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1.
Acta Pharmacol Sin ; 45(4): 857-866, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38200149

RESUMO

HER3 (human epidermal growth factor receptor 3) acts through heterodimerization with EGFR (epidermal growth factor receptor) or HER2 to play an essential role in activating phosphoinositide 3-kinase (PI3K) and AKT signaling-a crucial pathway that promotes tumor cell survival. HER3 is a promising target for cancer therapy, and several HER3-directed antibodies have already entered into clinical trials. In this study we characterized a novel anti-HER3 monoclonal antibody, SIBP-03. SIBP-03 (0.01-10 µg/mL) specifically and concentration-dependently blocked both neuregulin (NRG)-dependent and -independent HER3 activation, attenuated HER3-mediated downstream signaling and inhibited cell proliferation. This antitumor activity was dependent, at least in part, on SIBP-03-induced, cell-mediated cytotoxicity and cellular phagocytosis. Importantly, SIBP-03 enhanced the antitumor activity of EGFR- or HER2-targeted drugs (cetuximab or trastuzumab) in vitro and in vivo. The mechanisms underlying this synergy involve increased inhibition of HER3-mediated downstream signaling. Collectively, these results demonstrated that SIBP-03, which is currently undergoing a Phase I clinical trial in China, may offer a new treatment option for patients with cancers harboring activated HER3, particularly as part of a combinational therapeutic strategy.


Assuntos
Anticorpos Monoclonais , Antineoplásicos , Neoplasias , Receptor ErbB-3 , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Fosfatidilinositol 3-Quinases/metabolismo , Receptor ErbB-2/metabolismo , Receptor ErbB-3/antagonistas & inibidores , Receptor ErbB-3/metabolismo , Transdução de Sinais , Trastuzumab/farmacologia , Trastuzumab/uso terapêutico , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Neoplasias/terapia
2.
Acta Pharmacol Sin ; 44(7): 1475-1486, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-36725884

RESUMO

The KRASG12C mutant has emerged as an important therapeutic target in recent years. Covalent inhibitors have shown promising antitumor activity against KRASG12C-mutant cancers in the clinic. In this study, a structure-based and focused chemical library analysis was performed, which led to the identification of 143D as a novel, highly potent and selective KRASG12C inhibitor. The antitumor efficacy of 143D in vitro and in vivo was comparable with that of AMG510 and of MRTX849, two well-characterized KRASG12C inhibitors. At low nanomolar concentrations, 143D showed biochemical and cellular potency for inhibiting the effects of the KRASG12C mutation. 143D selectively inhibited cell proliferation and induced G1-phase cell cycle arrest and apoptosis by downregulating KRASG12C-dependent signal transduction. Compared with MRTX849, 143D exhibited a longer half-life and higher maximum concentration (Cmax) and area under the curve (AUC) values in mouse models, as determined by tissue distribution assays. Additionally, 143D crossed the blood‒brain barrier. Treatment with 143D led to the sustained inhibition of KRAS signaling and tumor regression in KRASG12C-mutant tumors. Moreover, 143D combined with EGFR/MEK/ERK signaling inhibitors showed enhanced antitumor activity both in vitro and in vivo. Taken together, our findings indicate that 143D may be a promising drug candidate with favorable pharmaceutical properties for the treatment of cancers harboring the KRASG12C mutation.


Assuntos
Proteínas Proto-Oncogênicas p21(ras) , Transdução de Sinais , Animais , Camundongos , Proteínas Proto-Oncogênicas p21(ras)/genética , Linhagem Celular Tumoral , Acetonitrilas/farmacologia , Mutação
3.
Am J Cancer Res ; 12(8): 3829-3842, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36119822

RESUMO

Inhibitors targeting the antiapoptotic molecule BCL-2 have therapeutic potential for the treatment of acute myeloid leukaemia (AML); however, BCL-2 inhibitors such as venetoclax exhibit limited monotherapy efficacy in relapsed or refractory human AML. PI3Kδ/AKT signalling has been shown to be constitutively active in AML patients. Here, we demonstrate that the combination of BCL-2 and PI3Kδ inhibitors exerts synergistic antitumour effects both in vitro and in vivo in AML. Cotreatment with venetoclax and the specific PI3Kδ inhibitor idelalisib significantly enhanced antiproliferative effects and induced caspase-dependent apoptosis in a panel of AML cell lines. The synergistic effects were mechanistically based on the inactivation of AKT/4E-BP-1 signalling and the reduction of MCL-1 expression, which diminished the binding of Bim to MCL-1. Notably, compared with the parental FLT3-ITD-positive MV-4-11, the acquired FLT3 inhibitor quizartinib-resistant xenograft model carrying the F691L mutation, exhibited a markedly higher sensitivity to venetoclax. Furthermore, venetoclax combined with idelalisib led to tumour regression in all animals in this quizartinib-resistant AML model. Thus, these data indicate that combined inhibition of BCL-2 and PI3Kδ may be a promising strategy in AML, especially for patients with FLT3-ITD and/or FLT3-TKD mutations.

4.
J Am Chem Soc ; 141(17): 6812-6816, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30998329

RESUMO

A 17-membered macrocyclolipopeptide, named dysoxylactam A (1) comprising an unprecedented branched C19 fatty acid and an l-valine, was isolated from the plants of Dysoxylum hongkongense. The challenging relative configuration of 1 was established by means of residual dipolar coupling-based NMR analysis. The absolute configuration of 1 was determined by single-crystal X-ray diffraction on its p-bromobenzoate derivative (2). Compound 1 dramatically reversed multidrug resistance in cancer cells with the fold-reversals ranging from 28.4 to 1039.7 at the noncytotoxic concentration of 10 µM. The mode-of-action study of 1 revealed that it inhibited the function of P-glycoprotein (P-gp), a key mediator in multidrug resistance.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Lipopeptídeos/farmacologia , Peptídeos Cíclicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/isolamento & purificação , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Lipopeptídeos/síntese química , Lipopeptídeos/química , Lipopeptídeos/isolamento & purificação , Meliaceae/química , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/isolamento & purificação
5.
Acta Pharmacol Sin ; 40(2): 268-278, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29777202

RESUMO

BRAF and MEK inhibitors have shown remarkable clinical efficacy in BRAF-mutant melanoma; however, most patients develop resistance, which limits the clinical benefit of these agents. In this study, we found that the human melanoma cell clones, A375-DR and A375-TR, with acquired resistance to BRAF inhibitor dabrafenib and MEK inhibitor trametinib, were cross resistant to other MAPK pathway inhibitors. In these resistant cells, phosphorylation of ribosomal protein S6 (rpS6) but not phosphorylation of ERK or p90 ribosomal S6 kinase (RSK) were unable to be inhibited by MAPK pathway inhibitors. Notably, knockdown of rpS6 in these cells effectively downregulated G1 phase-related proteins, including RB, cyclin D1, and CDK6, induced cell cycle arrest, and inhibited proliferation, suggesting that aberrant modulation of rpS6 phosphorylation contributed to the acquired resistance. Interestingly, RSK inhibitor had little effect on rpS6 phosphorylation and cell proliferation in resistant cells, whereas P70S6K inhibitor showed stronger inhibitory effects on rpS6 phosphorylation and cell proliferation in resistant cells than in parental cells. Thus regulation of rpS6 phosphorylation, which is predominantly mediated by BRAF/MEK/ERK/RSK signaling in parental cells, was switched to mTOR/P70S6K signaling in resistant cells. Furthermore, mTOR inhibitors alone overcame acquired resistance and rescued the sensitivity of the resistant cells when combined with BRAF/MEK inhibitors. Taken together, our findings indicate that RSK-independent phosphorylation of rpS6 confers resistance to MAPK pathway inhibitors in BRAF-mutant melanoma, and that mTOR inhibitor-based regimens may provide alternative strategies to overcome this acquired resistance.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteína S6 Ribossômica/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Linhagem Celular Tumoral , Humanos , Imidazóis/farmacologia , Melanoma/tratamento farmacológico , Melanoma/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Mutação , Oximas/farmacologia , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Piridonas/farmacologia , Pirimidinonas/farmacologia
6.
Acta Pharmacol Sin ; 39(6): 1048-1063, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29620050

RESUMO

Anlotinib is a new oral tyrosine kinase inhibitor; this study was designed to characterize its pharmacokinetics and disposition. Anlotinib was evaluated in rats, tumor-bearing mice, and dogs and also assessed in vitro to characterize its pharmacokinetics and disposition and drug interaction potential. Samples were analyzed by liquid chromatography/mass spectrometry. Anlotinib, having good membrane permeability, was rapidly absorbed with oral bioavailability of 28%-58% in rats and 41%-77% in dogs. Terminal half-life of anlotinib in dogs (22.8±11.0 h) was longer than that in rats (5.1±1.6 h). This difference appeared to be mainly associated with an interspecies difference in total plasma clearance (rats, 5.35±1.31 L·h-1·kg-1; dogs, 0.40±0.06 L·h-1/kg-1). Cytochrome P450-mediated metabolism was probably the major elimination pathway. Human CYP3A had the greatest metabolic capability with other human P450s playing minor roles. Anlotinib exhibited large apparent volumes of distribution in rats (27.6±3.1 L/kg) and dogs (6.6±2.5 L/kg) and was highly bound in rat (97%), dog (96%), and human plasma (93%). In human plasma, anlotinib was predominantly bound to albumin and lipoproteins, rather than to α1-acid glycoprotein or γ-globulins. Concentrations of anlotinib in various tissue homogenates of rat and in those of tumor-bearing mouse were significantly higher than the associated plasma concentrations. Anlotinib exhibited limited in vitro potency to inhibit many human P450s, UDP-glucuronosyltransferases, and transporters, except for CYP3A4 and CYP2C9 (in vitro half maximum inhibitory concentrations, <1 µmol/L). Based on early reported human pharmacokinetics, drug interaction indices were 0.16 for CYP3A4 and 0.02 for CYP2C9, suggesting that anlotinib had a low propensity to precipitate drug interactions on these enzymes. Anlotinib exhibits many pharmacokinetic characteristics similar to other tyrosine kinase inhibitors, except for terminal half-life, interactions with drug metabolizing enzymes and transporters, and plasma protein binding.


Assuntos
Indóis/administração & dosagem , Indóis/farmacocinética , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Quinolinas/administração & dosagem , Quinolinas/farmacocinética , Administração Oral , Animais , Área Sob a Curva , Disponibilidade Biológica , Células CACO-2 , Cromatografia Líquida , Neoplasias do Colo/metabolismo , Citocromo P-450 CYP2C9/metabolismo , Citocromo P-450 CYP3A/metabolismo , Cães , Interações Medicamentosas , Feminino , Células HEK293 , Meia-Vida , Xenoenxertos , Humanos , Absorção Intestinal , Masculino , Espectrometria de Massas , Taxa de Depuração Metabólica , Camundongos Endogâmicos BALB C , Camundongos Nus , Modelos Animais , Modelos Biológicos , Transplante de Neoplasias , Ligação Proteica , Ratos Sprague-Dawley , Especificidade da Espécie , Distribuição Tecidual
7.
Anticancer Drugs ; 23(7): 698-705, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22441567

RESUMO

OBJECTIVE: Lobaplatin is used to treat patients with breast cancer, small-cell lung cancer, and chronic myelogenous leukemia in China. In this study, we assessed the in-vitro and in-vivo activities of lobaplatin alone or in combination with antitubulin agents against human non-small-cell lung cancer (NSCLC). METHODS: The cytotoxicities of lobaplatin against NSCLC cells were determined by the sulforhodamine B (SRB) assay. Cell cycle analysis and apoptosis were assessed using flow cytometry, and the in-vivo antitumor activities were evaluated in human NSCLC xenografts in nude mice. RESULTS: The cytotoxicity of lobaplatin was similar to or higher than that of cisplatin and carboplatin, with a mean IC(50) of 2.5 µmol/l in a variety of NSCLC cells. In addition, lobaplatin arrested cells in the S phase and triggered apoptosis. The combination of lobaplatin with antitubulin agents yielded synergistic cytotoxic activity in vitro. In NSCLC xenografts, lobaplatin alone showed significant antitumor activity. The combination of lobaplatin with antitubulin agents, especially with paclitaxel, led to significantly enhanced activity, which was superior to that of cisplatin combined with antitubulin agents. CONCLUSION: These data demonstrate that the use of lobaplatin alone or in combination with antitubulin agents might be a rational and novel therapeutic strategy for human NSCLC and warrants further clinical investigation.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclobutanos/administração & dosagem , Ciclobutanos/farmacologia , Docetaxel , Sinergismo Farmacológico , Feminino , Humanos , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/farmacologia , Paclitaxel/administração & dosagem , Taxoides/administração & dosagem , Moduladores de Tubulina/administração & dosagem , Carga Tumoral/efeitos dos fármacos , Vimblastina/administração & dosagem , Vimblastina/análogos & derivados , Vinorelbina , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Exp Hematol ; 40(5): 386-92, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22269115

RESUMO

Preclinical in vivo assessment of the pharmacologic activity of nonpeptidyl thrombopoietin receptor (TPOR) agonists is very difficult because of the high species specificity of such agonists. In this study, we have developed a novel and simple in vivo hollow-fiber assay to preclinically evaluate TPOR agonists. The 32D-mpl cell line was generated by stable transfection of human TPOR into 32D lymphoblast cells and shown to be a specific model for nonpeptide TPOR agonists in vitro. Stably transfected 32D-mpl cells were then sealed in hollow fibers and implanted into nude mice. Cells in hollow fibers specifically responded to TPOR agonists, including thrombopoietin and eltrombopag, a nonpeptide small-molecule TPOR agonist, but not to granulocyte colony-stimulating factor or erythropoietin. Oral administration of eltrombopag stimulated 32D-mpl cell proliferation, prevented 32D-mpl cell apoptosis, and stimulated the phosphorylation of cellular signaling transducers and activators of transcription in a TPOR- and dose-dependent manner. These results indicate that the hollow-fiber assay is a specific and efficient model for rapidly evaluating the in vivo activity of small-molecule TPOR agonists.


Assuntos
Avaliação Pré-Clínica de Medicamentos/instrumentação , Receptores de Trombopoetina/agonistas , Animais , Benzoatos/farmacologia , Linhagem Celular/transplante , Ensaio de Unidades Formadoras de Colônias , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Eritropoetina/farmacologia , Feminino , Fator Estimulador de Colônias de Granulócitos/farmacologia , Humanos , Hidrazinas/farmacologia , Implantes Experimentais , Interleucina-3/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fosforilação/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Pirazóis/farmacologia , Proteínas Recombinantes de Fusão/agonistas , Proteínas Recombinantes/farmacologia , Fator de Transcrição STAT3/metabolismo , Trombopoetina/farmacologia , Transfecção
9.
Mol Cancer Ther ; 6(11): 3059-70, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18025289

RESUMO

14-Ethyl-2,5,11-trimethyl-4,13,19,20-tetraoxa-tricyclo[14.2.1.1(7,10)]eicosane-3,12-dione (MFTZ-1), a new macrolide compound isolated from Streptomyces sp. Is9131, displayed wide cytotoxicity in human tumor cell lines with an average IC(50) of 0.905 micromol/L. Notably, MFTZ-1 showed significant cytotoxicity in the three multidrug resistance cell lines with an average resistance factor of 2.08. The in vivo experiments showed that MFTZ-1 had inhibitory effects on the human ovarian carcinoma HO-8910 cell line xenotransplanted in nude mice. Further studies showed that MFTZ-1 induced DNA double-strand breaks and triggered mitochondria-dependent apoptosis in human leukemia HL-60 cells. Using a yeast genetic system, we found that topoisomerase (Topo) II rather than Topo I was the primary cellular target of MFTZ-1. Most importantly, MFTZ-1 functions as a novel nonintercalative Topo II poison via binding to ATPase of Topo II, characterized by its strong inhibition on the decatenation and relaxation of Topo II. The capacity of MFTZ-1 to stabilize Topo II-DNA covalent complexes was comparable with that of the classic Topo II poison, etoposide. Moreover, using a Topo II catalytic inhibitor aclarubicin and Topo II-deficient HL-60/MX2 cells, we further showed that MFTZ-1-triggered DNA double-strand breaks and apoptosis occurred in a Topo II-dependent manner. Together, the well-defined Topo II-poisoning function and the potent antitumor activity, with the appreciable anti-multidrug resistance action in particular, promises MFTZ-1 as a novel potential Topo II-targeted agent, which merits further research and development.


Assuntos
Actinobacteria/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Eicosanoides/isolamento & purificação , Eicosanoides/farmacologia , Macrolídeos/isolamento & purificação , Macrolídeos/farmacologia , Inibidores da Topoisomerase II , Adenosina Trifosfatases/metabolismo , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , DNA/metabolismo , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , DNA Topoisomerases Tipo I/metabolismo , Eicosanoides/química , Feminino , Humanos , Substâncias Intercalantes/farmacologia , Macrolídeos/química , Camundongos , Mitocôndrias/efeitos dos fármacos , Saccharomyces cerevisiae/citologia , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/enzimologia , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Cancer Biol Ther ; 6(4): 587-95, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17457040

RESUMO

Expression of the heparanase gene is associated with invasive, angiogenic and metastatic potential of diverse malignant tumors and cell lines. Here we used RNA interference strategies to evaluate the role of human heparanase in breast malignancy and to explore the therapeutic potential of its specific targeting. The siRNA targeting human heparanase almost completely inhibited the expression of heparanase in human breast carcinoma MDA-MB-435 cells, whereas the mismatched siRNA showed no effect. Cells transfected with heparanase siRNA expressed significantly less heparanase and profoundly reduced invasion and adhesion in vitro. In MDA-MB-435 cell xenograft model, tumors treated with siRNA were less vascularized and less metastatic than those treated with saline and the mismatched controls. The association of reduced levels of heparanase and altered tumorigenic properties in cells with anti-heparanase siRNA indicates that heparanase is important in cancer progress and has potential use as a target for anticancer drug development.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Carcinoma/tratamento farmacológico , Glucuronidase/antagonistas & inibidores , Neovascularização Patológica/tratamento farmacológico , RNA Interferente Pequeno/uso terapêutico , Animais , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/patologia , Carcinoma/irrigação sanguínea , Carcinoma/secundário , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Glucuronidase/genética , Humanos , Camundongos , Neovascularização Patológica/enzimologia , RNA Interferente Pequeno/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
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