiation. RNA-sequence results indicate that transcription activation of differentiation and maturation pathways plays an important role in this synergetic effect. Furthermore, the down-regulation of CDK2 sensitized AML cells to ATRA-induced engraftment prevention of leukemia cells in NOD-SCID mice and promotes the primary AML blasts differentiation when combined with ATRA. Thus, our work not only provides relevant experimental evidence for further validating CDK2 as a target for differentiation therapy, but also uncovers the future clinical application of CDK2 inhibitors in ATRA-based differentiation therapeutics for AML. [ABSTRACT FROM AUTHOR]

Crizotinib is an oral small-molecule tyrosine kinase inhibitor targeting anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) and MET proto-oncogene, receptor tyrosine kinase (MET). Unfortunately, hepatotoxicity is a serious limitation in its clinical application, and the reason remains largely unknown. In this study, we tested the effect of crizotinib in human hepatocyte cell line HL-7702 and human primary hepatocytes, and the results showed that crizotinib treatment caused hepatocyte damage, suggesting that crizotinib induced liver injury by causing hepatocyte death, consistent with the clinical cases. Mechanistically, crizotinib induced hepatocyte death via the apoptotic pathway, and cleaved PARP (c-PARP) was observed as a signaling protein. Moreover, mitochondrial membrane potential (MMP) decrease contributed to crizotinib-induced hepatocyte apoptosis accompanied by hepatocyte DNA damage and reactive oxygen species (ROS) generation. Importantly, crizotinib induced hepatocyte apoptosis independent of its targets, ALK, ROS1 and MET. In conclusion, our data showed that crizotinib induced liver injury through hepatocyte death via the apoptotic pathway which was independent of ALK, ROS1 and MET. And we also found that MMP decrease, DNA damage and ROS generation were involved in the process. Unlabelled Image • Crizotinib causes hepatocellular damage via the apoptotic pathway. • Mitochondrial membrane potential (MMP) decrease is involved in crizotinib-induced apoptosis. • Crizotinib induces reactive oxygen species (ROS) generation and DNA damage. • Crizotinib-induced hepatotoxicity is independent of ALK, ROS1 and MET. [ABSTRACT FROM AUTHOR]

Neohesperidin (NHP), derived from citrus fruits, has attracted considerable interest due to its preventative and therapeutic effects on numerous diseases. However, little progress has been made in determining the exact function of NHP on tumorigenesis. In the current study, we found that NHP inhibited colorectal tumorigenesis in the APC min/+ transgenic mouse model, as well as induced apoptosis and blocked angiogenesis in vivo. Our in-cell study suggested that this tumorigenic preventative effect of NHP is not due to the direct impact on tumor cells. Intriguingly, by utilizing 16 s rRNA gene-based microbiota sequencing, the relative abundance of Bacteroidetes was decreased, while Firmicutes and Proteobacteria were increased in the presence of NHP. Additionally, the fecal microbiota transplantation experiment further revealed that feeding with fecal of NHP-treated mice induced considerable inhibition of tumorigenesis, which indicates that the alteration of gut microbiota is responsible for NHP-mediated prevention of colorectal tumorigenesis. Thus, our study not only suggests the efficacy of NHP as a potent natural product for preventing colorectal cancer but also proposes a compelling model to connect the gut microbiota to the preventative effect of NHP on tumorigenesis. [ABSTRACT FROM AUTHOR]

Kelch-like gene family members (KLHLs) encode proteins with a bric-a-brac, tramtrack, broad complex (BTB)/poxvirus and zinc finger (POZ) domain, a BACK domain, and six Kelch motifs, which frequently interact with Cullin3 to form E3 ligase complexes that mediate the ubiquitination of substrate proteins. In recent years, studies have revealed that mutations and abnormal expression of KLHLs are closely related to the pathogenesis of various human diseases. Increasing evidence has shown that Kelch-like protein family members (KLHLs) exert important biological functions through the ubiquitination of specific substrates. This review provides an overview of the identified substrates of different KLHLs, summarizes the current knowledge of KLHLs and discusses the biological functions of KLHLs in different diseases. [ABSTRACT FROM AUTHOR]