Recent progress in TGF-β inhibitors for cancer therapy Huang, Cheng-Yi; Chung, Chih-Ling; Hu, Tsung-Hui ...
Biomedicine & pharmacotherapy,
February 2021, 2021-Feb, 2021-02-00, 20210201, 2021-02-01, Volume:
134
Journal Article
Peer reviewed
Open access
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•Summary of the basic studies, patents, and clinical trials inhibiting TGF-β signalling, a critical pathway in tumorigenesis and fibrosis.•Small molecular inhibitors and neutralizing ...antibodies against TGF-β signaling are potential strategies for cancer therapy.•Natural products and repurposed drugs should continue to be major resources for screening TGF-β inhibitors.•The future prospect of new sources and mechanisms of TGF-β inhibitors are discussed in this review.
Transforming growth factor-β (TGF-β) is a multifunctional cytokine that is involved in proliferation, metastasis, and many other important processes in malignancy. Inhibitors targeting TGF-β have been considered by pharmaceutical companies for cancer therapy, and some of them are in clinical trial now. Unfortunately, several of these programs have recently been relinquished, and most companies that remain in the contest are progressing slowly and cautiously. This review summarizes the TGF-β signal transduction pathway, its roles in oncogenesis and fibrotic diseases, and advancements in antibodies and small-molecule inhibitors of TGF-β.
Fluoroquinolones (FQs), commonly known for their antibiotic properties, exhibit additional pharmacological potential with anti-proliferative effects on various malignant cell types and ...immunomodulatory responses. Despite these observed effects, the precise mechanisms of action remain elusive. This study elucidates the biological impact of FQs on insulin-like growth factor–binding protein 3 (IGFBP-3) productions in a p53-dependent manner. Cultured cells and mouse models treated with FQs demonstrated increased IGFBP-3 mRNA expression and protein secretion. The FQ-induced IGFBP-3 was identified to impede cell growth by inhibiting IGF-I signaling and exerting effects through an IGF-independent pathway. Notably, FQ-mediated suppression of cell proliferation was reversed in p53-null and p53 knockdown cells, suggesting the pivotal role of p53 in FQ-induced IGFBP-3 production and IGFBP-3-mediated growth inhibition. Additionally, ciprofloxacin, a clinically used FQ, exhibited the induction of tumor cell apoptosis and attenuation of tumor growth in a syngeneic mouse hepatocellular carcinoma (HCC) model. These findings unveil a novel mechanism through which FQs act as anti-proliferative agents, prompting further exploration of their potential utility or derivative compounds in cancer treatment and prevention.
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Sinulariolide (SC-1) is a natural product extracted from the cultured-type soft coral
and possesses anti-inflammation, anti-proliferative, and anti-migratory in several types of cancer cells. ...However, the molecular pathway behind its effects on inflammation remains poorly understood. Since inflammatory cytokines such as TGFβ, TNFα, IL-1, IL-6, and IL-8 activate transcription factors such as Smads, NF-κB, STAT3, Snail, Twist, and Zeb that drive the epithelial-to-mesenchymal transition (EMT), in this study, we focus on the investigation in effects of SC-1 on TGFβ-induced interleukin-6 (IL-6) releases in an in vitro cell culture model. We showed that both intracellular IL-6 expression and secretion were stimulated by TGFβ and associated with strong upregulation of IL-6 mRNA and increased transcription in A549 cells. SC-1 blocked TGFβ-induced secretion of IL-6 while showing no effect on the induction of fibronectin and plasminogen activator inhibitor-1 genes, indicating that SC-1 interferes with only a subset of TGFβ activities. In addition, SC-1 inhibits TGFβ-induced IL-6 by suppressing p38 MAPK signaling and subsequently inhibits NF-κB and its nuclear translocation without affecting the canonical Smad pathway and receptor turnover. Overall, these data suggest that p38 may involve in the inhibition of SC-1 in IL-6 release, thus illustrating an inhibitory effect for SC-1 in the suppression of inflammation, EMT phenotype, and tumorigenesis.
Recent findings have revealed the role of membrane traffic in the signaling of transforming growth factor-β (TGF-β). These findings originate from the pivotal function of TGF-β in development, cell ...proliferation, tumor metastasis, and many other processes essential in malignancy. Actin and unconventional myosin have crucial roles in subcellular trafficking of receptors; research has also revealed a growing number of unconventional myosins that have crucial roles in TGF-β signaling. Unconventional myosins modulate the spatial organization of endocytic trafficking and tether membranes or transport them along the actin cytoskeletons. Current models do not fully explain how membrane traffic forms a bridge between TGF-β and the downstream effectors that produce its functional responsiveness, such as cell migration. In this review, we present a brief overview of the current knowledge of the TGF-β signaling pathway and the molecular components that comprise the core pathway as follows: ligands, receptors, and Smad mediators. Second, we highlight key role(s) of myosin motor-mediated protein trafficking and membrane domain segregation in the modulation of the TGF-β signaling pathway. Finally, we review future challenges and provide future prospects in this field.
Fluoroquinolones (FQs) are potent antimicrobials with multiple effects on host cells and tissues. Although FQs can attenuate cancer invasion and metastasis, the underlying molecular mechanisms remain ...unclear. Matrix metalloproteinase-9 (MMP-9) has functional roles in tumor angiogenesis, invasion, and metastasis, and is associated with cancer progression and poor prognosis, suggesting that inhibitors of MMP-9 activity and transcription are prime candidates for cancer therapy. Despite numerous preclinical data supporting the use of MMP-9 inhibitors as anticancer drugs, the few available examples are not therapeutically useful due to low specificity and off-target effects. We examined the effects of FQs on MMP-9 production in cancer cells following transforming growth factor beta (TGF-β) and phorbol 12-myristate 13-acetate (PMA) stimulation.
Using confluent cultures of HepG2 and A549 cells, the effects of FQs (ciprofloxacin, levofloxacin, clinafloxacin, gatifloxacin, and enrofloxacin) on TGF-β and PMA-induced MMP-9 mRNA expression and production were studied in RNA extracts and culture supernatants, respectively. FQs specifically abrogated TGF-β and PMA-induced MMP-9 levels and activity in a concentration and time-dependent manner, without affecting other MMPs or proteins involved in epithelial-mesenchymal transition. Additionally, FQs inhibited TGF-β and PMA-induced cell migration via p38 and cyclic AMP signaling pathways.
Overall, we demonstrated that FQs inhibit cancer cell migration and invasion by downregulating MMP-9 expression and revealed the cellular mechanisms underlying their potential value in cancer treatment.
Bone implants with surface modifications that promote the physiological activities of osteoblasts are the first step for osseointegration in bone repair. Hydroxyapatite is the main inorganic ...component in mammal bones and teeth, and nanoscaled hydroxyapatite promotes the adhesion of osteoblastic cells. In this study, we created a nano/micro hierarchical structure using micro-arc oxidation coatings and hydrothermal treatments at 150 °C, 175 °C, and 200 °C for 2, 6, 12, and 24 h. After undergoing hydrothermal treatment for 24 h, CaTiO
began forming regular-shaped crystals at the surface at 175 °C. In order to decrease the CaTiO
formations and increase the apatite fabrication, a shorter time of hydrothermal treatment was required at 175 °C. There was still surface damage on samples treated for 6 h at 175 °C; however, the nano/micro hierarchical structures were formed in 2 h at 175 °C. The normalized alkaline phosphatase (ALP) activities of the MC3T3-E1 cells with micro-arc oxidation (MAO) coatings and nano/micro hierarchical bioceramics coatings were 4.51 ± 0.26 and 7.36 ± 0.51 μmol p-NP/mg protein (*** P value of <0.001), respectively. The MC3T3-E1 cells with coatings showed highly statistically significant results in terms of the ALP activity. This proposed nano/micro hierarchical structure promoted cell proliferation and osteogenic differentiation of the osteoblast MC3T3-E1 cells. This study realized a promising nano system for osseointegration via bone implant surface treatments, which can promote the physiological activities of osteoblasts.
Objectives
The purpose of the study is to identify the recessive diseases currently affecting real‐world pediatric patients in Taiwan, and whether current extended carrier screening panels have the ...coverage and detective power to identify the pathogenic variants in the carrier parents.
Methods
A total of 132 trio‐samples were collected from May 2017 to March 2022. The participants were parents of pediatric intensive care unit patients who were critically ill or infants with abnormal newborn screening results. A retrospective carrier screening scheme was applied to analyze only the carrier status of pathogenic or likely pathogenic recessive variants resulting in diseases in their children. The recessive disorders diagnosed in our cohort were compared with the gene content in commercial panels.
Results
Mutations in COQ4, PEX1, OTC, and IKBKG were the most frequently identified. In the parents of 44 children with confirmed diagnoses of recessive diseases, 47 (53.40%) screened positive for being the carriers of the same recessive disorders diagnosed in their children. The commercial panels covered 35.13% to 54.05% of the disorders diagnosed in this cohort.
Conclusion
Clinicians and genetic counselors should be aware of the limitations of current extended carrier screening and interpret negative screening results with caution. Future panels should also consider genes with ethnically unique mutations such as pathogenic variants of the COQ4 gene in the East Asian population.
Synopsis
The design of carrier screening panels still needs to take into consideration ethnic uniqueness or founder mutations in the targeted population.
Pentachloropseudilin (PClP) is a chlorinated phenylpyrrole compound that was first isolated from Actinoplanes (ATCC33002), and its structure has been confirmed by chemical synthesis. PClP shows broad ...antimicrobial activity against Gram-negative and Gram-positive bacteria, protozoa, fungi, and yeast. In mammalian cells, PClP is known to act as a reversible and allosteric inhibitor of myosin 1c (Myo1c). Herein, we report that PCIP is a potent inhibitor of transforming growth factor-β (TGF-β)-stimulated signaling. PCIP inhibits TGF-β-stimulated Smad2/3 phosphorylation and plasminogen activator inhibitor-1 (PAI-1) promoter activation with an IC
of 0.1 μm in target cells (A549, HepG2, and Mv1Lu cells). In addition, PCIP attenuates TGF-β-stimulated expression of vimentin, N-cadherin, and fibronectin and, thus, blocks TGF-β-induced epithelial to mesenchymal transition (EMT) in these cells. Furthermore, cell-surface labeling and immunoblot analysis indicates that PCIP suppresses TGF-β-stimulated cellular responses by attenuating cell-surface expression of the type II TGF-β receptor through accelerating caveolae-mediated internalization followed by primarily lysosome-dependent degradation of the receptor, as demonstrated by sucrose density gradient analysis and immune fluorescence staining.
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Sorafenib is the only FDA approved drug for the treatment of advanced hepatocellular carcinoma (HCC) and other malignancies. Studies indicate that TGF-β signalling is associated with ...tumour progression in HCC. Autocrine and paracrine TGF-β promotes tumour growth and malignancy by inducing epithelial-mesenchymal transition (EMT). Sorafenib is believed to antagonize tumour progression by inhibiting TGF-β-induced EMT. It improves survival of patients but HCC later develops resistance and relapses. The underlying mechanism of resistance is unknown. Understanding of the molecular mechanism of sorafenib inhibition of TGF-β-induced signalling or responses in HCC may lead to development of adjunctive effective therapy for HCC. In this study, we demonstrate that sorafenib suppresses TGF-β responsiveness in hepatoma cells, hepatocytes, and animal liver, mainly by downregulating cell-surface type II TGF-β receptors (TβRII) localized in caveolae/lipid rafts and non-lipid raft microdomains via caveolae/lipid rafts-mediated internalization and degradation. Furthermore, sorafenib-induced downregulation and degradation of cell-surface TβRII is prevented by simultaneous treatment with a caveolae disruptor or lysosomal inhibitors. On the other hand, sorafenib only downregulates cell-surface TβRII localized in caveolae/lipid rafts but not localized in non-lipid raft microdomains in hepatic stellate cells. These results suggest that sorafenib inhibits TGF-β signalling mainly by inducing caveolae/lipid raft-mediated internalization and degradation of cell-surface TβR-II in target cells. They may also imply that treatment with agents which promote formation of caveolae/lipid rafts, TGF-β receptor kinase inhibitors (e.g., LY2157299) or TGF-β peptide antagonists (by liver-targeting delivery) may be considered as effective adjunct therapy with sorafenib for HCC.
In this study, we first analyze the usability of recycling products, and use the fuzzy set method to determine the main impact on recycling items and their corresponding weights by using the Analytic ...Hierarchy Process (AHP) to identify various impact recycling levels. The Group Decision Supporting System (GDSS) determines the test standards for the recycling rating. It provides a convenient way for recyclers or manufacturers to classify their own products and use fuzzy numbers to select a set of test standards. It can deduce the recovery rate and remanufacturing rate of different recycling processing levels through the Markov chain model to find out the inventory model and total cost. In the numerical analysis, we found that a recycling rate of more than 90% is probably a necessary decision. Since the processing cost of the 100% recovery rate is doubled, the inventory level and total cost will increase with it. Therefore, this study was combined with the reverse logistics method to find the appropriate decision-making strategy and plan, such as the optimal inventory level and recovery rate.
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