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Talaroconvolutin-A (TalaA) is a compound from the endophytic fungus T. convolutispora of the Chinese herbal medicine Panax notoginseng. Whether TalaA exerts anticancer activity in bladder cancer remains unknown. Using CCK8 assay, EdU staining, crystal violet staining, flow cytometry, living/dead cell staining, and Western blotting, we studied the anticancer activity of TalaA in vitro. Moreover, we performed xenograft tumor implantation. The antitumor effects were evaluated through H&E and immunohistochemistry staining. Proteomics was conducted to detect changes in the protein profile; transcriptomics was performed to detect changes in mRNA abundance; phosphoproteomics was used to detect changes in protein phosphorylation. TalaA inhibited tumor cell proliferation, DNA replication, and colony formation in a dose-dependent manner in bladder cancer cells. The IC 50 values of TalaA on SW780 and UM-UC-3 cells were 5.7 and 8.2 μM, respectively. TalaA (6.0 mg/kg) significantly repressed the growth of xenografted tumors and did not affect the body weight nor cause obvious hepatorenal toxicity. TalaA arrested the cell cycle by downregulating cyclinA2, cyclinB1, and AURKB and upregulating p21/CIP. TalaA also elevated intracellular reactive oxygen species and upregulated transferrin and heme oxygenase 1 to induce ferroptosis. Moreover, TalaA was able to bind to MAPKs (MAPK1, MAPK8, and MAPK14) to inhibit the phosphorylation of ∗SP∗ motif of transcription regulators. This study revealed that TalaA inhibited bladder cancer by arresting cell cycle to suppress proliferation and triggering ferroptosis to cause cell death. Conclusively, TalaA would be a potential candidate for treating bladder cancer by targeting MAPKs, suppressing the cell cycle, and inducing ferroptosis., Competing Interests: Conflict of interest The authors declare no known competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Cancer, also known as a malignant tumor, has developed into a type of disease with the highest fatality rate, seriously threatening the lives and health of people. Chemotherapy is one of the most important methods for the treatment of cancer. However, chemotherapy drugs have some problems, such as low solubility and lack of targeting, which severely limit their clinical applications. To solve these problems, we designed a block copolymer that has a disulfide bond response. The polymer uses RGD peptide (arginine-glycine-aspartic acid) as the active targeting group, PEG (polyethylene glycol) as the hydrophilic end, and PCL (polycaprolactone) as the hydrophobic end. Then we utilized the amphiphilic polymer as a carrier to simultaneously deliver DOC (docetaxel) and ICG (indocyanine green), to realize the combined application of chemotherapy and photothermal therapy. The antitumor efficacy in vivo and histology analysis showed that the DOC/ICG-loaded micelle exhibited higher antitumor activity. The drug delivery system improved the solubility of DOC and the stability of ICG, realized NIR-guided photothermal therapy, and achieved an ideal therapeutic effect.

Colorectal cancer (CRC) is the third leading malignant tumor in the world, which has high morbidity and mortality. In this study we found that trichodermic acid (TDA), a secondary metabolite isolated from the plant endophytic fungus Penicillium ochrochloronthe with a variety of biological and pharmacological activities, exhibited the antitumor effects on colorectal cancer cells in vitro and in vivo. Our results showed that TDA inhibited the proliferation of colon cancer cells in a dose-dependent manner. TDA induces sustained endoplasmic reticulum stress, which triggers apoptosis through IRE1α/XBP1 and PERK/ATF4/CHOP pathways. In addition, we found that TDA mediated endoplasmic reticulum stress also induces autophagy as a protective mechanism. Moreover, combined treatment of TDA with autophagy inhibitors significantly enhanced its anticancer effect. In conclusion, our results indicated that TDA can induce ER stress and autophagy mediated apoptosis, suggesting that targeting ER stress and autophagy may be an effective strategy for the treatment of CRC.

Six new cytochalasans, designated as 18-oxo-19,20-dihydrophomacin C (1), 18-oxo-19-methoxy-19,20- dihydrophomacin C (2), 18-oxo-19-hydroxyl-19,20-dihydrophomacin C (3), 19,20-dihydrophomacin C (4), 19-methoxy-19,20-dihydrophomacin C (5), 19-hydroxyl-19,20-dihydrophomacin C (6), and one new tyrosine-derived alkaloid named as gymnastatin Z (8), together with two known compounds, phomacin B (7) and triticone D (9), were isolated from a solid-substrate fermentation culture of Westerdykella dispersa which was derived from marine sediments. Their structures were established on the basis of spectroscopic analysis using 1D and 2D NMR techniques, and comparison of NMR data to those of known compounds. The anti-bacterial and cytotoxic activities assays of all isolated compounds were evaluated against eight human pathogenic bacteria and five human cancer cell lines, respectively. Compound 8 exhibited moderate activity against B. subtilis with MIC values of 12.5 µg/mL, while compounds 5, 7 and 8 displayed moderate inhibitory activities against five human cancer cell lines (MCF-7, HepG2, A549, HT-29 and SGC-7901), with IC 50 values ranging from 25.6 to 83.7 µM.

Antitubulin drugs are commonly used for the treatment of numerous cancers. However, either the intrinsic or acquired resistances of patients to these drugs result in the failure of the treatment and high mortality of cancers. Therefore, identifying genes or signalling pathways involved in antitubulin drug resistances is critical for future successful treatment of cancers.TAZ (Transcriptional coactivator with PDZ-binding motif), which is a core component of the Hippo pathway, is overexpressed in various cancers. We have recently shown that high levels of TAZ in cancer cells result in Taxol resistance through up-regulation of downstream targets Cyr61 and CTGF. However, how TAZ is regulated in response to Taxol is largely unknown. In this study, we found that Cdk1 (Cyclin-dependent kinase 1) directly phosphorylated TAZ on six novel sites independent of the Hippo pathway, which further resulted in TAZ degradation through proteasome system. Phosphorylation-mimicking TAZ mutant was unstable, and therefore abolished TAZ-induced antitubulin drug resistances. This study provides first evidence that Cdk1 is a novel kinase phosphorylating and regulating TAZ stability and suggests that Cdk1-TAZ signalling is a critical regulator of antitubulin drug response in cancer cells and may be a potential target for the treatment of antitubulin-drug resistant cancer patients.

Although antitubulin drugs are used widely to treat human cancer, many patients display intrinsic or acquired drug resistance that imposes major obstacles to successful therapy. Mounting evidence argues that cancer cell apoptosis triggered by antitubulin drugs relies upon activation of the cell-cycle kinase Cdk1; however, mechanistic connections of this event to apoptosis remain obscure. In this study, we identified the antiapoptotic protein YAP, a core component of the Hippo signaling pathway implicated in tumorigenesis, as a critical linker coupling Cdk1 activation to apoptosis in the antitubulin drug response. Antitubulin drugs activated Cdk1, which directly phosphorylated YAP on five sites independent of the Hippo pathway. Mutations in these phosphorylation sites on YAP relieved its ability to block antitubulin drug-induced apoptosis, further suggesting that YAP was inactivated by Cdk1 phosphorylation. Notably, we found that YAP was not phosphorylated and inactivated after antitubulin drug treatment in taxol-resistant cancer cells. Our findings suggest YAP and its phosphorylation status as candidate prognostic markers in predicting antitubulin drug response in patients., (©2014 American Association for Cancer Research.)

This study aimed to explore the role of GRP78-mediated endoplasmic reticulum stress (ERS) in the synergistic inhibition of colorectal cancer by epigallocatechin-3-gallate (EGCG) and irinotecan (IRI). Findings showed that EGCG alone or in combination with irinotecan can significantly promote intracellular GRP78 protein expression, reduce mitochondrial membrane potential and intracellular ROS in RKO and HCT 116 cells, and induce cell apoptosis. In addition, glucose regulatory protein 78 kDa (GRP78) is significantly over-expressed in both colorectal cancer (CRC) tumor specimens and mouse xenografts. The inhibition of GRP78 by small interfering RNA led to the decrease of the sensitivity of CRC cells to the drug combination, while the overexpression of it by plasmid significantly increased the apoptosis of cells after the drug combination. The experimental results in the mouse xenografts model showed that the combination of EGCG and irinotecan could inhibit the growth of subcutaneous tumors of HCT116 cells better than the two drugs alone. EGCG can induce GRP78-mediated endoplasmic reticulum stress and enhance the chemo-sensitivity of colorectal cancer cells when coadministered with irinotecan. [ABSTRACT FROM AUTHOR]

Antibodies targeting PD-1 have been demonstrated durable anti-cancer activity in certain cancer types. However, the anti-PD-1 antibodies are less or not efficacious in many situations, which might be attributed to co-expression of multiple inhibitory receptors or presence of immunosuppressive cells in the tumor microenvironment. Most of the anti-PD-1 antibodies used in clinical studies are of IgG4 isotype with the S228P mutation (IgG4S228P). The functional impact by the interaction of anti-PD-1 IgG4S228P antibody with Fc gamma receptors (FcγRs) is poorly understood. To assess the effects, we generated a pair of anti-PD-1 antibodies: BGB-A317/IgG4S228P and BGB-A317/IgG4-variant (abbreviated as BGB-A317), with the same variable regions but two different IgG4 Fc-hinge sequences. There was no significant difference between these two antibodies in binding to PD-1. However, BGB-A317/IgG4S228P binds to human FcγRI with high affinity and mediates crosslinking between PD-1 and FcγRI. In contrast, BGB-A317 does neither. Further cell-based assays showed that such crosslinking could reverse the function of an anti-PD-1 antibody from blocking to activating. More importantly, the crosslinking induces FcγRI+ macrophages to phagocytose PD-1+ T cells. In a mouse model transplanted with allogeneic human cancer cells and PBMCs, BGB-A317 showed significant tumor growth inhibition, whereas BGB-A317/IgG4S228P had no such inhibition. Immunohistochemistry study revealed an inverse correlation between FcγRI+ murine macrophage infiltration and the density of CD8+PD-1+ human T cells within tumors in the BGB-A317/IgG4S228P-treated group. These evidences suggested that FcγRI+ binding and crosslinking had negative impact on the anti-PD-1 antibody-mediated anti-cancer activity. [ABSTRACT FROM AUTHOR]

The simple and functional modification of the nanoparticle's surface is used to efficiently deliver chemotherapeutic drugs for anti-cancer treatment. Here, we construct a nanocrystalline drug delivery system with doxorubicin wrapped in red blood cell membranes for the treatment of mouse breast cancer models. Compared with traditional free drug treatments, the biodegradable natural red blood cell membrane is combined with pure crystalline drugs. The nanoparticles obtained by the preparation method have superior properties, such as good stability, significantly delaying the release of drugs and enhancing the inhibitory effect on tumor cells. This study shows that the design of RBC as an outsourced drug delivery system provides a promising foundation for the continued development, clinical trials, and nanomedicine research of anti-cancer drug nanocarriers in the future. [ABSTRACT FROM AUTHOR]

The Hippo pathway has emerged as a key signaling pathway that regulates a broad range of biological functions, and dysregulation of the Hippo pathway is a feature of a variety of cancers. Given this, some have suggested that disrupting the interaction of the Hippo core component YAP and its paralog TAZ with transcriptional factor TEAD may be an effective strategy for cancer therapy. However, there are currently no clinically available drugs targeting the YAP/TAZ–TEAD interaction for cancer treatment. To facilitate screens for small molecule compounds that disrupt the YAP–TEAD interaction, we have developed the first ultra-bright NanoLuc biosensor to quantify YAP/TAZ–TEAD protein–protein interaction (PPI) both in living cells and also in vitro using biosensor fusion proteins purified from bacteria. Using this biosensor, we have performed an in vitro high throughput screen (HTS) of small molecule compounds and have identified and validated the drug Celastrol as a novel inhibitor of YAP/TAZ–TEAD interaction. We have also demonstrated that Celastrol can inhibit cancer cell proliferation, transformation, and cell migration. In this study, we describe a new inhibitor of the YAP/TAZ–TEAD interaction warranting further investigation and offer a novel biosensor tool for the discovery of other new Hippo-targeting drugs in future work. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is one of the most prominent diseases in the world, and the treatments for BC have many limitations, such as resistance and a lack of reliable biomarkers. Currently the Hippo pathway is emerging as a tumor suppressor pathway with its four core components that regulate downstream transcriptional targets. In this review, we introduce the present targeted therapies of BC, and then discuss the roles of the Hippo pathway in BC. Finally, we summarize the evidence of the small molecule inhibitors that target the Hippo pathway, and then discuss the possibilities and future direction of the Hippo-targeted drugs for BC therapy. [ABSTRACT FROM AUTHOR]