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1.
Eur J Pharmacol ; 977: 176697, 2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38823760

RESUMO

Gastric cancer (GC) remains a global challenge due to the lack of early detection and precision therapies. Genkwadaphnin (DD1), a natural diterpene isolated from the bud of Flos GenkWa (Thymelaeaceae), serves as a Karyopherin ß1 (KPNB1) inhibitor. In this study, we investigated the anti-tumor effect of DD1 in both cell culture and animal models. Our findings reveal that KPNB1, a protein involved in nuclear import, was highly expressed in GC tissues and associated with a poor prognosis in patients. We demonstrated that DD1, alongside the established KPNB1 inhibitor importazole (IPZ), inhibited GC cell proliferation and tumor growth by enhancing both genomic and non-genomic activity of Nur77. DD1 and IPZ reduced the interaction between KPNB1 and Nur77, resulting in Nur77 cytoplasmic accumulation and triggering mitochondrial apoptosis. The inhibitors also increased the expression of the Nur77 target apoptotic genes ATF3, RB1CC1 and PMAIP1, inducing apoptosis in GC cell. More importantly, loss of Nur77 effectively rescued the inhibitory effect of DD1 and IPZ on GC cells in both in vitro and in vivo experiments. In this study, we for the first time explored the relationship between KPNB1 and Nur77, and found KPNB1 inhibition could significantly increase the expression of Nur77. Moreover, we investigated the function of KPNB1 in GC for the first time, and the results suggested that KPNB1 could be a potential target for cancer therapy, and DD1 might be a prospective therapeutic candidate.

2.
Cell Rep Med ; 5(5): 101519, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38692271

RESUMO

Osteosarcoma (OS) is the most common malignant bone tumor with a poor prognosis. Here, we show that the nuclear receptor RORγ may serve as a potential therapeutic target in OS. OS exhibits a hyperactivated oxidative phosphorylation (OXPHOS) program, which fuels the carbon source to promote tumor progression. We found that RORγ is overexpressed in OS tumors and is linked to hyperactivated OXPHOS. RORγ induces the expression of PGC-1ß and physically interacts with it to activate the OXPHOS program by upregulating the expression of respiratory chain component genes. Inhibition of RORγ strongly inhibits OXPHOS activation, downregulates mitochondrial functions, and increases ROS production, which results in OS cell apoptosis and ferroptosis. RORγ inverse agonists strongly suppressed OS tumor growth and progression and sensitized OS tumors to chemotherapy. Taken together, our results indicate that RORγ is a critical regulator of the OXPHOS program in OS and provides an effective therapeutic strategy for this deadly disease.


Assuntos
Neoplasias Ósseas , Mitocôndrias , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares , Osteossarcoma , Fosforilação Oxidativa , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Osteossarcoma/genética , Humanos , Fosforilação Oxidativa/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Linhagem Celular Tumoral , Animais , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Neoplasias Ósseas/genética , Neoplasias Ósseas/tratamento farmacológico , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Apoptose/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Ferroptose/genética , Ferroptose/efeitos dos fármacos , Camundongos Nus , Masculino , Proliferação de Células , Proteínas de Ligação a RNA
3.
Mol Ther ; 32(3): 749-765, 2024 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-38310356

RESUMO

Approximately 80%-90% of hepatocellular carcinomas (HCC) occur in a premalignant environment of fibrosis and abnormal extracellular matrix (ECM), highlighting an essential role of ECM in the tumorigenesis and progress of HCC. However, the determinants of ECM in HCC are poorly defined. Here, we show that nuclear receptor RORγ is highly expressed and amplified in HCC tumors. RORγ functions as an essential activator of the matrisome program via directly driving the expression of major ECM genes in HCC cells. Elevated RORγ increases fibronectin-1 deposition, cell-matrix adhesion, and collagen production, creating a favorable microenvironment to boost liver cancer metastasis. Moreover, RORγ antagonists effectively inhibit tumor growth and metastasis in multiple HCC xenografts and immune-intact models, and they effectively sensitize HCC tumors to sorafenib therapy in mice. Notably, elevated RORγ expression is associated with ECM remodeling and metastasis in patients with HCC. Taken together, we identify RORγ as a key player of ECM remodeling in HCC and as an attractive therapeutic target for advanced HCC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Animais , Camundongos , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/metabolismo , Linhagem Celular Tumoral , Sorafenibe , Colágeno/metabolismo , Microambiente Tumoral
4.
Chem Biol Interact ; 382: 110618, 2023 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-37394161

RESUMO

Gastric cancer (GC) is a highly aggressive and deadly disease worldwide. Given the limitations of current treatments, it is crucial to discover more effective antitumor drugs. Here, we demonstrated that arthpyrone M (Art-M), a novel 4-hydroxy-2-pyridone alkaloid derived from the marine fungus Arthrinium arundinis, inhibited the proliferation, invasion and migration of GC both in vivo and in vitro. The underlying mechanism of Art-M in GC cells was explored by RNA-sequencing analysis, qRT-PCR and immunoblotting, which demonstrated that Art-M significantly suppressed the mTORC1 pathway by decreasing phosphorylated mTOR and p70S6K. Moreover, Art-M feedback increased the activities of AKT and ERK. Co-immunoprecipitation and immunoblotting analysis revealed that Art-M induced dissociation of Raptor from mTOR and promoted Raptor degradation, leading to the inhibition of mTORC1 activity. Art-M was identified as a novel and potent mTORC1 antagonist. Furthermore, Art-M enhanced GC cell sensitivity to apatinib, and the combination of Art-M and apatinib showed better efficacy in the treatment of GC. Taken together, these results demonstrate that Art-M is a promising candidate drug for the treatment of GC by suppressing the mTORC1 pathway.


Assuntos
Alcaloides , Antineoplásicos , Neoplasias Gástricas , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Neoplasias Gástricas/patologia , Linhagem Celular Tumoral , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Proliferação de Células , Alcaloides/farmacologia , Alcaloides/uso terapêutico , Fungos , Proteínas Proto-Oncogênicas c-akt/metabolismo
5.
Acta Pharm Sin B ; 12(4): 1871-1884, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35847493

RESUMO

Metabolic and epigenetic reprogramming play important roles in cancer therapeutic resistance. However, their interplays are poorly understood. We report here that elevated TIGAR (TP53-induced glycolysis and apoptosis regulator), an antioxidant and glucose metabolic regulator and a target of oncogenic histone methyltransferase NSD2 (nuclear receptor binding SET domain protein 2), is mainly localized in the nucleus of therapeutic resistant tumor cells where it stimulates NSD2 expression and elevates global H3K36me2 mark. Mechanistically, TIGAR directly interacts with the antioxidant master regulator NRF2 and facilitates chromatin recruitment of NRF2, H3K4me3 methylase MLL1 and elongating Pol-II to stimulate the expression of both new (NSD2) and established (NQO1/2, PRDX1 and GSTM4) targets of NRF2, independent of its enzymatic activity. Nuclear TIGAR confers cancer cell resistance to chemotherapy and hormonal therapy in vitro and in tumors through effective maintenance of redox homeostasis. In addition, nuclear accumulation of TIGAR is positively associated with NSD2 expression in clinical tumors and strongly correlated with poor survival. These findings define a nuclear TIGAR-mediated epigenetic autoregulatory loop in redox rebalance for tumor therapeutic resistance.

6.
Pharmacol Res ; 178: 106160, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35259480

RESUMO

Small cell lung cancer (SCLC) is an aggressive and exceptionally fatal disease. Unlike non- small cell lung cancer (NSCLC), no targetable genetic driver events have been identified in SCLC to date. Here, we investigate the function of RAR-related orphan receptor gamma (RORγ) and identified the anti-cancer activity of its natural inhibitor against SCLC and illustrate the underlying mechanism. We show that RORγ depletion affected cell growth both in 2-D cell proliferation and 3-D organoids formation. Natural marine product N-hydroxyapiosporamide (N-hydap) directly bound to RORγ and inhibited its transcriptional activity, leading to the blocking of transmission process of RORγ signaling. Gene expression profiling analysis revealed that N-hydap reprograms neuroendocrine fate via inhibiting RORγ activity in SCLC. Chromatin immunoprecipitation analysis showed that N-hydap strongly reduced RORγ occupancy and transcriptional activation-linked histone marks H3K27ac on the promoter and/or enhancer sites of neurogenesis markers gene including aurora kinase a (AURKA), delta like canonical Notch ligand 3 (DLL3) and tubulin beta 3 class III (TUBB3). Therapeutically, N-hydap exhibited a strong inhibitory effect on tumor growth and did not show significant toxicity in SCLC mice xenograft models. Taken together, RORγ could be an attractive target for SCLC and thus N-hydap can be a promising therapeutic drug candidate for SCLC by inhibiting the RORγ activation.


Assuntos
Produtos Biológicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Animais , Produtos Biológicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteínas de Membrana/metabolismo , Camundongos , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/patologia
7.
Cell Death Dis ; 13(2): 161, 2022 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-35184132

RESUMO

Advanced gastric cancer (GCa) remains highly lethal due to the lack of effective therapies. Identifying promising therapeutic targets and developing effective treatment against GCa are urgently needed. Through mRNA and protein analysis of GCa clinical tumor samples, we found that autophagy-related gene 4B (ATG4B) was overexpressed in GCa tumors and that its high expression was associated with patients' poor prognosis. Knockdown of ATG4B significantly inhibited GCa cell survival and tumor growth. To further probe the role of ATG4B in GCa by pharmacological means, we screened an in-house marine natural compound library against ATG4B and identified Azalomycin F4a (Am-F4a) as a novel and potent ATG4B inhibitor. Am-F4a directly bound to ATG4B with high affinity and effectively suppressed GCa cell autophagy via inhibition of ATG4B both in vitro and in vivo. Moreover, Am-F4a or ATG4B knockdown significantly suppressed tumor growth as well as GCa cell migration and invasion. Am-F4a effectively blocked the metastatic progression of primary GCa and sensitized tumors to chemotherapy. Taken together, our findings indicate that ATG4B is a potential therapeutic target against GCa and the natural product Am-F4a is a novel ATG4B inhibitor that can be further developed for the treatment of GCa.


Assuntos
Proteínas Relacionadas à Autofagia , Produtos Biológicos , Inibidores de Cisteína Proteinase , Macrolídeos , Neoplasias Gástricas , Autofagia , Proteínas Relacionadas à Autofagia/antagonistas & inibidores , Produtos Biológicos/farmacologia , Cisteína Endopeptidases/metabolismo , Inibidores de Cisteína Proteinase/farmacologia , Humanos , Macrolídeos/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética
8.
Acta Pharmacol Sin ; 43(4): 1024-1032, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34321613

RESUMO

Androgen receptor (AR) serves as a main therapeutic target for prostate cancer (PCa). However, resistance to anti-androgen therapy (SAT) inevitably occurs. Indomethacin is a nonsteroidal anti-inflammatory drug that exhibits activity against prostate cancer. Recently, we designed and synthesized a series of new indomethacin derivatives (CZ compounds) via Pd (II)-catalyzed synthesis of substituted N-benzoylindole. In this study, we evaluated the antitumor effect of these novel indomethacin derivatives in castration-resistant prostate cancer (CRPC). Upon employing CCK-8 cell viability assays and colony formation assays, we found that these derivatives had high efficacy against CRPC tumor growth in vitro. Among these derivatives, CZ-212-3 exhibited the most potent efficacy against CRPC cell survival and on apoptosis induction. Mechanistically, CZ-212-3 significantly suppressed the expression of AR target gene networks by degrading AR and its variants. Consistently, CZ-212-3 significantly inhibited tumor growth in CRPC cell line-based xenograft and PDX models in vivo. Taken together, the data show that the indomethacin derivative CZ-212-3 significantly inhibited CRPC tumor growth by degrading AR and its variants and could be a promising agent for CRPC therapy.


Assuntos
Neoplasias de Próstata Resistentes à Castração , Linhagem Celular Tumoral , Proliferação de Células , Xenoenxertos , Humanos , Indometacina/farmacologia , Indometacina/uso terapêutico , Masculino , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Receptores Androgênicos/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
9.
J Med Chem ; 64(18): 13918-13932, 2021 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-34516133

RESUMO

Human dihydroorotate dehydrogenase (hDHODH) is an attractive tumor target essential to de novo pyrimidine biosynthesis. Novel potent hDHODH inhibitors with low toxicity are urgently needed. Herein, we demonstrate the isolation of 25 ascochlorin (ASC) derivatives, including 13 new ones, from the coral-derived fungus Acremonium sclerotigenum, and several of them showed pronounced inhibitions against hDHODH and triple-negative breast cancer (TNBC) cell lines, MDA-MB-231/-468. Interestingly, we found that hDHODH is required for proliferation and survival of TNBC cells, and several ASCs significantly inhibited TNBC cell growth and induced their apoptosis via hDHODH inhibition. Furthermore, the novel and potent hDHODH inhibitors (1 and 21) efficiently suppressed tumor growth in patient-derived TNBC xenograft models without obvious body weight loss or overt toxicity in mice. Collectively, our findings offered a novel lead scaffold as the hDHODH inhibitor for further development of potent anticancer agents and a potential therapeutic strategy for TNBC.


Assuntos
Alcenos/uso terapêutico , Antineoplásicos/uso terapêutico , Di-Hidro-Orotato Desidrogenase/antagonistas & inibidores , Inibidores Enzimáticos/uso terapêutico , Fenóis/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Acremonium/química , Alcenos/química , Alcenos/isolamento & purificação , Alcenos/metabolismo , Animais , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Di-Hidro-Orotato Desidrogenase/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Inibidores Enzimáticos/metabolismo , Humanos , Masculino , Camundongos Endogâmicos NOD , Camundongos SCID , Estrutura Molecular , Fenóis/química , Fenóis/isolamento & purificação , Fenóis/metabolismo , Relação Estrutura-Atividade , Neoplasias de Mama Triplo Negativas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Mar Drugs ; 17(7)2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31284448

RESUMO

The sponge-derived fungus Penicillium sp. SCSIO41015 cultured on solid rice medium yielded twenty-one compounds (1-21), including two new alkaloids (1 and 2) and one new pyrone derivative (3). Their structures were elucidated by analysis of 1D/2D NMR data and HR-ESI-MS. Their absolute configurations were established by single-crystal X-ray diffraction analysis and comparison of the experimental with reported specific rotation values. Compound 16 exhibited selective cytotoxic activity against the human gastric cancer cells MGC803, with IC50 value of 5.19 µM. Compounds 9 and 18 showed weak antibacterial activity against Staphylococcus aureus and Acinetobacter baumannii, respectively, both with MIC values of 57 µg/mL. Furthermore, compound 16 displayed potent antibacterial activity against S. aureus with an MIC value of 3.75 µg/mL.


Assuntos
Alcaloides/química , Organismos Aquáticos/química , Fungos/química , Penicillium/química , Policetídeos/química , Poríferos/microbiologia , Células A549 , Alcaloides/farmacologia , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Testes de Sensibilidade Microbiana/métodos , Policetídeos/farmacologia , Pironas/química , Pironas/farmacologia
11.
Phytother Res ; 32(2): 251-258, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29193354

RESUMO

Decursin, the major bioactive component of Angelica gigas Nakai, exhibited neuroprotective properties. Our previous studies showed that decursin conferred neuroprotective effects in PC12 cells induced by Amyloid-ß (Aß)25-35 via antiapoptosis and antioxidant. In this study, the antiinflammatory effects of decursin against PC12 cells injury stimulated by Aß25-35 were assessed. Our results demonstrated that decursin suppressed the expression of cyclooxygenase-2 protein and prostaglandin E2 content which was stimulated by Aß25-35 in PC12 cells. Meanwhile, the nuclear translocation of nuclear factor-κB in Aß25-35 -treated PC12 cells was also inhibited by decursin. In addition, decursin suppressed phosphorylation of the two upstream pathway kinases, p38 and c-Jun N-terminal kinase. Overall, our findings indicate that decursin exerts protective effects against neuroinflammation stimulated by Aß25-35 in PC12 cells by abolishing cyclooxygenase-2 protein expression through inactivation of nuclear factor-κB via the upstream kinases including p38 and c-Jun N-terminal kinase. This work provides a new insight into the pharmacological mode of decursin and should facilitate its therapeutic application in treatment of inflammatory disorders.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Benzopiranos/química , Butiratos/química , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Células PC12/metabolismo , Fragmentos de Peptídeos/metabolismo , Animais , Fármacos Neuroprotetores/farmacologia , Ratos
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