RESUMO
The Chinese medicine formula Pien Tze Huang (PZH) has been applied to the treatment of various diseases, the reported anti-tumor mechanisms included regulation of inflammation-associated cytokine secretion and cancer growth pathways. However, the potential influence of PZH on tumor metabolism remains unclear. This study aimed to investigate the global effect of PZH on hepatocellular carcinoma (HCC) compared with the anti-tumor agent sorafenib based on tandem mass tag (TMT) label proteomic and phosphoproteomic analysis in addition to parallel reaction monitoring (PRM) verification. It was observed that PZH could inhibit tumor weight by 59-69% in different concentrations. TMT proteomic studies indicated that fructose/mannose metabolism and glucagon signaling pathway in PZH group, and arachidonic acid metabolism and PPAR signaling pathway in sorafenib group, were significantly enriched, while glycolysis/gluconeogenesis pathway was found to be enriched remarkably both in PZH and sorafenib groups in TMT phosphoproteomic study. PRM verification further indicated that both PZH and sorafenib could down-regulate phosphorylations of the glycolytic enzymes phosphofructokinases 1, fructose-bisphosphate Aldolase A, phosphoglycerate mutase 2 and lactate dehydrogenase A chain, while phosphorylations of long chain fatty acid CoA ligase in fatty acid activation and acetyl-coenzyme A synthetase in glycolysis were significantly inhibited by PZH and sorafenib, respectively. This study proposed that PZH shared a similar anti-tumor mechanism of metabolic regulation to sorafenib, but differed in the regulation of some metabolic nodes. This is the first time to uncover the relationship between the anti-tumor effect of PZH and metabolic related enzymes, which distinguished from the known mechanisms of PZH. These data provided the potential molecular basis for PZH acting as a therapeutic drug for HCC, and offered cues of manipulation on Warburg effect under the treatment of PZH.
Assuntos
Carcinoma Hepatocelular , Medicamentos de Ervas Chinesas , Neoplasias Hepáticas , Camundongos , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Fosforilação , Sorafenibe/farmacologia , Proteômica , Apoptose , Neoplasias Hepáticas/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêuticoRESUMO
This study aims to investigate the inhibitory effect of Pien Tze Huang(PZH) on enterovirus 71(EV71). To be speci-fic, chemiluminescence method was adopted to evaluate the toxicity of PZH to African green monkey kidney(Vero) cells and human rhabdomyosarcoma(RD) cells, and cytopathic effect(CPE) method to assess the inhibition on EV71-GFP reporter virus and EV71 C4 wild-type virus. The results showed that PZH had low cytotoxicity to Vero cells and RD cells, with the half-maximal cytotoxic concentration(CC_(50)) of about 0.691 3-0.879 2 mg·mL~(-1) for the two. In addition, PZH can effectively inhibit the replication of EV71 within the non-cytotoxic concentration range, and dose-dependently alleviate the cytopathic changes caused by virus infection, with the half-maximal effective concentration(EC_(50)) of 0.009 2-0.106 3 mg·mL~(-1). On the basis of the above results, the green fluorescent protein(GFP), indirect immunofluorescence assay(IFA), and median tissue culture infective dose(TCID_(50)) were employed to assess and verify the anti-EV71-GFP and anti-EV71 C4 activity of PZH. The results demonstrated that PZH can dose-dependently lower the expression of GFP by EV71-GFP and structural protein VP-1 by EV71 C4 and decrease the production of progeny infectious viruses. The EC_(50) of PZH for EV71-GFP and EV71 C4 was about 0.006 0-0.006 2 mg·mL~(-1) and 0.006 6-0.025 6 mg·mL~(-1), respectively. This study suggested that PZH may exert antiviral activity by acting on EV71 and interfering with the expression of VP-1. At the moment, there is still a lack of specific anti-EV71 drugs. This study proposed a new idea for the symptomatic treatment of EV71 infections such as hand-foot-mouth disease and verified an effective drug for the treatment of EV71 infections.
Assuntos
Medicamentos de Ervas Chinesas , Enterovirus Humano A , Doença de Mão, Pé e Boca , Animais , Chlorocebus aethiops , Medicamentos de Ervas Chinesas/farmacologia , Enterovirus Humano A/fisiologia , Células VeroRESUMO
Photothermal therapy (PTT) is a promising strategy for cancer treatment. However, the development of highly efficient photothermal agents with excellent biosafety, particularly with low liver retention, is very meaningful for clinical applications, but it is also challenging. We herein prepared a pH-sensitive nanoagent (NanoPc3) by the self-assembly of a zinc(ii) phthalocyanine substituted with hexadeca-sulphonates linked by hydrazone bonds for photoacoustic imaging and PTT. Due to the highly negative surface potential (-30.80 mV in water), NanoPc3 could effectively escape the phagocytosis of the reticuloendothelial system and be rapidly cleared from normal tissues, leading to little accumulation in the liver and excellent biosafety. The highly negatively-charged NanoPc3 changed into nearly neutral nanoparticles (NanoPc3H) under slightly acidic conditions, resulting in enhanced cellular uptake and retention time in tumor tissues. Moreover, the tumor of H22 tumor-bearing mice treated with NanoPc3 almost disappeared, suggesting an outstanding photothermal antitumor effect. NanoPc3 also hardly showed skin phototoxicity under irradiation. Its excellent antitumor effect and biosafety make NanoPc3 highly promising in clinical applications. This work will provide a new strategy for the design of tumor-targeted photothermal nanoagents with high biosafety.
Assuntos
Antineoplásicos/farmacologia , Indóis/farmacologia , Nanopartículas/química , Terapia Fototérmica , Zinco/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Concentração de Íons de Hidrogênio , Indóis/química , Isoindóis , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas Experimentais/patologia , Camundongos , Estrutura Molecular , Zinco/químicaRESUMO
A series of zinc(II) phthalocyanines (ZnPcs) mono-substituted and tetra-substituted with morpholinyl moieties and their quaternized derivatives have been synthesized and evaluated for their antifungal photodynamic activities toward Candida albicans. The α-substituted, quaternized, and mono-substituted ZnPcs are found to have higher antifungal photoactivity than ß-substituted, neutral, and tetra-substituted counterparts. The cationic α-mono-substituted ZnPc (6a) exhibits the highest photocytotoxicity. Moreover, it is more potent than axially di-substituted analogue. The different photocytotoxicities of these compounds have also been rationalized by investigating their spectroscopic and photochemical properties, aggregation trend, partition coefficients, and cellular uptake. The IC90 value of 6a against C. albicans cells is as low as 3.3 µM with a light dose of 27 J cm(-2), meaning that 6a is a promising candidate as the antifungal photosensitizer for future investigations.
Assuntos
Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Indóis/química , Indóis/farmacologia , Compostos Organometálicos/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Zinco/química , Antifúngicos/síntese química , Antifúngicos/química , Candida albicans/citologia , Relação Dose-Resposta a Droga , Isoindóis , Testes de Sensibilidade Microbiana , Estrutura Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Relação Estrutura-Atividade , Zinco/farmacologiaRESUMO
Two new tetra- or di-α-substituted zinc(II) phthalocyanines 5 and 6 have been prepared through a "side-strapped" method. In the molecules, the adjacent benzene rings of the phthalocyanine core are linked at α-position through a triethylene glycol bridge to form a hybrid aza-/oxa-crown ether. The tetra-α-substituted phthalocyanine 5 shows an eclipsed self-assembly property in CH2Cl2 and the effect on the di-α-substituted analogue 6 is significantly weakened. Furthermore, the crown ethers of these compounds can selectively complex with Fe(3+) or Cu(2+) ion in DMF, leading to formation of J-aggregated nano-assemblies, which can be disaggregated in the presence of some organic or inorganic ligands, such as triethylamine, tetramethylethylenediamine, CH3COO(-), or OH(-). In addition, both compounds are efficient singlet oxygen generators with the singlet oxygen quantum yields (Φ(Δ)) of 0.54-0.74 in DMF relative to unsubstituted zinc(II) phthalocyanine (Φ(Δ)=0.56). They exhibit photodynamic activities toward HepG2 human hepatocarcinoma cells, but the compound 6, which has more than 40-fold lower IC50 value (0.08 µM) compared to the analogue 5 (IC50=3.31 µM), shows remarkablely higher in vitro photocytotoxicity due to its significantly higher cellular uptake and singlet oxygen generation efficiency. The results suggest that these compounds can serve as promising multifunctional materials both in (opto)electronic field and photodynamic therapy.