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1.
Cell Mol Life Sci ; 81(1): 238, 2024 May 25.
Article in English | MEDLINE | ID: mdl-38795180

ABSTRACT

BRAFV600E represents a constitutively active onco-kinase and stands as the most prevalent genetic alteration in thyroid cancer. However, the clinical efficacy of small-molecule inhibitors targeting BRAFV600E is often limited by acquired resistance. Here, we find that nerve/glial antigen 2 (NG2), also known as chondroitin sulfate proteoglycan 4 (CSPG4), is up-regulated in thyroid cancers, and its expression is increased with tumor progression in a BRAFV600E-driven thyroid cancer mouse model. Functional studies show that NG2 knockout almost does not affect tumor growth, but significantly improves the response of BRAF-mutant thyroid cancer cells to BRAF inhibitor PLX4720. Mechanistically, the blockade of ERK-dependent feedback by BRAF inhibitor can activate receptor tyrosine kinase (RTK) signaling, causing the resistance to this inhibitor. NG2 knockout attenuates the PLX4720-mediated feedback activation of several RTKs, improving the sensitivity of BRAF-mutant thyroid cancer cells to this inhibitor. Based on this finding, we propose and demonstrate an alternative strategy for targeting NG2 to effectively treat BRAF-mutant thyroid cancers by combining multiple kinase inhibitor (MKI) Sorafenib or Lenvatinib with PLX4720. Thus, this study uncovers a new mechanism in which NG2 contributes to the resistance of BRAF-mutant thyroid cancer cells to BRAF inhibitor, and provides a promising therapeutic option for BRAF-mutant thyroid cancers.


Subject(s)
Drug Resistance, Neoplasm , Indoles , Protein Kinase Inhibitors , Proto-Oncogene Proteins B-raf , Sulfonamides , Thyroid Neoplasms , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Proto-Oncogene Proteins B-raf/metabolism , Humans , Animals , Thyroid Neoplasms/drug therapy , Thyroid Neoplasms/genetics , Thyroid Neoplasms/pathology , Thyroid Neoplasms/metabolism , Indoles/pharmacology , Mice , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/genetics , Sulfonamides/pharmacology , Protein Kinase Inhibitors/pharmacology , Cell Line, Tumor , Phenylurea Compounds/pharmacology , Phenylurea Compounds/therapeutic use , Sorafenib/pharmacology , Quinolines/pharmacology , Mutation , Antigens/metabolism , Proteoglycans/metabolism , Membrane Proteins , Chondroitin Sulfate Proteoglycans
2.
Anticancer Res ; 44(6): 2377-2392, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38821582

ABSTRACT

BACKGROUND/AIM: Oral squamous cell carcinoma (OSCC) is characterized by early metastasis, clinical resistance and poor prognosis. Recently, we showed that aggressive OSCC cells co-express endothelial cell markers and can form tube-like structures, known as vasculogenic mimicry (VM), a process associated with poor prognosis in head and neck cancers. Given the limited success of current antiangiogenic therapy in treating OSCC, this study sought to explore the efficiency of these drugs in targeting an ex vivo model of VM. MATERIALS AND METHODS: OSCC cell lines from the tongue and floor of the mouth in addition to human endothelial cells were used. The treatments comprised a set of clinically relevant antiangiogenic drugs: sorafenib, sunitinib, and axitinib, which were administered in different doses. Multiple ex vivo approaches including cell tubulogenesis, proliferation, apoptosis, and migration assays were used. RESULTS: Although these drugs inhibited the formation of endothelial cell capillaries, they showed clear differential effects on OSCC cell-derived VM and cell morphology. Sorafenib inhibited the tubulogenesis of aggressive OSCC cells compared with the limited effect of sunitinib and axitinib. Furthermore, our data consistently demonstrated a preferential efficacy of certain drugs over others. Sorafenib and sunitinib exhibited anti-cancer effects on tumor cell proliferation, apoptosis, and cell migration, compared with the limited effect of axitinib. CONCLUSION: The antiangiogenic drugs, except sorafenib, had limited effect on VM formation in vitro and exhibited varying anti-cancer effects on OSCC cells. These data support the notion that VM formation may in part explain the development of drug resistance in OSCC cells.


Subject(s)
Angiogenesis Inhibitors , Axitinib , Cell Movement , Cell Proliferation , Mouth Neoplasms , Neovascularization, Pathologic , Sorafenib , Sunitinib , Humans , Angiogenesis Inhibitors/pharmacology , Angiogenesis Inhibitors/therapeutic use , Mouth Neoplasms/drug therapy , Mouth Neoplasms/pathology , Mouth Neoplasms/blood supply , Mouth Neoplasms/metabolism , Cell Line, Tumor , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/pathology , Sorafenib/pharmacology , Sorafenib/therapeutic use , Sunitinib/pharmacology , Sunitinib/therapeutic use , Cell Proliferation/drug effects , Cell Movement/drug effects , Axitinib/pharmacology , Apoptosis/drug effects , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/blood supply , Carcinoma, Squamous Cell/metabolism , Endothelial Cells/drug effects , Endothelial Cells/pathology , Endothelial Cells/metabolism , Phenylurea Compounds/pharmacology , Phenylurea Compounds/therapeutic use , Niacinamide/analogs & derivatives , Niacinamide/pharmacology , Niacinamide/therapeutic use
3.
FASEB J ; 38(10): e23692, 2024 May 31.
Article in English | MEDLINE | ID: mdl-38786655

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection involves an initial viral infection phase followed by a host-response phase that includes an eicosanoid and cytokine storm, lung inflammation and respiratory failure. While vaccination and early anti-viral therapies are effective in preventing or limiting the pathogenic host response, this latter phase is poorly understood with no highly effective treatment options. Inhibitors of soluble epoxide hydrolase (sEH) increase levels of anti-inflammatory molecules called epoxyeicosatrienoic acids (EETs). This study aimed to investigate the impact of sEH inhibition on the host response to SARS-CoV-2 infection in a mouse model with human angiotensin-converting enzyme 2 (ACE2) expression. Mice were infected with SARS-CoV-2 and treated with either vehicle or the sEH inhibitor 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU). At day 5 post-infection, SARS-CoV-2 induced weight loss, clinical signs, a cytokine storm, an eicosanoid storm, and severe lung inflammation with ~50% mortality on days 6-8 post-infection. SARS-CoV-2 infection induced lung expression of phospholipase A2 (PLA2), cyclooxygenase (COX) and lipoxygenase (LOX) pathway genes, while suppressing expression of most cytochrome P450 genes. Treatment with the sEH inhibitor TPPU delayed weight loss but did not alter clinical signs, lung cytokine expression or overall survival of infected mice. Interestingly, TPPU treatment significantly reversed the eicosanoid storm and attenuated viral-induced elevation of 39 fatty acids and oxylipins from COX, LOX and P450 pathways, which suggests the effects at the level of PLA2 activation. The suppression of the eicosanoid storm by TPPU without corresponding changes in lung cytokines, lung inflammation or mortality reveals a surprising dissociation between systemic oxylipin and cytokine signaling pathways during SARS-CoV-2 infection and suggests that the cytokine storm is primarily responsible for morbidity and mortality in this animal model.


Subject(s)
COVID-19 Drug Treatment , COVID-19 , Cytokine Release Syndrome , Eicosanoids , Epoxide Hydrolases , SARS-CoV-2 , Animals , Mice , Eicosanoids/metabolism , COVID-19/immunology , COVID-19/virology , COVID-19/metabolism , SARS-CoV-2/drug effects , Epoxide Hydrolases/antagonists & inhibitors , Epoxide Hydrolases/metabolism , Cytokine Release Syndrome/drug therapy , Piperidines/pharmacology , Piperidines/therapeutic use , Cytokines/metabolism , Humans , Lung/virology , Lung/metabolism , Lung/pathology , Lung/drug effects , Angiotensin-Converting Enzyme 2/metabolism , Disease Models, Animal , Phenylurea Compounds/pharmacology , Phenylurea Compounds/therapeutic use , Female
4.
Int Immunopharmacol ; 134: 112144, 2024 Jun 15.
Article in English | MEDLINE | ID: mdl-38733820

ABSTRACT

Radiofrequency ablation (RFA), an effective local treatment method for early-stage Hepatocellular Carcinoma (HCC), combined with PD-1 blocking and anti-angiogenic therapy is being extensively explored in advanced HCC, however, the definite results and underlying mechanisms still remain to be elucidated. Therefore, whether non-ablative RFA-based combined therapy can play a synergistic anti-tumor effect through improving tumor immune microenvironment was investigated by us in HCC mouse models. Our results showed that non-ablative RFA could regulate multilayered immunity, such as inducing immunogenic death of tumor cells, upregulating the secretion of inflammatory cytokines, mainly IFN-γ, TNF-α, and IL-10, and subsequently promoting the infiltration of CD8 + T cells. As a result, a significant synergistic anti-tumor effect was demonstrated in the combination therapy group. Similarly, in the real-world setting, non-curative RFA combined with PD-1 blocking and Lenvatinib for 12 patients with Barcelona Clinic Liver Cancer (BCLC) stage C achieve promising results, with 6.9 months (95 % CI: 3.23-15.73) median progression-free survival (mPFS) and 12.7 months (95 % CI: 7.40-19.73) median overall survival (mOS). The common treatment-related adverse reactions were pneumonia and thyroiditis with low prevalence, both less than grade 3 and manageable by symptomatic treatment. Summarily, local non-ablative RFA should be a clinically preferred strategy in combination with PD-1 blocking and anti-angiogenic therapy, because this more flexible scheme abandons its historical concept of tumor eradication, but fully utilizes the immune regulatory function by inducing immunogenic tumor death and has higher-level of safety. Therefore, this is a two-pronged and highly balanced approach to achieved favorable treatment outcomes, while conclusive evidence is still pending, it can be attempted in the real world anyway.


Subject(s)
Angiogenesis Inhibitors , Carcinoma, Hepatocellular , Immune Checkpoint Inhibitors , Liver Neoplasms , Programmed Cell Death 1 Receptor , Radiofrequency Ablation , Tumor Microenvironment , Carcinoma, Hepatocellular/therapy , Carcinoma, Hepatocellular/immunology , Carcinoma, Hepatocellular/mortality , Animals , Liver Neoplasms/therapy , Liver Neoplasms/immunology , Humans , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Male , Radiofrequency Ablation/methods , Female , Combined Modality Therapy , Mice , Middle Aged , Immune Checkpoint Inhibitors/therapeutic use , Immune Checkpoint Inhibitors/pharmacology , Angiogenesis Inhibitors/therapeutic use , Angiogenesis Inhibitors/pharmacology , Aged , Phenylurea Compounds/therapeutic use , Phenylurea Compounds/pharmacology , Cell Line, Tumor , Cytokines/metabolism , Angiogenesis , Quinolines
5.
J Transl Med ; 22(1): 517, 2024 May 30.
Article in English | MEDLINE | ID: mdl-38816735

ABSTRACT

BACKGROUND: Circular RNAs (circRNAs), which are a new type of single-stranded circular RNA, have significant involvement in progression of many diseases, including tumors. Currently, multiple circRNAs have been identified in hepatocellular carcinoma (HCC). Our study aims to investigate the function and mechanism of circDCAF8 in HCC. METHODS: The expression of circDCAF8 (hsa_circ_0014879) in HCC and para-carcinoma tissue samples was determined using quantitative real-time polymerase chain reaction (qRT-PCR). The biological function of circDCAF8 in HCC was confirmed by experiments conducted both in vitro and in vivo. And the relationship between circDCAF8, miR-217 and NAP1L1 was predicted by database and verified using qRT-PCR, RNA-binding protein immunoprecipitation (RIP) and dual-luciferase reporter assays. Exosomes isolated from HCC cells were utilized to assess the connection of exosomal circDCAF8 with HCC angiogenesis and regorafenib resistance. RESULTS: CircDCAF8 is upregulated in HCC tissues and cell lines, and is linked to an unfavourable prognosis for HCC patients. Functionally, circDCAF8 was proved to facilitate proliferation, migration, invasion and Epithelial-Mesenchymal Transformation (EMT) in HCC cells. Animal examinations also validated the tumor-promoting characteristics of circDCAF8 on HCC. Besides, exosomal circDCAF8 promoted angiogenesis in HUVECs. Mechanistically, circDCAF8 interacted with miR-217 and NAP1L1 was a downstream protein of miR-217. CircDCAF8 promoted NAP1L1 expression by sponging miR-217. In addition, exosomes may transfer circDCAF8 from regorafenib-resistant HCC cells to sensitive cells, where it would confer a resistant phenotype. CONCLUSION: CircDCAF8 facilitates HCC proliferation and metastasis via the miR-217/NAP1L1 axis. Meanwhile, circDCAF8 can promote angiogenesis and drive resistance to regorafenib, making it a viable therapeutic target for HCC patients.


Subject(s)
Carcinoma, Hepatocellular , Disease Progression , Drug Resistance, Neoplasm , Exosomes , Liver Neoplasms , MicroRNAs , Neovascularization, Pathologic , Phenylurea Compounds , Pyridines , RNA, Circular , Humans , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/metabolism , MicroRNAs/genetics , MicroRNAs/metabolism , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Liver Neoplasms/metabolism , Exosomes/metabolism , RNA, Circular/genetics , RNA, Circular/metabolism , Drug Resistance, Neoplasm/genetics , Neovascularization, Pathologic/genetics , Animals , Phenylurea Compounds/pharmacology , Phenylurea Compounds/therapeutic use , Cell Line, Tumor , Pyridines/pharmacology , Mice, Nude , Gene Expression Regulation, Neoplastic , Male , Cell Proliferation/drug effects , Cell Proliferation/genetics , Mice , Mice, Inbred BALB C , Female , Base Sequence , Human Umbilical Vein Endothelial Cells/metabolism , Middle Aged , Angiogenesis
6.
Cell Chem Biol ; 31(5): 962-972.e4, 2024 May 16.
Article in English | MEDLINE | ID: mdl-38759620

ABSTRACT

The Nod-like receptor protein 3 (NLRP3) inflammasome is activated by stimuli that induce perturbations in cell homeostasis, which commonly converge on cellular potassium efflux. NLRP3 has thus emerged as a sensor for ionic flux. Here, we identify forchlorfenuron (FCF) as an inflammasome activator that triggers NLRP3 signaling independently of potassium efflux. FCF triggers the rearrangement of septins, key cytoskeletal proteins that regulate mitochondrial function. We report that FCF triggered the rearrangement of SEPT2 into tubular aggregates and stimulated SEPT2-independent NLRP3 inflammasome signaling. Similar to imiquimod, FCF induced the collapse of the mitochondrial membrane potential and mitochondrial respiration. FCF thereby joins the imidazoquinolines as a structurally distinct class of molecules that triggers NLRP3 inflammasome signaling independent of potassium efflux, likely by inducing mitochondrial damage.


Subject(s)
Mitochondria , NLR Family, Pyrin Domain-Containing 3 Protein , Phenylurea Compounds , Potassium , Mitochondria/metabolism , Mitochondria/drug effects , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Potassium/metabolism , Humans , Phenylurea Compounds/pharmacology , Phenylurea Compounds/chemistry , Animals , Mice , Septins/metabolism , Inflammasomes/metabolism , Pyridines/pharmacology , Pyridines/chemistry , Mice, Inbred C57BL , Membrane Potential, Mitochondrial/drug effects , Signal Transduction/drug effects
7.
J Hazard Mater ; 473: 134625, 2024 Jul 15.
Article in English | MEDLINE | ID: mdl-38759408

ABSTRACT

Development of a biotechnological system for rapid degradation of pesticides is important to mitigate the environmental, food security, and health risks that they pose. Degradation of atrazine (ATZ) and isoproturon (IPU) in rice crops promoted by the brassinosteroid (BR) signaling component BRASSINAZOLE RESISTANT4 (OsBZR4) is explored. OsBZR4 is localized in the plasma membrane and nucleus, and is strongly induced by ATZ and IPU exposure. Transgenic rice OsBZR4-overexpression (OE) significantly enhances resistance to ATZ and IPU toxicity, improving growth, and reducing ATZ and IPU accumulation (particularly in grains) in rice crops. Genetic destruction of OsBZR4 (CRISPR/Cas9) increases rice sensitivity and leads to increased accumulation of ATZ and IPU. OE plants promote phase I, II, and III metabolic reactions, and expression of corresponding pesticide degradation genes under ATZ and IPU stress. UPLC-Q-TOF-MS/MS analysis reveals increased relative contents of ATZ and IPU metabolites and conjugates in OE plants, suggesting an increased OsBZR4 expression and consequent detoxification of ATZ and IPU in rice and the environment. The role of OsBZR4 in pesticide degradation is revealed, and its potential application in enhancing plant resistance to pesticides, and facilitating the breakdown of pesticides in rice and the environment, is discussed.


Subject(s)
Atrazine , Brassinosteroids , Oryza , Phenylurea Compounds , Plants, Genetically Modified , Oryza/metabolism , Oryza/genetics , Oryza/drug effects , Oryza/growth & development , Phenylurea Compounds/pharmacology , Phenylurea Compounds/metabolism , Brassinosteroids/metabolism , Atrazine/toxicity , Atrazine/metabolism , Plant Proteins/metabolism , Plant Proteins/genetics , Herbicides/metabolism , Herbicides/toxicity , Biodegradation, Environmental , Signal Transduction/drug effects , Gene Expression Regulation, Plant/drug effects
8.
Target Oncol ; 19(3): 371-382, 2024 May.
Article in English | MEDLINE | ID: mdl-38613732

ABSTRACT

BACKGROUND: There are few molecular markers driving treatment selection in later lines of treatment for advanced colorectal cancer patients. The vast majority of patients who progress after first- and second-line therapy undergo chemotherapy regardless of molecular data. OBJECTIVE: We aimed to assess the prognostic and predictive effects of specific RAS mutations on overall survival of patients receiving regorafenib (rego), trifluridine/tipiracil (TFD/TPI), or both. PATIENTS AND METHODS: This was a retrospective observational study based on data from a previous study of our research network, involving nine Italian institutions over a 10-year timeframe (2012-2022). Extended RAS analysis, involving KRAS exon 2-4 and NRAS exon 2-4, and BRAF were the main criteria for inclusion in this retrospective evaluation. Patients with BRAF mutation were excluded. Patients were classified according to treatment (rego- or TFD/TPI-treated) and RAS mutational status (wild-type [WT], KRAS codon 12 mutations, KRAS codon 13 mutations, KRAS rare mutations and NRAS mutations, KRAS G12C mutation and KRAS G12D mutation). RESULTS: Overall, 582 patients were included in the present analysis. Overall survival did not significantly differ in rego-treated patients according to RAS extended analysis, although a trend toward a better median survival in patients carrying G12D mutation (12.0 months), Codon 13 mutation (8.0 months), and Codon 12 mutation (7.0 months) has been observed, when compared with WT patients (6.0 months). Overall survival did not significantly differ in TFD/TPI-treated patients according to RAS extended analysis, although a trend toward a better median survival in WT patients had been observed (9.0 months) in comparison with the entire population (7.0 months). Patients receiving both drugs displayed a longer survival when compared with the population of patients receiving rego alone (p = 0.005) as well as the population receiving TFD/TPI alone (p < 0.001), suggesting a group enriched for favorable prognostic factors. However, when each group was analyzed separately, the addition of TFD/TPI therapy to the rego-treated group improved survival only in all-RAS WT patients (p = 0.003). Differently, the addition of rego therapy to TFD/TPI-treated patients significantly improved OS in the Codon 12 group (p = 0.0004), G12D group (p = 0.003), and the rare mutations group (p = 0.02), in addition to all-RAS WT patients (p = 0.002). The rego-TFD/TPI sequence, compared with the reverse sequence, significantly improved OS only in the KRAS codon 12 group (p = 0.003). CONCLUSIONS: Our data demonstrate that RAS mutations do not affect outcome in rego-treated patients as well as TFD/TPI-treated patients. Nevertheless, a trend toward a higher efficacy of rego in RAS-mutated (in particular codon 12, rare RAS mutations, and G12D) patients has been recorded. The rego-TFD/TPI sequence seems to be superior to the reverse sequence in patients carrying an RAS codon 12 mutation, although the impact of other factors as disease burden or performance status cannot be excluded.


Subject(s)
Colorectal Neoplasms , Phenylurea Compounds , Pyridines , Pyrrolidines , Trifluridine , Humans , Retrospective Studies , Male , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Female , Trifluridine/therapeutic use , Trifluridine/pharmacology , Pyridines/therapeutic use , Pyridines/pharmacology , Phenylurea Compounds/therapeutic use , Phenylurea Compounds/pharmacology , Pyrrolidines/therapeutic use , Pyrrolidines/pharmacology , Aged , Middle Aged , Thymine/pharmacology , Thymine/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Drug Combinations , Neoplasm Metastasis , Adult , Mutation , Aged, 80 and over , Uracil/therapeutic use , Uracil/analogs & derivatives , Uracil/pharmacology
9.
J Vector Borne Dis ; 61(1): 129-135, 2024 Jan 01.
Article in English | MEDLINE | ID: mdl-38648415

ABSTRACT

BACKGROUND OBJECTIVES: Insect growth regulators (IGRs) are biological hormone analogue or mimics used as pesticides to inhibit the growth of larva during their molting and skin shedding. This study aimed to test the effect of IGRs on the eggs hatching and post-hatching inhibition of Aedes mosquitoes and understanding its effect in the mosquito breeding habitats for reduction in adult emergence. METHODS: Experiments on the evaluation of three insect growth regulators (IGRs) for the control of different stages of Aedes aegypti was carried out during 2020-21. Each experiment consisted of four treatments viz., Pyriproxyfen, Novaluron, and Larvicol at 1.0 ppm and distilled water as a control. All experiments were carried out in completely randomized design (CRD) except eggs which were carried out in factorial design each with three replications. RESULTS: All tested IGRs performed better in affecting eggs, larval and pupal stages of Ae. aegypti. Highest eggs hatching inhibition (80%) of fresh eggs occurred in Pyriproxyfen followed by Novaluron (66%) and lowest in Larvicol (62%). Eggs hatch inhibition of embryonated eggs was lower than fresh eggs. Pyriproxyfen caused 69%, Novaluron 59% and Larvicol 39% eggs hatch inhibition of embryonated eggs. Both Pyriproxyfen and Novaluron performed better in causing 98-100% larval mortality followed by Larvicol (39%). Larval development to pupal stage was completely prevented by both Pyriproxyfen and Novaluron. Although Larvicol resulted in lowest eggs hatch and larval inhibition but prevented pupae to emerge as adults. Results further showed 70-89% mortality of 3rd instar larvae of Ae. aegypti when exposed to Pyriproxyfen and Novaluron solutions after 30 days storage at lab. temperature (27±2°C), RH 70±5. INTERPRETATION CONCLUSION: None of the IGRs was more effective at the pupal stage but showed carry-on activity of growth inhibition and mortality of the successive stages of development when used against eggs stages. Therefore, we recommend early application of IGRs at mosquito habitats during the beginning and onset of the season when very early stages of mosquitoes are available in the field.


Subject(s)
Aedes , Juvenile Hormones , Larva , Mosquito Control , Phenylurea Compounds , Pupa , Pyridines , Animals , Aedes/drug effects , Aedes/growth & development , Aedes/physiology , Juvenile Hormones/pharmacology , Larva/drug effects , Larva/growth & development , Mosquito Control/methods , Pyridines/pharmacology , Phenylurea Compounds/pharmacology , Pupa/drug effects , Pupa/growth & development , Female , Nitriles/pharmacology , Insecticides/pharmacology , Ovum/drug effects
10.
BMC Cancer ; 24(1): 525, 2024 Apr 25.
Article in English | MEDLINE | ID: mdl-38664644

ABSTRACT

BACKGROUND: Regorafenib, a multi-targeted kinase inhibitor, has been used in the treatment of Hepatocellular carcinoma (HCC). The purpose of this study is to investigate the mechanism of Regorafenib in HCC. METHODS: Regorafenib's impact on the sensitivity of HCC cells was assessed using CCK8. Differential gene expression analysis was performed by conducting mRNA sequencing after treatment with Regorafenib. The m6A methylation status of CHOP and differential expression of m6A methylation-related proteins were assessed by RIP and Western Blot. To explore the molecular mechanisms involved in the therapeutic effects of Regorafenib in HCC and the impact of METTL14 and CHOP on Regorafenib treatment, we employed shRNA/overexpression approaches to transfect METTL14 and CHOP genes, as well as conducted in vivo experiments. RESULTS: Treatment with Regorafenib led to a notable decrease in viability and proliferation of SK-Hep-1 and HCC-LM3 cells. The expression level of CHOP was upregulated after Regorafenib intervention, and CHOP underwent m6A methylation. Among the m6A methylation-related proteins, METTL14 exhibited the most significant downregulation. Mechanistic studies revealed that Regorafenib regulated the cell cycle arrest in HCC through METTL14-mediated modulation of CHOP, and the METTL14/CHOP axis affected the sensitivity of HCC to Regorafenib. In vivo, CHOP enhanced the anticancer effect of Regorafenib. CONCLUSION: The inhibition of HCC development by Regorafenib is attributed to its modulation of m6A expression of CHOP, mediated by METTL14, and the METTL14/CHOP axis enhances the sensitivity of HCC to Regorafenib. These findings provide insights into the treatment of HCC and the issue of drug resistance to Regorafenib.


Subject(s)
Adenosine/analogs & derivatives , Carcinoma, Hepatocellular , Cell Cycle Checkpoints , Liver Neoplasms , Methyltransferases , Phenylurea Compounds , Pyridines , Transcription Factor CHOP , Humans , Pyridines/pharmacology , Pyridines/therapeutic use , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/metabolism , Phenylurea Compounds/pharmacology , Phenylurea Compounds/therapeutic use , Liver Neoplasms/drug therapy , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Liver Neoplasms/metabolism , Mice , Animals , Cell Line, Tumor , Cell Cycle Checkpoints/drug effects , Methyltransferases/metabolism , Methyltransferases/genetics , Transcription Factor CHOP/metabolism , Transcription Factor CHOP/genetics , Cell Proliferation/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Drug Resistance, Neoplasm/genetics , Xenograft Model Antitumor Assays , Mice, Nude
11.
Biochem Biophys Res Commun ; 709: 149812, 2024 May 21.
Article in English | MEDLINE | ID: mdl-38564942

ABSTRACT

Colorectal cancer (CRC) is the third most common cancer globally. Regorafenib, a multi-target kinase inhibitor, has been approved for treating metastatic colorectal cancer patients who have undergone at least two prior standard anti-cancer therapies. However, regorafenib efficacy as a single agent remains suboptimal. A promising target at the crossroads of multiple signaling pathways is the Src homology 2 domain-containing protein tyrosine phosphatase (SHP2). However, a combination approach using SHP2 inhibitors (SHP099) and anti-angiogenic drugs (Regorafenib) has not been reported in current research. In this study, we conducted in vitro experiments combining SHP099 and regorafenib and established an MC-38 colon cancer allograft mouse model. Our results revealed that co-treatment with SHP099 and regorafenib significantly inhibited cell viability and altered the biological characteristics of tumor cells compared with treatment alone in vitro. Furthermore, the combination strategy demonstrated superior therapeutic efficacy compared to monotherapy with either drug. This was evidenced by reduced tumor size, decreased proliferation, increased apoptosis, normalized tumor microvasculature, and improved antitumor immune response in vivo. These findings suggest that the combination of an SHP2 inhibitor and regorafenib is a promising therapeutic approach for patients with colorectal cancer.


Subject(s)
Antineoplastic Agents , Colonic Neoplasms , Animals , Mice , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Colonic Neoplasms/drug therapy , Phenylurea Compounds/pharmacology , Phenylurea Compounds/therapeutic use , Pyridines/pharmacology , Pyridines/therapeutic use
12.
ESMO Open ; 9(4): 102943, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38492275

ABSTRACT

BACKGROUND: In the randomized phase II REGOMA trial, regorafenib showed promising activity in patients with recurrent glioblastoma. We conducted a large, multicenter, prospective, observational study to confirm the REGOMA data in a real-world setting. PATIENTS AND METHODS: The major inclusion criteria were histologically confirmed diagnosis of glioblastoma according to the World Health Organization (WHO) 2016 classification and relapse after radiotherapy with concurrent/adjuvant temozolomide treatment, good performance status [Eastern Cooperative Oncology Group performance status (ECOG PS 0-1)] and good liver function. Regorafenib was administered at the standard dose of 160 mg/day for 3 weeks on/1 week off. Brain magnetic resonance imaging was carried out within 14 days before starting regorafenib and every 8-12 weeks. The primary endpoint was overall survival (OS). The secondary endpoints were progression-free survival (PFS), objective response rate, disease control rate (DCR), safety and health-related quality of life. The Response Assessment in Neuro-Oncology (RANO) criteria were used for response evaluation and Common Terminology Criteria for Adverse Events (CTCAE) version 5 for assessment of adverse events (AEs). RESULTS: From September 2020 to October 2022, 190 patients with recurrent glioblastoma were enrolled from 30 cancer centers in Italy: their median age was 58.5 years [interquartile range (IQR) 53-67 years], 68% were male and 85 (44.7%) were in optimal clinical condition (ECOG PS 0). The number of patients taking steroids at baseline was 113 (60%); the second surgery was carried out in 39 (20.5%). O6-methylguanine-DNA methyltransferase (MGMT) was methylated in 80 patients (50.3%) and 147 (92.4%) of the patients analyzed had isocitrate dehydrogenase (IDH) wild type. The median follow-up period was 20 months (IQR 15.6-25.5 months). The median OS was 7.9 months ([95% confidence interval (CI) 6.5-9.2 months] and the median PFS was 2.6 months (95% CI 2.3-2.9 months). Radiological response was partial response and stable disease in 13 (7.3%) and 26 (14.6%) patients, respectively, with a DCR of 21.9%. The median number of regorafenib cycles per patient was 3 (IQR 2.0-4.0). Grade 3-4 drug-related adverse events were reported in 22.6% of patients. A dose reduction due to AEs was required in 36% of patients. No deaths were considered as treatment-related AEs. CONCLUSIONS: This large, real-world observational study showed similar OS with better tolerability of regorafenib in patients with relapsed glioblastoma compared with the REGOMA study.


Subject(s)
Brain Neoplasms , Glioblastoma , Neoplasm Recurrence, Local , Phenylurea Compounds , Pyridines , Humans , Glioblastoma/drug therapy , Male , Female , Middle Aged , Prospective Studies , Pyridines/therapeutic use , Pyridines/pharmacology , Aged , Phenylurea Compounds/therapeutic use , Phenylurea Compounds/pharmacology , Brain Neoplasms/drug therapy , Italy , Adult , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/pharmacology , Quality of Life , Treatment Outcome
13.
Int J Mol Sci ; 25(6)2024 Mar 15.
Article in English | MEDLINE | ID: mdl-38542308

ABSTRACT

Natural and synthetic phytohormones are widely used in agriculture. The synthetic cytokinin ethylenediurea (EDU) induces protection in plants against ozone phytotoxicity. In our study, new hybrid derivatives of EDU were synthesized and tested for phytoactivity. The germination potential (Gp), germination of seeds (G), and relative water content in leaves (RWC), characterizing the drought resistance of plants, were determined. The results of laboratory studies showed that EDU and its hybrid derivatives have a positive effect on root length, the growth and development of shoots, as well as the ability of plants to tolerate stress caused by a lack of water.


Subject(s)
Air Pollutants , Ozone , Phenylurea Compounds/pharmacology , Plants , Water
14.
Target Oncol ; 19(2): 161-173, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38466535

ABSTRACT

IMPORTANCE: Chemotherapy agents are typically initially tested in their most promising indications; however, following initial US FDA approval, new clinical trials are often initiated in less promising indications where patients experience a worse burden-benefit ratio. The current literature on the burden-benefit profile of lenvatinib in non-FDA-approved indications is lacking. OBJECTIVE: This study aimed to evaluate published clinical trials of lenvatinib in order to determine the burden-benefit profile for patients over time. EVIDENCE REVIEW: On 25 May 2023, we searched the Pubmed/MEDLINE, Embase, Cochrane CENTRAL, and ClinicalTrials.gov databases for clinical trials of lenvatinib used to treat solid cancers. Eligible articles were clinical trials, containing adult participants, published in English, and involving solid tumors. Screening and data collection took place in a masked, duplicate fashion. For each eligible study, we collected adverse event data, trial characteristics, progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). Trials were classified as positive when meeting their primary endpoint and safety, negative (not meeting either criteria), or indeterminate (lacking prespecified primary endpoint). FINDINGS: Expansion of clinical trial testing beyond lenvatinib's initial FDA indication demonstrated a consistent rise in cumulative adverse events, along with a decline in drug efficacy. Lenvatinib was tested in 16 cancer indications, receiving FDA approval in 4. A total of 5390 Grade 3-5 adverse events were experienced across 6225 clinical trial participants. Expanded indication testing further demonstrated widely variable ORR (11-69%), OS (6.2-32 months), and PFS (3.6-15.7 months) across all indications. After initial FDA approval, clinical trial results in expanded indications were less likely to meet their primary endpoints, particularly among non-randomized clinical trials. CONCLUSION AND RELEVANCE: Our paper evaluated the effectiveness of lenvatinib for its FDA-approved indications; however, expansion of clinical trials into novel indications was characterized by diminished efficacy, while patients experienced a high burden of adverse events consistent with lenvatinib's established safety profile. Furthermore, clinical trials testing in novel indications was marked by repeated phase I and II clinical trials along with a failure to progress to phase III clinical trials. Future clinical trials using lenvatinib as an intervention should carefully evaluate the potential benefits and burden patients may experience.


Subject(s)
Antineoplastic Agents , Neoplasms , Quinolines , Humans , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Neoplasms/drug therapy , Phenylurea Compounds/pharmacology , Phenylurea Compounds/therapeutic use , Quinolines/pharmacology , Quinolines/therapeutic use , Clinical Trials as Topic
15.
J Environ Sci (China) ; 142: 193-203, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38527884

ABSTRACT

Neburon is a phenylurea herbicide that is widely used worldwide, but its toxicity is poorly studied. In our previous study, we found that neburon has strong aryl hydrocarbon receptor (AhR) agonist activity, but whether it causes reproductive toxicity is not clear. In the present study, zebrafish were conducted as a model organism to evaluate whether environmental concentrations of neburon (0.1, 1 and 10 µg/L) induce reproductive disorder in males. After exposure to neburon for 150 days from embryo to adult, that the average spawning egg number in high concentration group was 106.40, which was significantly lower than 193.00 in control group. This result was mainly due to the abnormal male reproductive behavior caused by abnormal transcription of genes associated with reproductive behavior in the brain, such as secretogranin-2a. The proportions of spermatozoa in the medium and high concentration groups were 82.40% and 83.84%, respectively, which were significantly lower than 89.45% in control group. This result was mainly caused by hormonal disturbances and an increased proportion of apoptotic cells. The hormonal disruption was due to the significant changes in the transcription levels of key genes in the hypothalamus-pituitary-gonadal axis following neburon treatment. Neburon treatment also significantly activated the AhR signaling pathway, causing oxidative stress damage and eventually leading to a significant increase in apoptosis in the exposed group. Together, these data filled the currently more vacant profile of neburon toxicity and might provide information to assess the ecotoxicity of neburon on male reproduction at environmentally relevant concentrations.


Subject(s)
Water Pollutants, Chemical , Zebrafish , Animals , Male , Zebrafish/metabolism , Receptors, Aryl Hydrocarbon/metabolism , Phenylurea Compounds/pharmacology , Reproduction , Water Pollutants, Chemical/metabolism
16.
ESMO Open ; 9(4): 102386, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38507897

ABSTRACT

BACKGROUND: Immune checkpoint inhibitors (CPIs) have not been shown to be active in well-differentiated neuroendocrine tumors (NETs), with response rates <5%. Lenvatinib is a multitargeted tyrosine kinase inhibitor which binds to vascular endothelial growth factor and fibroblast growth factor receptors and has demonstrated efficacy in pancreatic and gastrointestinal NETs [44% and 16% objective radiographic response rate (ORR), respectively]. The combination of antiangiogenic and CPI therapies can be synergistic. We therefore evaluated the combination of lenvatinib and pembrolizumab in well-differentiated gastrointestinal (GI) and thoracic NETs. PATIENTS AND METHODS: A prospective, phase II trial evaluated patients with advanced GI/thoracic NETs (pancreatic NETs were excluded due to high response rate of lenvatinib monotherapy in this patient population), with evidence of progression within 8 months of study entry and at least two prior lines of systemic therapy. Patients received lenvatinib 20 mg daily and pembrolizumab 200 mg intravenously every 3 weeks until unacceptable toxicity or progression of disease. Primary endpoint was objective response rate, and an interim analysis was planned once 20 patients were enrolled. Four ORRs were required to continue enrollment. RESULTS: Twenty patients were enrolled on protocol from April 2021 to January 2022 (nine small intestine, five lung, two thymic, two unknown primary, one cecal, one presacral primaries). Two patients (10%) achieved a partial response (atypical lung and small intestinal primaries). Median progression-free survival (PFS) was 8 months (95% confidence interval 5.8-10.2 months). Twelve (60%) patients experienced probably or definitely associated grade 3 adverse events (10 hypertension). Fourteen patients (70%) required dose reductions or discontinued one of the medications. Two patients discontinued treatment before radiographic assessment. CONCLUSIONS: The combination of pembrolizumab and lenvatinib did not show sufficient response in patients with NETs to warrant continued enrollment on trial.


Subject(s)
Antibodies, Monoclonal, Humanized , Neuroendocrine Tumors , Phenylurea Compounds , Quinolines , Humans , Quinolines/therapeutic use , Quinolines/pharmacology , Male , Phenylurea Compounds/therapeutic use , Phenylurea Compounds/pharmacology , Female , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/pharmacology , Neuroendocrine Tumors/drug therapy , Middle Aged , Aged , Prospective Studies , Adult , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/pharmacology
17.
J Med Chem ; 67(6): 4463-4482, 2024 Mar 28.
Article in English | MEDLINE | ID: mdl-38471014

ABSTRACT

Sorafenib, a multiple kinase inhibitor, is widely used as a first-line treatment for hepatocellular carcinoma. However, there is a need for more effective alternatives when sorafenib proves insufficient. In this study, we aimed to design a structure that surpasses sorafenib's efficacy, leading us to synthesize sorafenib-ruthenium complexes for the first time and investigate their properties. Our results indicate that the sorafenib-ruthenium complexes exhibit superior epidermal growth factor receptor (EGFR) inhibition compared to sorafenib alone. Interestingly, among these complexes, Ru3S demonstrated high activity against various cancer cell lines including sorafenib-resistant HepG2 cells while exhibiting significantly lower cytotoxicity than sorafenib in healthy cell lines. Further evaluation of cell cycle, cell apoptosis, and antiangiogenic effects, molecular docking, and molecular dynamics studies revealed that Ru3S holds great potential as a drug candidate. Additionally, when free Ru3S was encapsulated into polymeric micelles M1, enhanced cytotoxicity on HepG2 cells was observed. Collectively, these findings position Ru3S as a promising candidate for EGFR inhibition and warrant further exploration for drug development purposes.


Subject(s)
Antineoplastic Agents , Carcinoma, Hepatocellular , Liver Neoplasms , Ruthenium , Humans , Sorafenib/pharmacology , Ruthenium/pharmacology , Molecular Docking Simulation , Liver Neoplasms/drug therapy , Phenylurea Compounds/pharmacology , Niacinamide/pharmacology , Cell Line, Tumor , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Carcinoma, Hepatocellular/drug therapy , ErbB Receptors/metabolism , Apoptosis , Drug Delivery Systems , Cell Proliferation
18.
Environ Sci Pollut Res Int ; 31(18): 26997-27013, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38503953

ABSTRACT

Ground-level ozone (O3) is the most phytotoxic secondary air pollutant in the atmosphere, severely affecting crop yields worldwide. The role of nanoparticles (NP) in the alleviation of ozone-induced yield losses in crops is not known. Therefore, in the present study, we investigated the effects of biogenicB-AgNPs on the mitigation of ozone-induced phytotoxicity in mung bean and compared its results with ethylenediurea (EDU) for the first time. Two mung bean cultivars (Vigna radiata L., Cv. SML-668 and PDM-139) were foliar sprayed with weekly applications of B-AgNPs (0 = control, 10 and 25 ppm) and EDU (0 = control, 200 and 300 ppm) until maturation phase. Morphological, physiological, enzymatic, and non-enzymatic antioxidant data were collected 30 and 60 days after germination (DAG). The mean O3 and AOT40 values (8 h day-1) during the cultivation period were approximately 52 ppb and 4.4 ppm.h, respectively. More biomass was accumulated at the vegetative phase due to the impact of B-AgNPs and EDU, and more photosynthates were transported to the reproductive phase, increasing yield. We observed that the 10 ppm B-AgNPs treatment had a more noticeable impact on yield parameters and lower Ag accumulation in seeds for both cultivars. Specifically, SML-668 cultivar treated with 10 ppm B-AgNPs (SN1) showed greater increases in seed weight plant-1 (124.97%), hundred seed weight (33.45%), and harvest index (37.53%) in comparison to control. Our findings suggest that B-AgNPs can enhance growth, biomass, yield, and seed quality, and can improve mung bean ozone tolerance. Therefore, B-AgNPs may be a promising protectant for mung bean.


Subject(s)
Metal Nanoparticles , Oxidative Stress , Ozone , Silver , Vigna , Vigna/drug effects , Metal Nanoparticles/toxicity , Oxidative Stress/drug effects , Silver/toxicity , Phenylurea Compounds/pharmacology
19.
Mol Immunol ; 169: 50-65, 2024 May.
Article in English | MEDLINE | ID: mdl-38493581

ABSTRACT

Macrophages play a crucial role in the inflammatory response following sciatic nerve injury. Studies have demonstrated that C-X-C motif chemokine (CXCL) 1 recruit macrophages by binding to C-X-C chemokine receptor (CXCR) 2 and participates in the inflammatory response of various diseases. Based on these findings, we aimed to explore the role of the CXCL1-CXCR2 axis in the repair process after peripheral nerve injury. Initially, we simulated sciatic nerve injury and observed an increased expression of CXCL1 and CXCR2 in the nerves of the injury group. Both in vivo and in vitro experiments confirmed that the heightened CXCL1 expression occurs in Schwann cells and is secreted, while the elevated CXCR2 is expressed by recruited macrophages. In addition, in vitro experiments demonstrated that the binding of CXCL1 to CXCR2 can activate the NLRP3 inflammasome and promote the production of interleukin-1 beta (IL-1ß) in macrophages. However, after mice were subjected to sciatic nerve injury, the number of macrophages and the expression of inflammatory factors in the sciatic nerve were reduced following treatment with the CXCR2 inhibitor SB225002. Simultaneously, we evaluated the sciatic nerve function index, the expression of p75 neurotrophic factor receptor (p75NTR), and myelin proteins, and all of these results were improved with the use of SB225002. Thus, our results suggest that after sciatic nerve injury, the CXCL1-CXCR2 axis mediates the inflammatory response by promoting the recruitment and activation of macrophages, which is detrimental to the repair of the injured nerves. In contrast, treatment with SB225002 promotes the repair of injured sciatic nerves.


Subject(s)
Chemokine CXCL1 , Peripheral Nerve Injuries , Receptors, Interleukin-8B , Animals , Mice , Chemokine CXCL1/metabolism , Macrophages/metabolism , Phenylurea Compounds/pharmacology , Sciatic Nerve
20.
Biol Direct ; 19(1): 15, 2024 02 23.
Article in English | MEDLINE | ID: mdl-38388961

ABSTRACT

BACKGROUND: Lenvatinib is an oral small molecule inhibitor approved for treating patients with unresectable hepatocellular carcinoma (HCC) worldwide. Increasing cell sensitivity to lenvatinib would be an effective method of improving therapeutic efficacy. METHODS: High throughput methods was used to scan the differentially expressed genes (DEGs) related to lenvatinib sensitivity in HCC cells. Gain- and loss-function experiments were used to explore the functions of these DEGs in HCC and lenvatinib sensitivity. CO-IP assay and rescue experiments were utilized to investigate the mechanism. RESULTS: We identified that RAR responder protein 1 (RARRES1), a podocyte-specific growth arrest gene, was among significantly upregulated DEGs in HCC cells following lenvatinib treatment. Functional analysis showed that ectopic RARRES1 expression decreased HCC progression in vitro and in vivo, as well as improving tumor sensitivity to lenvatinib, while RARRES1 silencing increased HCC cell proliferation and migration. Mechanistically, co-immunoprecipitation assays demonstrated that RARRES1 interacted with serine protease inhibitor Kazal-type 2 (SPINK2) in HCC cells. Further, SPINK2 overexpression suppressed HCC cell proliferation and migration, as well as increasing sensitivity to lenvatinib whereas SPINK2 knockdown promoted cell progression and decreased lenvatinib sensitivity. The mRNA and protein levels of RARRES1 and SPINK2 were low in HCC tissue samples, relative to those in normal liver tissue. CONCLUSIONS: Our findings highlighted that RARRES1 can inhibit HCC progression and regulate HCC sensitivity to lenvatinib by interacting SPINK2, representing a new tumor suppressor RARRES1/SPINK2 axis in HCC that modulates sensitivity to lenvatinib.


Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Quinolines , Humans , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/genetics , Liver Neoplasms/drug therapy , Liver Neoplasms/genetics , Serine Proteinase Inhibitors/therapeutic use , Phenylurea Compounds/pharmacology , Phenylurea Compounds/therapeutic use , Cell Line, Tumor , Membrane Proteins/metabolism
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