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1.
J Pharm Pharmacol ; 2024 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-38767973

RESUMO

OBJECTIVES: GL-V9 exhibited anti-tumour effects on various types of tumours. This study aimed to verify if GL-V9 synergized with oxaliplatin in suppressing colorectal cancer (CRC) and to explore the synergistic mechanism. METHODS: The synergy effect was tested by MTT assays and the mechanism was examined by comet assay, western blotting and immunohistochemistry (IHC). Xenograft model was constructed to substantiated the synergy effect and its mechanism in vivo. RESULTS: GL-V9 was verified to enhance the DNA damage effect of oxaliplatin, so as to synergistically suppress colon cancer cells in vitro and in vivo. In HCT-116 cells, GL-V9 accelerated the degradation of Wee1 and induced the abrogation of cell cycle arrest and mis-entry into mitosis, bypassing the DNA damage response caused by oxaliplatin. Our findings suggested that GL-V9 binding to HSP90 was responsible for the degradation of Wee1 and the vulnerability of colon cancer cells to oxaliplatin. Functionally, overexpression of either HSP90 or WEE1 annulled the synergistic effect of GL-V9 and oxaliplatin. CONCLUSIONS: Collectively, our findings revealed that GL-V9 synergized with oxaliplatin to suppress CRC and displayed a promising strategy to improve the efficacy of oxaliplatin.

2.
Neoplasia ; 53: 101004, 2024 07.
Artigo em Inglês | MEDLINE | ID: mdl-38733769

RESUMO

Thioredoxin reductases are frequently overexpressed in various solid tumors as a protective mechanism against heightened oxidative stress. Inhibitors of this system, such as Auranofin, are effective in eradicating cancer cells. However, the clinical significance of thioredoxin reductase 1 (TrxR1) in lung cancer, as well as the potential for its antagonist as a treatment option, necessitated further experimental validation. In this study, we observed significant upregulation of TrxR1 specifically in non-small cell lung cancer (NSCLC), rather than small cell lung cancer. Moreover, TrxR1 expression exhibited associations with survival rate, tumor volume, and histological classification. We developed a novel TrxR1 inhibitor named LW-216 and assessed its antitumor efficacy in NSCLC. Our results revealed that LW-216 is effectively bound with intracellular TrxR1 at sites R371 and G442, facilitating TrxR1 ubiquitination and suppressing TrxR1 expression, while not affecting TrxR2 expression. Treatment of LW-216-induced DNA damage and cell apoptosis in NSCLC cells through the generation of reactive oxygen species (ROS). Importantly, supplementation with N-acetylcysteine (NAC) or ectopic TrxR1 expression reversed LW-216-induced apoptosis. Furthermore, LW-216 displayed potent tumor growth inhibition in NSCLC cell-implanted mice, reducing TrxR1 expression in xenografts. Remarkably, LW-216 exhibited superior antitumor activity compared to Auranofin in vivo. Collectively, our research provides compelling evidence supporting the potential of targeting TrxR1 by LW-216 as a promising therapeutic strategy for NSCLC.


Assuntos
Apoptose , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Espécies Reativas de Oxigênio , Tiorredoxina Redutase 1 , Ubiquitinação , Ensaios Antitumorais Modelo de Xenoenxerto , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Humanos , Tiorredoxina Redutase 1/metabolismo , Tiorredoxina Redutase 1/genética , Espécies Reativas de Oxigênio/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/tratamento farmacológico , Apoptose/efeitos dos fármacos , Animais , Camundongos , Linhagem Celular Tumoral , Proteólise , Proliferação de Células/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Modelos Animais de Doenças , Masculino , Antineoplásicos/farmacologia
3.
J Transl Med ; 22(1): 350, 2024 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-38609979

RESUMO

BACKGROUND: Olfactory dysfunction occurs frequently in Parkinson's disease (PD). In this study, we aimed to explore the potential biomarkers and underlying molecular pathways of nicotine for the treatment of olfactory dysfunction in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced PD mice. METHODS: MPTP was introduced into C57BL/6 male mice to generate a PD model. Regarding in vivo experiments, we performed behavioral tests to estimate the protective effects of nicotine in MPTP-induced PD mice. RNA sequencing and traditional molecular methods were used to identify molecules, pathways, and biological processes in the olfactory bulb of PD mouse models. Then, in vitro experiments were conducted to evaluate whether nicotine can activate the prok2R/Akt/FoxO3a signaling pathway in both HEK293T cell lines and primary olfactory neurons treated with 1-methyl-4-phenylpyridinium (MPP+). Next, prok2R overexpression (prok2R+) and knockdown (prok2R-) were introduced with lentivirus, and the Akt/FoxO3a signaling pathway was further explored. Finally, the damaging effects of MPP+ were evaluated in prok2R overexpression (prok2R+) HEK293T cell lines. RESULTS: Nicotine intervention significantly alleviated olfactory and motor dysfunctions in mice with PD. The prok2R/Akt/FoxO3a signaling pathway was activated after nicotine treatment. Consequently, apoptosis of olfactory sensory neurons was significantly reduced. Furthermore, prok2R+ and prok2R- HEK293T cell lines exhibited upregulation and downregulation of the Akt/FoxO3a signaling pathway, respectively. Additionally, prok2R+ HEK293T cells were resistant to MPP+-induced apoptosis. CONCLUSIONS: This study showed the effectiveness and underlying mechanisms of nicotine in improving hyposmia in PD mice. These improvements were correlated with reduced apoptosis of olfactory sensory neurons via activated prok2R/Akt/FoxO3a axis. These results explained the potential protective functions of nicotine in PD patients.


Assuntos
Transtornos do Olfato , Doença de Parkinson , Humanos , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células HEK293 , Nicotina/farmacologia , Doença de Parkinson/complicações , Proteínas Proto-Oncogênicas c-akt , Transtornos do Olfato/complicações , Transtornos do Olfato/tratamento farmacológico
4.
Chin Med ; 19(1): 26, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38360696

RESUMO

BACKGROUND: Immune checkpoint inhibitors, which have attracted much attention in recent years, have achieved good efficacy, but their use is limited by the high incidence of acquired drug resistance. Therefore, there is an urgent need to develop new immunotherapy drugs. Compound taxus chinensis capsule (CTC) is an oral paclitaxel compound drug, clinical results showed it can change the number of regulatory T cells and T helper cell 17 in peripheral blood. Regulating the balance between regulatory T cells and T helper cell 17 is considered to be an effective anticancer strategy. Paclitaxel and ginsenoside metabolite compound K are the main immunomodulatory components, it is not clear that paclitaxel combined with compound K can inhibit tumor development by regulating the balance between regulatory T cell and T helper cell 17. METHODS: MTT, EdU proliferation and plate colony formation assay were used to determine the concentration of paclitaxel and compound K. AnnexinV-FITC/PI staining, ELISA, Western Blot assay, Flow Cytometry and Immunofluorescence were used to investigate the effect of paclitaxel combined with compound K on Lewis cell cultured alone or co-cultured with splenic lymphocyte. Finally, transplanted tumor C57BL/6 mice model was constructed to investigate the anti-cancer effect in vivo. RESULTS: According to the results of MTT, EdU proliferation and plate colony formation assay, paclitaxel (10 nM) and compound K (60 µM) was used to explore the mechanism. The results of Flow Cytometry demonstrated that paclitaxel combined with compound K increased the number of T helper cell 17 and decreased the number of regulatory T cells, which induced pyroptosis of cancer cells. The balance was mediated by the JAK-STAT pathway according to the results of Western Blot and Immunofluorescence. Finally, the in vivo results showed that paclitaxel combined with compound K significantly inhibit the progression of lung cancer. CONCLUSIONS: In this study, we found that paclitaxel combined with compound K can activate CD8+ T cells and induce pyroptosis of tumor cells by regulating the balance between regulatory T cells and T helper cell 17. These results demonstrated that this is a feasible treatment strategy for lung cancer.

5.
Microbiol Spectr ; 11(6): e0023423, 2023 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-37800955

RESUMO

IMPORTANCE: The gut and salivary microbiomes have been widely reported to be significantly associated with a number of neurological disorders. The stability of the microbiome in the oral cavity makes it a potentially ideal sample that can be conveniently obtained for the investigation of microbiome-based pathogenesis in diseases. In the present study, we used a single-molecule long-read sequencing technique to study the distribution of the salivary microbiota in patients with pituitary adenoma (PA) and healthy individuals, as well as among four clinical phenotypes of PA. We found that the diversity of salivary microbes was more abundant in PA patients than in healthy individuals. We also observed some unique genera in different PA phenotypes. The bioinformatics-based functional predictions identified potential links between microbes and different clinical phenotypes of PA. This study improves the existing understanding of the pathogenesis of PA and may provide diagnostic and therapeutic targets for PA.


Assuntos
Microbiota , Neoplasias Hipofisárias , Humanos , Saliva , Neoplasias Hipofisárias/diagnóstico , Neoplasias Hipofisárias/genética , RNA Ribossômico 16S/genética , Fenótipo
6.
Eur J Pharmacol ; 957: 176037, 2023 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-37660969

RESUMO

Although oroxylin A, a natural flavonoid compound, suppressed progression of hepatocellular carcinoma, whether the tumor microenvironment especially the communication between cancer cells and immune cells was under its modulation remained obscure. Here we investigated the effect of extracellular vesicles from cancer cells elicited by oroxylin A on macrophages in vitro. The data shows oroxylin A elicits apoptosis-related extracellular vesicles through caspase-3-mediated activation of ROCK1in HCC cells, which regulates M1-like polarization of macrophage. Moreover, oroxylin A downregulates the population of M2-like macrophage and promotes T cells infiltration in tumor microenvironment, accompanied by suppression of HCC development and enhancement of immune checkpoint inhibitor treatment in mice model. Mechanistically, glycolytic proteins enriched in oroxylin A-elicited extracellular vesicles from HCC cells are transferred to macrophages where ROS-dependent NLRP3 inflammasome is activated, therefore contributing to anti-tumor phenotype of macrophage. Taken together, this study highlights that oroxylin A promotes metabolic shifts between tumor cells and immune cells, facilitates to inhibit tumor development, and improves immunotherapy response in HCC model.


Assuntos
Carcinoma Hepatocelular , Vesículas Extracelulares , Neoplasias Hepáticas , Animais , Camundongos , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Microambiente Tumoral
7.
J Colloid Interface Sci ; 651: 47-58, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37540929

RESUMO

Photothermal therapy (PTT) effectively suppresses tumor growth with high selectivity. Nevertheless, PTT may cause an inflammatory response that leads to tumor recurrence and treatment resistance, which are the main disadvantages of PTT. Herein, monodisperse hafnium carbide nanoparticles (HfC NPs) were successfully prepared for noninflammatory PTT of cancer. HfC NPs possessed satisfactory near-infrared (NIR) absorption, good photothermal conversion efficiency (PTCE, 36.8 %) and photothermal stability. Furthermore, holding large surface areas and intrinsic redox-active sites, HfC NPs exhibited excellent anti-inflammatory properties due to their antioxidant and superoxide dismutase (SOD) enzymatic activities. In vitro and in vivo experiments confirmed that HfC NPs converted light energy into heat energy upon NIR laser irradiation to kill cancer cells through PTT and achieved a better therapeutic effect by anti-inflammatory effects after PTT. This work highlights that multifunctional HfC NPs can be applied in noninflammatory PTT with outstanding safety and efficacy.


Assuntos
Nanopartículas , Neoplasias , Humanos , Terapia Fototérmica , Háfnio , Fototerapia , Nanopartículas/química , Neoplasias/terapia , Linhagem Celular Tumoral
8.
J Med Chem ; 66(14): 9537-9560, 2023 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-37409679

RESUMO

Aldo-keto reductase 1C3 (AKR1C3) is correlated with tumor development and chemotherapy resistance. The catalytic activity of the enzyme has been recognized as one of the important factors in inducing anthracycline (ANT) resistance in cancer cells. Inhibition of AKR1C3 activity may provide a promising approach to restore the chemosensitivity of ANT-resistant cancers. Herein, a series of biaryl-containing AKR1C3 inhibitors has been developed. The best analogue S07-1066 selectively blocked AKR1C3-mediated reduction of doxorubicin (DOX) in MCF-7 transfected cell models. Furthermore, co-treatment of S07-1066 significantly synergized DOX cytotoxicity and reversed the DOX resistance in MCF-7 cells overexpressing AKR1C3. The potential synergism of S07-1066 over DOX cytotoxicity was demonstrated in vitro and in vivo. Our findings indicate that inhibition of AKR1C3 potentially enhances the therapeutic efficacy of ANTs and even suggests that AKR1C3 inhibitors may serve as effective adjuvants to overcome AKR1C3-mediated chemotherapy resistance in cancer treatment.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Neoplasias , Humanos , Membro C3 da Família 1 de alfa-Ceto Redutase , Doxorrubicina/farmacologia , Antraciclinas , Antibióticos Antineoplásicos/farmacologia , Células MCF-7 , 3-Hidroxiesteroide Desidrogenases/farmacologia , Hidroxiprostaglandina Desidrogenases , Linhagem Celular Tumoral , Inibidores Enzimáticos/farmacologia
9.
Cancer Lett ; 566: 216240, 2023 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-37217071

RESUMO

HCC remains one of the most prevalent and deadliest cancers. Serum AFP level is a biomarker for clinical diagnosis of HCC, instead the contribution of AFP to HCC development is clearly highly complex. Here, we discussed the effect of AFP deletion in the tumorigenesis and progression of HCC. AFP deletion in HepG2 cells inhibited the cell proliferation by inactivating PI3K/AKT signaling. Surprisingly, AFP KO HepG2 cells appeared the increasing metastatic capacity and EMT phenotype, which was attributed to the activation of WNT5A/ß-catenin signal. Further studies revealed that the activating mutations of CTNNB1 was closely related with the unconventional pro-metastatic roles of AFP deletion. Consistently, the results of DEN/CCl4-induced HCC mouse model also suggested that AFP knockout suppressed the growth of HCC primary tumors, but promoted lung metastasis. Despite the discordant effect of AFP deletion in HCC progression, a drug candidate named OA showed the potent suppression of HCC tumor growth by interrupting AFP-PTEN interaction and, importantly, reduced the lung metastasis of HCC via angiogenesis suppression. Thus, this study demonstrates an unconventional effect of AFP in HCC progression, and suggests a potent candidate strategy for HCC therapy.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Neoplasias Pulmonares , Animais , Camundongos , alfa-Fetoproteínas/genética , Carcinogênese/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Neoplasias Hepáticas/patologia , Mutação , Fosfatidilinositol 3-Quinases/genética , Humanos
10.
Clin Transl Med ; 13(3): e1229, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36959764

RESUMO

BACKGROUND: T cell malignancies proliferate vigorously, are highly dependent on lysosomal function, with limited therapeutic options. Deregulation of lysosomal structure and function has been confirmed to be a key role in the treatment of hematologic malignant disease. METHODS: Cell counting kit 8 and Annexin V/PI staining were used to assess the cell viability and apoptosis rate. Flow cytometry, liquid chromatography mass spectrometry, immunofluorescence and western blot were performed to detect the effect on lysosomes. Drug affinity responsive target stability, molecular docking and cellular thermal shift assay were employed to confirm the target protein of V8 on lysosomes. A xenograft model was constructed in NOD/SCID mice to assess the effect and mechanism. RESULTS: V8, a new lysosomotropic compound, could be rapidly trapped by lysosomes and accumulation in lysosomes, contributing to lysosomal-dependent cell death by evoking lysosomal membrane permeabilization (LMP), accompanied with disrupted lysosome and autophagic flux. Mechanistically, heat shock protein 70 (HSP70) was identified as the binding target of V8 in lysosome. As a downstream effect of targeting HSP70, enzymatic activity of acid sphingomyelinase (ASM) was inhibited, which induced disturbance of lipid metabolism, instability of lysosomal membrane, and leakage of cathepsin B and D, leading to LMP-mediated cell death. In vivo study showed V8 well controlled the growth of the tumour and confirmed lysosomal cell death induced by V8. CONCLUSIONS: Collectively, this study suggests targeting lysosomal HSP70-ASM axis by V8 illustrates the great value of drug therapy for T cell malignancies and the unlimited potential of lysosomal targeting for cancer therapy.


Assuntos
Neoplasias , Esfingomielina Fosfodiesterase , Camundongos , Animais , Humanos , Esfingomielina Fosfodiesterase/metabolismo , Esfingomielina Fosfodiesterase/farmacologia , Proteínas de Choque Térmico HSP70/metabolismo , Metabolismo dos Lipídeos , Simulação de Acoplamento Molecular , Camundongos Endogâmicos NOD , Camundongos SCID , Linfócitos T/metabolismo , Morte Celular , Neoplasias/patologia , Lisossomos/metabolismo
11.
J Zhejiang Univ Sci B ; 24(2): 101-114, 2023 Feb 15.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-36751697

RESUMO

Given its state of stable proliferative inhibition, cellular senescence is primarily depicted as a critical mechanism by which organisms delay the progression of carcinogenesis. Cells undergoing senescence are often associated with the alteration of a series of specific features and functions, such as metabolic shifts, stemness induction, and microenvironment remodeling. However, recent research has revealed more complexity associated with senescence, including adverse effects on both physiological and pathological processes. How organisms evade these harmful consequences and survive has become an urgent research issue. Several therapeutic strategies targeting senescence, including senolytics, senomorphics, immunotherapy, and function restoration, have achieved initial success in certain scenarios. In this review, we describe in detail the characteristic changes associated with cellular senescence and summarize currently available countermeasures.


Assuntos
Carcinogênese , Senescência Celular , Humanos , Imunoterapia , Envelhecimento , Microambiente Tumoral
12.
Eur J Med Chem ; 247: 115013, 2023 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-36566714

RESUMO

Aldo-keto reductase 1C3 (AKR1C3) is overexpressed in multiple hormone related cancers, such as breast and prostate cancer, and is correlated with tumor development and aggressiveness. As a phase I biotransformation enzyme, AKR1C3 catalyzes the metabolic processes that lead to resistance to anthracyclines, the "gold standard" for breast cancer treatment. Novel approaches to restore the chemotherapy sensitivity of breast cancer are urgently required. Herein, we developed a new class of AKR1C3 inhibitors that demonstrated potent inhibitory activity and exquisite selectivity for closely related isoforms. The best derivative 27 (S19-1035) exhibits an IC50 value of 3.04 nM for AKR1C3 and >3289-fold selectivity over other isoforms. We determined the co-crystal structures of AKR1C3 with three of the inhibitors, providing a solid foundation for further structure-based drug optimization. Co-administration of these AKR1C3 inhibitors significantly reversed the doxorubicin (DOX) resistance in a resistant breast cancer cell line. Therefore, the novel AKR1C3 specific inhibitors developed in this work may serve as effective adjuvants to overcome DOX resistance in breast cancer treatment.


Assuntos
Neoplasias da Mama , Masculino , Humanos , Neoplasias da Mama/tratamento farmacológico , Preparações Farmacêuticas , Hidroxiprostaglandina Desidrogenases/química , Hidroxiprostaglandina Desidrogenases/metabolismo , 3-Hidroxiesteroide Desidrogenases/metabolismo , Membro C3 da Família 1 de alfa-Ceto Redutase , Antibióticos Antineoplásicos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química
13.
Nanoscale ; 14(40): 14935-14949, 2022 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-36196973

RESUMO

Glioma is characterized by highly invasive, progressive, and lethal features. In addition, conventional treatments have been poorly effective in treating glioma. To overcome this challenge, synergistic therapies combining radiotherapy (RT) with photothermal therapy (PTT) have been proposed and extensively explored as a highly feasible cancer treatment strategy. Herein, ultrasmall zirconium carbide (ZrC) nanodots were successfully synthesized with high near-infrared absorption and strong photon attenuation for synergistic PTT-RT of glioma. ZrC-PVP nanodots with an average size of approximately 4.36 nm were prepared by the liquid exfoliation method and modified with the surfactant polyvinylpyrrolidone (PVP), with a satisfactory absorption and photothermal conversion efficiency (53.4%) in the near-infrared region. Furthermore, ZrC-PVP nanodots can also act as radiosensitizers to kill residual tumor cells after mild PTT due to their excellent photon attenuating ability, thus achieving a significant synergistic therapeutic effect by combining RT and PTT. Most importantly, both in vitro and in vivo experimental results further validate the high biosafety of ZrC-PVP NDs at the injected dose. This work systematically evaluates the feasibility of ZrC-PVP NDs for glioma treatment and provides evidence of the application of zirconium-based nanomaterials in photothermal radiotherapy.


Assuntos
Glioma , Fototerapia , Humanos , Glioma/terapia , Povidona/farmacologia , Tensoativos , Zircônio/farmacologia
14.
Food Chem Toxicol ; 169: 113450, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36208653

RESUMO

Prostate cancer (PCa) cells exploit cellular metabolic reprogramming as their survival advantage, especially aberrant lipid signaling and metabolism. Although recent studies deemed that PCa tends to rely on lipid fuel in comparison with aerobic glycolysis, the relationship between lipid metabolism and cancer growth remains unknown. We demonstrated that wogonin, a naturally occurring mono-flavonoid, could induce apoptosis of PCa cells in vivo and in vitro. Mechanistically, 100 µM wogonin significantly increased the expression of proteins related to the fatty acid synthesis and accumulation as a result of stimulation of AKT phosphorylation and nuclear accumulation of sterol regulatory element-binding protein 1 (SREBP1). The wogonin-induced up-regulation of fatty acid synthase (FASN) promoted fatty acid synthesis and storage, while increased oxidation in mitochondria driven by carnitine palmitoyl-transferase 1A (CPT1A) resulted in the loss of mitochondrial membrane potential and reactive oxygen species (ROS) accumulation, ultimately inducing apoptosis in DU145 and 22Rv1 cells. In vivo, 100 mg/kg of wogonin (i.v.) significantly repressed tumor growth without any obvious toxicity in the PCa xenograft model. In short, we proved that wogonin regulated the fatty acid metabolism and induced apoptosis by activating the AKT-SREBP1-FASN signaling network in human PCa cells, and it exhibited potent anti-tumor effects both in vivo and vitro. Thus it might be a promising candidate for the development of anti-cancer drugs.


Assuntos
Antineoplásicos , Apoptose , Ácido Graxo Sintase Tipo I , Ácidos Graxos , Flavanonas , Neoplasias da Próstata , Proteína de Ligação a Elemento Regulador de Esterol 1 , Humanos , Masculino , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Ácido Graxo Sintase Tipo I/metabolismo , Ácidos Graxos/metabolismo , Flavanonas/farmacologia , Metabolismo dos Lipídeos , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Carnitina O-Acetiltransferase/metabolismo
15.
Acta Biomater ; 152: 562-574, 2022 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-36067874

RESUMO

Sonodynamic therapy (SDT) is a promising strategy for tumor treatment that satisfies all requirements of penetrating deep-seated tissues without causing additional trauma. However, the hypoxic tumor microenvironment impairs the therapeutic effect of SDT. The synergistic treatment of oxygen concentration-dependent SDT and bio-reductive therapy has been proven to be an effective approach to improve the therapeutic efficiency of SDT by exploiting tumor hypoxia. Herein, a biomimetic drug delivery system (C-TiO2/TPZ@CM) was successfully synthesized for combined SDT and hypoxia-activated chemotherapy, which was composed of tirapazamine (TPZ)-loaded C-TiO2 hollow nanoshells (HNSs) as the inner cores and cancer cell membrane (CM) as the outer shells. C-TiO2 HNSs coated with CM achieved tumor targeting via homologous binding. C-TiO2@CM as a nanocarrier loaded with TPZ in the presence of the trapping ability of CM and the special cavity structure of C-TiO2 HNSs. Moreover, C-TiO2 HNSs as sonosensitizers killed cancer cells under ultrasound (US) irradiation. Oxygen depletion during SDT induced a hypoxic environment in the tumor to activate the killing effect of co-delivered TPZ, thereby obtaining satisfactory synergistic therapeutic effects. In addition, C-TiO2@CM exhibited remarkable biocompatibility without manifest damage and toxicity to the blood and major organs of the mice. The study highlighted that C-TiO2/TPZ@CM served as a powerful biomimetic drug delivery system for effective SDT by exploiting tumor hypoxia. STATEMENT OF SIGNIFICANCE: • C-TiO2@CM achieved tumor targeting via homologous binding. • C-TiO2 hollow nanoshells could be used as a sonosensitizer and drug carrier for synergistic SDT and hypoxia-activated chemotherapy. • C-TiO2/TPZ@CM showed no obvious toxicity under the injection dose.


Assuntos
Nanoconchas , Neoplasias , Terapia por Ultrassom , Animais , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Portadores de Fármacos/metabolismo , Hipóxia , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Oxigênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Tirapazamina/metabolismo , Tirapazamina/farmacologia , Titânio
16.
ACS Infect Dis ; 8(10): 2019-2027, 2022 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-36048501

RESUMO

ATP provides energy in the biosynthesis of cellular metabolites as well as regulates protein functions through phosphorylation. Many ATP-dependent enzymes are antibacterial and anticancer targets including human kinases acted on by most of the successful drugs. In search of new chemotherapeutics for tuberculosis (TB), we screened repurposing compounds against the essential glutamine synthase (GlnA1) of Mycobacterium tuberculosis (Mtb) and identified linsitinib, a clinical-stage drug originally targeting kinase IGF1R/IR as a potent GlnA1 inhibitor. Linsitinib has direct antimycobacterial activity. Biochemical, molecular modeling, and target engagement analyses revealed the inhibition is ATP-competitive and specific in Mtb. Linsitinib also improves autophagy flux in both Mtb-infected and uninfected THP1 macrophages, as demonstrated by the decreased p-mTOR and p62 and the increased lipid-bound LC3B-II and autophagosome forming puncta. Linsitinib-mediated autophagy reduces intracellular growth of wild-type and isoniazid-resistant Mtb alone or in combination with bedaquiline. We have demonstrated that an IGF-IR/IR inhibitor can potentially be used to treat TB. Our study reinforces the concept of targeting ATP-dependent enzymes for novel anti-TB therapy.


Assuntos
Mycobacterium tuberculosis , Tuberculose , Trifosfato de Adenosina/metabolismo , Antibacterianos/metabolismo , Glutamina/metabolismo , Humanos , Imidazóis , Isoniazida , Lipídeos , Mycobacterium tuberculosis/metabolismo , Inibidores de Proteínas Quinases , Pirazinas , Receptor IGF Tipo 1/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia
17.
ACS Med Chem Lett ; 13(8): 1286-1294, 2022 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-35978698

RESUMO

As a crucial target which is overexpressed in a variety of cancers, aldo-keto reductase 1C3 (AKR1C3) confers chemotherapeutic resistance to many clinical agents. However, a limited number of AKR1C3-selective inhibitors are applied clinically, which indicates the importance of identifying active compounds. Herein, we report the discovery, synthesis, and evaluation of novel and potent AKR1C3 inhibitors with structural diversity. Molecular dynamics simulations of these active compounds provide reasonable clarification of the interpreted biological data. Moreover, we demonstrate that AKR1C3 inhibitors have the potential to be superior therapeutic agents for re-sensitizing drug-resistant cell lines to chemotherapy, especially the pan-AKR1C inhibitor S07-2010. Our study identifies new structural classes of AKR1C3 inhibitors and enriches the structural diversity, which facilitates the future rational design of inhibitors and structural optimization. Moreover, these compounds may serve as promising therapeutic adjuvants toward new therapeutics for countering drug resistance.

18.
J Neural Eng ; 19(4)2022 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-35785769

RESUMO

Objective. Accurate identification of functional cortical regions is essential in neurological resection. The central sulcus (CS) is an important landmark that delineates functional cortical regions. Median nerve stimulation (MNS) is a standard procedure to identify the position of the CS intraoperatively. In this paper, we introduce an automated procedure that uses MNS to rapidly localize the CS and create functional somatotopic maps.Approach. We recorded electrocorticographic signals from 13 patients who underwent MNS in the course of an awake craniotomy. We analyzed these signals to develop an automated procedure that determines the location of the CS and that also produces functional somatotopic maps.Main results. The comparison between our automated method and visual inspection performed by the neurosurgeon shows that our procedure has a high sensitivity (89%) in identifying the CS. Further, we found substantial concordance between the functional somatotopic maps generated by our method and passive functional mapping (92% sensitivity).Significance. Our automated MNS-based method can rapidly localize the CS and create functional somatotopic maps without imposing additional burden on the clinical procedure. With additional development and validation, our method may lead to a diagnostic tool that guides neurosurgeons and reduces postoperative morbidity in patients undergoing resective brain surgery.


Assuntos
Mapeamento Encefálico , Nervo Mediano , Mapeamento Encefálico/métodos , Córtex Cerebral , Craniotomia , Eletrocorticografia/métodos , Humanos
19.
Mil Med Res ; 9(1): 26, 2022 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-35676737

RESUMO

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor, and it is associated with poor prognosis. Its characteristics of being highly invasive and undergoing heterogeneous genetic mutation, as well as the presence of the blood-brain barrier (BBB), have reduced the efficacy of GBM treatment. The emergence of a novel therapeutic method, namely, sonodynamic therapy (SDT), provides a promising strategy for eradicating tumors via activated sonosensitizers coupled with low-intensity ultrasound. SDT can provide tumor killing effects for deep-seated tumors, such as brain tumors. However, conventional sonosensitizers cannot effectively reach the tumor region and kill additional tumor cells, especially brain tumor cells. Efforts should be made to develop a method to help therapeutic agents pass through the BBB and accumulate in brain tumors. With the development of novel multifunctional nanosensitizers and newly emerging combination strategies, the killing ability and selectivity of SDT have greatly improved and are accompanied with fewer side effects. In this review, we systematically summarize the findings of previous studies on SDT for GBM, with a focus on recent developments and promising directions for future research.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Terapia por Ultrassom , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Glioblastoma/terapia , Humanos , Terapia por Ultrassom/métodos , Ultrassonografia
20.
Oncogene ; 41(31): 3846-3858, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35773412

RESUMO

Aldo-keto reductase family 1 member C3 (AKR1C3) serves as a contributor to numerous kinds of tumors, and its expression is elevated in patients with hepatocellular carcinoma (HCC). However, the biological function of AKR1C3 in HCC remains unclear. Here we investigated the role of AKR1C3 in liver carcinogenesis using in vitro and in vivo models. We determined that AKR1C3 is frequently increased in HCC tissues with poor prognosis. Genetically manipulated cells with AKR1C3 construction were examined to highlight the pro-tumoral growth of both wild-type AKR1C3 and mutant in vitro and in vivo. We observed promising treatment effects of AKR1C3 shRNA by intratumoral injection in mice. Mechanically, we demonstrated that the transcription factor heterodimer NRF2/MAFG was able to bind directly to AKR1C3 promoter to activate its transcription. Further, AKR1C3 stabilized PARP1 by decreasing its ubiquitination, which resulted in HCC cell proliferation and low sensitivity of Cisplatin. Moreover, we discovered that the tumorigenic role of AKR1C3 was non-catalytic dependent and the NRF2/MAFG-AKR1C3-PARP1 axis might be one of the important proliferation pathways in HCC. In conclusion, blockage of AKR1C3 expression provides potential therapeutic benefits against HCC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , 3-Hidroxiesteroide Desidrogenases/genética , Membro C3 da Família 1 de alfa-Ceto Redutase/metabolismo , Animais , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Hidroxiprostaglandina Desidrogenases/genética , Neoplasias Hepáticas/genética , Fator de Transcrição MafG/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Poli(ADP-Ribose) Polimerase-1/metabolismo , Proteínas Repressoras/metabolismo
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