RESUMO
Dried toad skin (TS) and toad venom (TV) are the dried skin of the Bufo bufo gargarizans Cantor and the Bufo melanostictus Schneider, which remove the internal organs and the white secretions of the skin and retroauricular glands. Since 2005, cinobufacini preparations have been approved by the State Food and Drug Administration for use as adjuvant therapies in the treatment of various advanced cancers. Meanwhile, bufalenolides has been identified as the main component of TS/TV, exhibiting antitumor activity, inducing apoptosis of cancer cells and inhibiting cancer cell proliferation or metastasis through a variety of signaling pathways. However, clinical agents frequently face limitations such as inherent toxicity at high concentrations and insufficient tumor targeting. Additionally, the development and utilization of these active ingredients are hindered by poor water solubility, low bioavailability, and rapid clearance from the bloodstream. To address these challenges, the design of a targeted drug delivery system (TDDS) aims to enhance drug bioavailability, improve targeting within the body, increase drug efficacy, and reduce adverse reactions. This article reviews the TDDS for TS/TV, and their active components, including passive, active, and stimuli-responsive TDDS, to provide a reference for advancing their clinical development and use.
Assuntos
Venenos de Anfíbios , Bufanolídeos , Pele , Animais , Venenos de Anfíbios/química , Venenos de Anfíbios/farmacologia , Venenos de Anfíbios/farmacocinética , Humanos , Pele/efeitos dos fármacos , Pele/química , Bufanolídeos/química , Bufanolídeos/farmacologia , Bufanolídeos/farmacocinética , Bufanolídeos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Bufo bufo , Bufonidae , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Neoplasias/tratamento farmacológico , Disponibilidade BiológicaRESUMO
OBJECTIVE: To retrospectively analyse the effects of cinobufotalin capsule combined with zoledronic acid on pain symptoms and clinical efficacy of prostate cancer patients with bone metastases. METHODS: Patients with prostate cancer with bone metastasis admitted to our hospital from January 2021 to December 2022 were selected as study subjects. They were divided into the control group (treated with zoledronic acid) and the combined group (cinobufotalin capsules were added on the control group basis) according to different recorded treatment methods. The efficacies of the two groups after matching, lumbar L1-4 bone mineral density (BMD), serum calcium, serum phosphorus, visual analogue scale (VAS) score and Karnofsky performance status (KPS) score before and after treatment were compared, and adverse reactions were statistically analysed. RESULTS: A total of 102 patients were included in the study, encompassing 52 patients in the combined group and 50 patients in the control group. After 1:1 preference score matching, 64 patients were included in the two groups. No significant difference in baseline data was found between the two groups (p > 0.05). The total effective rate of the combination group was higher than that of the control group (p < 0.05). No significant differences in L1-4 bone mineral density, serum calcium and phosphorus, VAS score and KPS score were observed between the two groups prior to treatment (p > 0.05). After treatment, the L1-4 bone mineral density (BMD) and KPS score of the combined group decreased to less than those of the control group, the VAS score was lower than that of the control group, and the serum calcium and phosphorus level increased but less than that of the control group (p < 0.05). No significant difference in adverse reactions was found between the two groups (p > 0.05). CONCLUSIONS: Cinobufotalin capsule combined with zoledronic acid had ideal efficacy in the treatment of prostate cancer in patients with bone metastasis. This approach could improve their bone density and quality of life, improve their calcium and phosphorus metabolism, reduce their pain symptoms and provide increased safety. It may have an important guiding role in formulating future clinical treatment plans for patients with prostate cancer and bone metastasis.
Assuntos
Conservadores da Densidade Óssea , Neoplasias Ósseas , Bufanolídeos , Neoplasias da Próstata , Ácido Zoledrônico , Humanos , Masculino , Ácido Zoledrônico/uso terapêutico , Ácido Zoledrônico/administração & dosagem , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Neoplasias da Próstata/complicações , Estudos Retrospectivos , Idoso , Conservadores da Densidade Óssea/uso terapêutico , Conservadores da Densidade Óssea/administração & dosagem , Neoplasias Ósseas/secundário , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/complicações , Bufanolídeos/uso terapêutico , Bufanolídeos/administração & dosagem , Pessoa de Meia-Idade , Resultado do Tratamento , Cápsulas , Quimioterapia Combinada , Dor do Câncer/tratamento farmacológicoRESUMO
Purpose: Cinobufotalin injection has obvious curative effects on liver cancer patients with less toxicity and fewer side effects than other therapeutic approaches. However, the core ingredients and mechanism underlying these anti-liver cancer effects have not been fully clarified due to its complex composition. Methods: Multidimensional network analysis was used to screen the core ingredients, key targets and pathways underlying the therapeutic effects of cinobufotalin injection on liver cancer, and in vitro and in vivo experiments were performed to confirm the findings. Results: By construction of ingredient networks and integrated analysis, eight core ingredients and ten key targets were finally identified in cinobufotalin injection, and all of the core ingredients are tightly linked with the key targets, and these key targets are highly associated with the cell cycle-related pathways, supporting that both cinobufotalin injection and its core ingredients exert anti-liver cancer roles by blocking cell cycle-related pathways. Moreover, in vitro and in vivo experiments confirmed that either cinobufotalin injection or one of its core ingredients, cinobufagin, significantly inhibited cell proliferation, colony formation, cell cycle progression and xenograft tumor growth, and the key target molecules involved in the cell cycle pathway such as CDK1, CDK4, CCNB1, CHEK1 and CCNE1, exhibit consistent changes in expression after treatment with cinobufotalin injection or cinobufagin. Interestingly, some key targets CDK1, CDK4, PLK1, CHEK1, TTK were predicted to bind with multiple of core ingredients of cinobufotalin injection, and the affinity between one of the critical ingredients cinobufagin and key target CDK1 was further confirmed by SPR assay. Conclusion: Cinobufotalin injection was confirmed to includes eight core ingredients, and they play therapeutic effects in liver cancer by blocking cell cycle-related pathways, which provides important insights for the mechanism of cinobufotalin injection antagonizing liver cancer and the development of novel small molecule anti-cancer drugs.
Assuntos
Antineoplásicos , Bufanolídeos , Proliferação de Células , Neoplasias Hepáticas , Bufanolídeos/farmacologia , Bufanolídeos/química , Bufanolídeos/administração & dosagem , Humanos , Animais , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Proliferação de Células/efeitos dos fármacos , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/química , Ensaios de Seleção de Medicamentos Antitumorais , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas Experimentais/patologia , Neoplasias Hepáticas Experimentais/metabolismo , Camundongos Endogâmicos BALB C , Ciclo Celular/efeitos dos fármacos , Camundongos Nus , Relação Dose-Resposta a Droga , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Neoplasias Experimentais/metabolismo , Células Tumorais Cultivadas , Relação Estrutura-Atividade , Estrutura Molecular , InjeçõesRESUMO
Breast cancer stem cells (BCSCs) play a key role in therapeutic resistance in breast cancer treatments and disease recurrence. This study aimed to develop a combination therapy loaded with pH-sensitive liposomes to kill both BCSCs and the okbulk cancer cells using trastuzumab-sensitive and resistant human epidermal growth factor receptor 2 positive (HER2+) breast cancer cell models. The anti-BCSCs effect and cytotoxicity of all-trans retinoic acid, salinomycin, and bufalin alone or in combination with doxorubicin were compared in HER2+ cell line BT-474 and a validated trastuzumab-resistant cell line, BT-474R. The most potent anti-BCSC agent was selected and loaded into a pH-sensitive liposome system. The effects of the liposomal combination on BCSCs and bulk cancer cells were assessed. Compared with BT-474, the aldehyde dehydrogenase positive BCSC population was elevated in BT-474R (3.9 vs. 23.1%). Bufalin was the most potent agent and suppressed tumorigenesis of BCSCs by â¼50%, and showed strong synergism with doxorubicin in both BT-474 and BT-474R cell lines. The liposomal combination of bufalin and doxorubicin significantly reduced the BCSC population size by 85%, and inhibited both tumorigenesis and self-renewal, although it had little effect on the migration and invasiveness. The cytotoxicity against the bulk cancer cells was also enhanced by the liposomal combination than either formulation alone in both cell lines (p < 0.001). The liposomal bufalin and doxorubicin combination therapy may effectively target both BCSCs and bulk cancer cells for a better outcome in trastuzumab-resistant HER2+ breast cancer.
Assuntos
Neoplasias da Mama , Bufanolídeos , Doxorrubicina , Resistencia a Medicamentos Antineoplásicos , Lipossomos , Células-Tronco Neoplásicas , Trastuzumab , Humanos , Doxorrubicina/farmacologia , Doxorrubicina/administração & dosagem , Bufanolídeos/farmacologia , Bufanolídeos/administração & dosagem , Bufanolídeos/química , Células-Tronco Neoplásicas/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Lipossomos/química , Feminino , Trastuzumab/farmacologia , Trastuzumab/administração & dosagem , Linhagem Celular Tumoral , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Receptor ErbB-2/metabolismo , Sobrevivência Celular/efeitos dos fármacosRESUMO
BACKGROUND: BF211, a derivative of bufalin (BF), shows significantly improved solubility and potent antitumor efficiency compared to BF. Unfortunately, the unwanted toxicity such as cardiotoxicity caused by unspecific distribution has hindered its clinical use. METHODS: PEGylated BF211 liposomes (BF211@Lipo) were designed and optimizely prepared based on the pre-prescription research. In vitro and in vivo cardiotoxicity was evaluated. In vivo pharmacokinetics and biodistribution of BF211@Lipo were investigated. In vivo antitumor activity and toxicity were evaluated in HepG2 cell xenograft models. The rapid-release triggered by Poloxamer 188 (P188) was assessed in vitro and in vivo. RESULTS: The optimized BF211@Lipo displayed a spherical morphology with a size of (164.6 ± 10.3) nm and a high encapsulation efficiency of (93.24 ± 2.15) %. The in vivo concentration-time curves of BF211 loaded in liposomes showed a prolonged half-life in plasma and increased tumor accumulation. No obvious abnormality in electrocardiograms was observed in guinea pigs even at 9 mg/kg. Moreover, to improve the efficient release of BF211@Lipo, a surfactant-assisted rapid-release strategy was developed, and the release-promoting mechanism was revealed by the fluorescence resonance energy transfer (FRET) and fluorescence nanoparticle tracking analysis (fl-NTA) technology. Sequential injection of BF211@Lipo and P188 could ignite the "cold" liposomes locally in tumor regions, facilitating the burst release of BF211 and enhancing the therapeutic index. CONCLUSION: Our progressive efforts that begin with preparation technology and dosage regimen enable BF211 to like a drug, providing a promising nano platform to deliver the cardiac glycosides and alleviate the side effects by decreasing unspecific biodistribution.
Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Bufanolídeos/administração & dosagem , Bufanolídeos/farmacologia , Coração/efeitos dos fármacos , Tensoativos/química , Animais , Antineoplásicos/química , Antineoplásicos/toxicidade , Bufanolídeos/química , Bufanolídeos/toxicidade , Cobaias , Células Hep G2 , Humanos , Lipossomos , Nanopartículas/química , Poloxâmero/química , Solubilidade , Distribuição Tecidual , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A novel albumin polymer hybrid with a core-shell structure was designed to target delivery of bufalin, which is an antineoplastic monomer with serious cardiotoxicity. The sheath layer was composed of ursodeoxycholic acid (UA)-modified bovine serum albumin (UA-BSA), while the stable core consisted of poly n-butyl cyanoacrylate (PBCA) nanoparticles. The UA-BSA was synthetized, and the substitution degree was characterized. The physical properties of bufalin-loaded UA-modified protein-PBCA nanocomplexes (BF-uPPNCs), such as morphology, particle size, and encapsulation efficiency, were evaluated. FTIR and DSC revealed the bufalin to be in an amorphous state. Furthermore, the in vitro release study indicated a sustained release profile of BF-uPPNCs. The MTT and cellular uptake study demonstrated that BF-uPPNCs significantly improved the inhibitory effect of the bufalin accompanied with an enhanced cell uptake capacity on HepG2 cells. In addition, in vivo research demonstrated that BF-uPPNCs had a better antitumor effect coupled with improved therapeutic effect, and reduced hemolysis, vascular irritation, and cardiotoxicity. This work therefore presented a novel albumin polymer hybrid with favorable stability, efficient tumor-targeted delivery potential, and side effect reduction ability, which can be a potential vehicle for an anticancer drug.
Assuntos
Antineoplásicos/administração & dosagem , Bufanolídeos/administração & dosagem , Cardiotoxicidade/prevenção & controle , Portadores de Fármacos/química , Hemólise/efeitos dos fármacos , Polímeros/química , Animais , Antineoplásicos/farmacologia , Bufanolídeos/farmacologia , Morte Celular/efeitos dos fármacos , Células Hep G2 , Humanos , Nanopartículas/química , Neoplasias/tratamento farmacológico , Tamanho da Partícula , Soroalbumina Bovina/químicaRESUMO
BACKGROUND: Bufalin is an active component of the traditional Chinese medicine "Chan Su" and is reported to play anti-tumor roles in cancer development, but its functional mechanism is largely unclear. This study intends to explore a potential action mode of bufalin in NSCLC. MATERIALS AND METHODS: The malignant properties of NSCLC, including cell viability, proliferation, adhesion capacity, migration and invasion, were monitored by cell counting kit-8 (CCK-8), adhesion assay and transwell assay, respectively. The expression of circ_0046264 and miR-522-3p was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The expression of proliferation- and migration-related markers was examined by western blot. The putative relationship between circ_0046264 and miR-522-3p was verified by dual-luciferase reporter assay, RIP assay and RNA pull-down assay. Animal experiments in nude mice were performed to investigate the role of bufalin in vivo. RESULTS: Bufalin treatment inhibited cell viability, colony formation, cell adhesion capacity, migration and invasion in NSCLC cells. Bufalin facilitated the expression of circ_0046264, and circ_0046264 overexpression also inhibited NSCLC cell viability, colony formation, cell adhesion capacity, migration and invasion. Besides, circ_0046264 knockdown partially counteracted the effects of bufalin. Further, miR-522-3p was identified as a target of circ_0046264, and its deficiency reversed the effects of circ_0046264 knockdown to suppress malignant activities of NSCLC cells. In addition, bufalin restrained the tumor growth and development in vivo via enhancing the expression of circ_0046264. CONCLUSION: Bufalin played an anti-tumor role in NSCLC by modulating the circ_0046264/miR-522-3p pathway, which might be a potential functional mechanism of bufalin in NSCLC.
Assuntos
Antineoplásicos/administração & dosagem , Bufanolídeos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , MicroRNAs/genética , RNA Circular/genética , Células A549 , Animais , Antineoplásicos/farmacologia , Bufanolídeos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/genética , Masculino , Camundongos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Toad venom contains a large number of bufadienolides, which have a variety of pharmacological activities, including antitumor, cardiovascular, anti-inflammatory, analgesic and immunomodulatory effects. The strong antitumor effect of bufadienolides has attracted considerable attention in recent years, but the clinical application of bufadienolides is limited due to their low solubility and poor bioavailability. In order to overcome these shortcomings, many strategies have been explored, such as structural modification, solid dispersion, cyclodextrin inclusion, microemulsion and nanodrug delivery systems, etc. In this review, we have tried to summarize the pharmacological activities and structure-activity relationship of bufadienolides. Furthermore, the strategies for solubility and bioavailability enhancement of bufadienolides also are discussed. This review can provide a basis for further study on bufadienolides.
Assuntos
Bufanolídeos/química , Bufanolídeos/farmacocinética , Venenos de Anfíbios/química , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacocinética , Disponibilidade Biológica , Bufanolídeos/administração & dosagem , Sistemas de Liberação de Medicamentos , Humanos , Estrutura Molecular , Solubilidade , Relação Estrutura-AtividadeRESUMO
he resistance against antimalarial drugs represents a global challenge in the fight and control of malaria. The Brazilian biodiversity can be an important tool for research and development of new medicinal products. In this context, toxinology is a multidisciplinary approach on the development of new drugs, including the isolation, purification, and evaluation of the pharmacological activities of natural toxins. The present study aimed to evaluate the cytotoxicity, as well as the antimalarial activity in silico and in vitro of four compounds isolated from Rhinella marina venom as potential oral drug prototypes. Methods: Four compounds were challenged against 35 target proteins from P. falciparum and screened to evaluate their physicochemical properties using docking assay in Brazilian Malaria Molecular Targets (BraMMT) software and in silico assay in OCTOPUS® software. The in vitro antimalarial activity of the compounds against the 3D7 Plasmodium falciparum clones were assessed using the SYBR Green I based assay (IC50). For the cytotoxic tests, the LD50 was determined in human pulmonary fibroblast cell line using the [3(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] (MTT) assay. Results: All compounds presented a ligand-receptor interaction with ten Plasmodium falciparum-related protein targets, as well as antimalarial activity against chloroquine resistant strain (IC50 = 3.44 µM to 19.11 µM). Three of them (dehydrobufotenine, marinobufagin, and bufalin) showed adequate conditions for oral drug prototypes, with satisfactory prediction of absorption, permeability, and absence of toxicity. In the cell viability assay, only dehydrobufotenin was selective for the parasite. Conclusions: Dehydrobufotenin revealed to be a potential oral drug prototype presenting adequate antimalarial activity and absence of cytotoxicity, therefore should be subjected to further studies.(AU)
Assuntos
Bufanolídeos/administração & dosagem , Bufonidae , Biodiversidade , Malária/imunologia , Antimaláricos , Técnicas In Vitro , Simulação por ComputadorRESUMO
Anti-fibrotic therapies are of increasing interest to combat cardiac remodeling and heart failure progression. Recently, anti-fibrotic circular RNAs (circRNAs) have been identified in human and rodent cardiac tissue. In vivo (rodent) experiments proved cardiac anti-fibrotic effects of the natural compounds bufalin and lycorine by downregulating miRNA-671-5p, associated with a theoretic increase in the tissue level of circRNA CDR1as. Accordingly, we hypothesized that both anti-fibrotic drugs may inhibit focal myocardial fibrosis of the remodeled left ventricle (LV) also in a translational large animal model of heart failure (HF). Domestic pigs were repeatedly treated with subcutaneous injections of either bufalin, lycorine, or saline, (n = 5/group) between days 7-21 post acute myocardial infarction (AMI). At the 2-month follow-up, both bufalin and lycorine led to significantly reduced cardiac fibrosis. Bufalin treatment additionally led to smaller end-diastolic volumes, higher LV ejection fraction (EF), and increased expression of CDR1as of the AMI region. Elevated tissue levels of the circRNA CDR1as in the AMI region of the pig heart correlated significantly with LV and right ventricular EF, LV stroke volume, and negatively with infarct size. In conclusion, we successfully identified the circRNA CDR1as in pig hearts and show a significant association with improved LV and RV function by anti-fibrotic therapies in a translational animal model of HF.
Assuntos
Alcaloides de Amaryllidaceae/administração & dosagem , Bufanolídeos/administração & dosagem , Infarto do Miocárdio/tratamento farmacológico , Fenantridinas/administração & dosagem , RNA Circular/genética , RNA Longo não Codificante/economia , Remodelação Ventricular/efeitos dos fármacos , Alcaloides de Amaryllidaceae/farmacologia , Animais , Bufanolídeos/farmacologia , Modelos Animais de Doenças , Humanos , Injeções Subcutâneas , Masculino , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/genética , Infarto do Miocárdio/fisiopatologia , Fenantridinas/farmacologia , Volume Sistólico/efeitos dos fármacos , Suínos , Resultado do Tratamento , Regulação para Cima/efeitos dos fármacosRESUMO
BACKGROUND: The main component of cinobufacini injection is dry toad skin, which is used as adjuvant therapy for stage III/IV non-small cell lung cancer patients in long-term combination with vinorelbine and cisplatin. However, the efficacy and safety of this combination therapy remain unclear. METHODS: A systematic review and meta-analysis will be conducted following the preferred reported items for systematic review and meta-analysis guidelines. Two independent reviewers (LRL and ZLN) will carry out a comprehensive search of the PubMed, Web of Science, Cochrane Library, EMBASE, the Chinese Science and Technology Periodical Database, China National Knowledge Infrastructure, Wanfang Databases, China Biology Medicine. The last search date will be July 30, 2020. Reference list of all selected articles will independently screened to identify additional studies left out in the initial search. The Cochrane Risk of Bias Tool will be used to evaluate the risk of bias of the randomized controlled trials. Outcome index: The main efficacy indicators were based on the objective efficacy evaluation criteria of the World Health Organization antineoplastic drugs or the objective efficacy evaluation criteria of solid tumors established by RECIST. Secondary criteria Karnofsky performance scale (KPS) score, pain efficacy criteria, side effects of chemotherapy such as myelosuppression and gastrointestinal symptoms. Assessment of risk of bias and data synthesis will be conducted using Review Manager V5.3 software. RESULTS: This study will systematically evaluate the efficacy and safety of cinobufacini combined with vinorelbine and cisplatin in the treatment of stage III/IV non-small cell lung cancer. The results of this systematic review will be published in peer-reviewed scientific journals. ETHICS: The ethical approval is not required since systematic review is based on published studies. INPLASY REGISTRATION NUMBER: INPLASY202060091.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bufanolídeos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bufanolídeos/administração & dosagem , Bufanolídeos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/patologia , Cisplatino/uso terapêutico , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/efeitos adversos , Humanos , Neoplasias Pulmonares/patologia , Estadiamento de Neoplasias , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , Vinorelbina/uso terapêutico , Metanálise como AssuntoRESUMO
BACKGROUND AND OBJECTIVE: Cinobufotalin injection (CFI), a kind of Chinese medicine, has been considered as a promising complementary therapy option for advanced non-small cell lung cancer (NSCLC), but their efficacy and safety remain controversial. This study aimed to systematically evaluate the efficacy and safety of CFI and chemotherapy-combined therapy for advanced NSCLC. METHODS: Clinical trials were searched from Web of Science, Cochrane Library, PubMed, Embase, China National Knowledge Infrastructure (CNKI), Chinese Biological Medicine Database (CBM), Chinese Medical Citation Index (CMCI), Wanfang database and Chinese Scientific Journal Database (VIP). Main measurements, including therapeutic efficacy, quality of life (QoL) and adverse events, were extracted from the retrieved publications and were systematically evaluated. RESULTS: The 29 trials including 2300 advanced NSCLC patients were involved in this study. Compared with chemotherapy alone, its combination with CFI significantly prolonged the patients' 1-, 2- and 3-year overall survival rate (OS) (1-year OS, ORâ=â1.94, 95% CIâ=â1.42-2.65, Pâ<â.0001; 2-year OS, ORâ=â2.31, 95% CIâ=â1.55-3.45, Pâ<â.0001; 3-year OS, ORâ=â4.69, 95% CIâ=â1.78-12.39, Pâ=â.002) and improved patients' overall response (ORR, ORâ=â1.84, CIâ=â1.54-2.18, Pâ<â.00001), disease control rate (DCR, ORâ=â2.09, 95% CIâ=â1.68-2.60, Pâ<â.00001) and QoL (quality of life improved rate, QIR, ORâ=â2.64, 95% CIâ=â1.98-3.52, Pâ<â.00001; karnofsky performance score, KPS, ORâ=â10.97, 95% CIâ=â5.48-16.47, Pâ<â.0001). Most adverse events caused by chemotherapy were obviously alleviated (Pâ<â.05) when CFI was also applied to patients. CONCLUSION: The combination of CFI and chemotherapy is safe, and is more effective in treating NSCLC than chemotherapy alone. Therefore, CFI mediated therapy could be recommended as an adjuvant treatment method for NSCLC.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bufanolídeos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bufanolídeos/administração & dosagem , Bufanolídeos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/mortalidade , China , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/efeitos adversos , Feminino , Humanos , Avaliação de Estado de Karnofsky , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Análise de SobrevidaRESUMO
BACKGROUND: Resibufogenin is one of the main active compounds of Venenum Bufonis and exhibits diverse pharmacological activities. It is brought into focus for its potency in heart failure and cancer therapy. PURPOSE: The purpose of this study was to establish a convenient and effective method which was used to simultaneously determine the resibufogenin and its metabolites in rat plasma for further understanding the metabolic profiles of resibufogenin in vivo and pharmacokinetic study by LC-MS/MS. METHODS: The analytes were separated on a BEH C18 column with a mobile phase of water containing 0.05% formic acid and acetonitrile under gradient elution at a flow rate of 0.4â¯ml/min. Resibufogenin and its eight metabolites were quantified in positive electrospray ionization and MRM mode with transitions of m/z 385.5â349.2 for resibufogenin; m/z 513.7â145.3 for IS (internal standard); m/z 401.23â365.21, m/z 417.23â285.21 and m/z 385.24â349.21 for three main metabolites (hydroxylated-resibufogenin; dihydroxylated-resibufogenin and 3-epi-resibufogenin, respectively). RESULTS: This method was successfully validated with a good linearity over the concentration ranges of 1-200â¯ng/ml for resibufogenin and the correlation coefficients was more than 0.990. The lower limit of quantification was 1â¯ng/ml and the precision and accuracy values were less than 15%. The method was applied to study the metabolic profiles of resibufogenin in rat plasma after oral administration of 20â¯mg/kg. The results indicated that the metabolic reactions of resibufogenin were mainly hydroxylation, dihydroxylation, dehydrogenation and isomerization. Totally eleven metabolites were identified, among which eight were successfully quantified. CONCLUSION: The results could provide further research foundation for the mechanisms study of activity and toxicity in vivo and facilitate the appropriate clinical application of resibufogenin.
Assuntos
Bufanolídeos/farmacocinética , Metaboloma , Administração Oral , Animais , Bufanolídeos/administração & dosagem , Bufanolídeos/metabolismo , Cromatografia Líquida , Estabilidade de Medicamentos , Medicamentos de Ervas Chinesas , Masculino , Ratos , Ratos Wistar , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espectrometria de Massas em TandemRESUMO
Inducing angiogenesis is a hallmark of cancers that sustains tumor growth and metastasis. Neovascularization is a surprisingly early event during the multistage progression of cancer. Cinobufagin, an important bufadienolide originating from Chan Su, has been clinically used to treat cancer in China since the Tang dynasty. Here, we show that cinobufagin suppresses colorectal cancer (CRC) growth in vivo by downregulating angiogenesis. The hierarchized neovasculature is significantly decreased and the vascular network formation is disrupted in HUVEC by cinobufagin in a dose-dependent way. Endothelial apoptosis is observed by inducing reactive oxygen species (ROS) accumulation and mitochondrial dysfunction which can be neutralized by N-acetyl-l-cysteine (NAC). Expression of hypoxia-inducible factor 1α (HIF-1α) is reduced and phosphorylation of mTOR at Ser2481 and Akt at Ser473 is downregulated in HUVEC. Endothelial apoptosis is triggered by cinobufagin by stimulation of Bax and cascade activation of caspase 9 and caspase 3. Increased endothelial apoptosis rate and alterations in the HIF-1α/mTOR pathway are recapitulated in tumor-bearing mice in vivo. Further, the anti-angiogenesis function of cinobufagin is consolidated based on its pro-apoptotic effects on an EOMA-derived hemangioendothelioma model. In conclusion, cinobufagin suppresses tumor neovascularization by disrupting the endothelial mTOR/HIF-1α pathway to trigger ROS-mediated vascular endothelial cell apoptosis. Cinobufagin is a promising natural anti-angiogenetic drug that has clinical translation potential and practical application value.
Assuntos
Inibidores da Angiogênese/administração & dosagem , Bufanolídeos/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Inibidores da Angiogênese/farmacologia , Animais , Bufanolídeos/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais/irrigação sanguínea , Neoplasias Colorretais/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , Camundongos , Transplante de Neoplasias , Fosforilação , Espécies Reativas de Oxigênio/metabolismoRESUMO
In this study, we developed novel thermal and redox-responsive micelles based on the Pluronic F127 tri-block copolymer and employed these for redox-responsive intratumor release of bufalin, an anti-cancer drug. Pluronic F127 was first functionalized with carboxylate groups, and then assembled into micelles. The HOOC-F127-COOH micelles are 20⯱â¯4â¯nm in size at 37⯰C, but expand to 281⯱â¯5â¯nm when cooled to 4⯰C. This allows for the free diffusion of bufalin into the micellar cores at low temperatures, while at 37⯰C the micelles are much more compact and the drug molecules can be effectively held in their interiors. A high encapsulation efficiency and loading content were obtained via drug incorporation at 4⯰C. The drug-loaded micelles were cross-linked with cystamine, which contains a disulfide bond responsive to the local cancer microenvironment. In vitro studies showed that drug release from the cross-linked micelles was low under normal physiological conditions, but markedly accelerated upon exposure to conditions representative of the intracellular tumor environment. Confocal microscopy revealed that the cross-linked micelles gave high levels of drug release inside the cells. In vivo studies in mice showed the drug-loaded cross-linked micelles have potent anti-tumor activity, leading to high levels of apoptosis of tumor cells and significant reductions in tumor volume. The drug-loaded cross-linked micelles did not significantly influence body weight, and there was no evidence for detrimental off-target effects. These results indicate that the Pluronic-based micelles developed in this work are promising drug delivery systems for the targeted treatment of cancer.
Assuntos
Bufanolídeos/química , Poloxâmero/química , Animais , Apoptose/efeitos dos fármacos , Bufanolídeos/administração & dosagem , Linhagem Celular , Linhagem Celular Tumoral , Cistamina/química , Dissulfetos/química , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Feminino , Camundongos , Camundongos Endogâmicos ICR , Micelas , Tamanho da Partícula , Polímeros/química , Microambiente Tumoral/efeitos dos fármacosRESUMO
Cinobufagin (CBG) has been shown to have antinociceptive properties. Nevertheless, the antinociceptive effect and mechanism of CBG are still unclear. The present study was designed to investigate the antinociceptive effect of CBG in the thermal and chemical pain models and further to explore the molecular target and potential signal pathway. As shown in the hot-plate test, formalin test, and acetic acid writhing test in mice, administration of CBG produced significant antinociceptive activity in a dose-dependent manner, and the antinociceptive effect was blocked by intraperitoneal pretreatment of methyllycaconitine citrate (an α7 nicotinic receptor antagonist) and intrathecal delivery of an α7 nicotinic receptor antagonist siRNA (α7-siRNA). Immunofluorescence demonstrated that the α7 nicotinic receptor and IκB/NF-κB were coexpressed in primary cultured lumbar DRG neurons. In the chemical pain models and primary cultured DRG neurons, Western blot analysis showed that the formation of p-IκB and p-NF-κB was regulated by CBG, and the effect of CBG was inhibited by α7-siRNA, and ELISA analysis indicated that CBG also regulated the expression of inflammatory cytokines through the α7 nicotinic receptor in DRG. These results suggest that CBG may activate an α7 nicotinic receptor, thereby triggering the inhibition of the DRG NF-κB signaling pathway, resulting in an antinociceptive effect in mice.
Assuntos
Analgésicos/administração & dosagem , Bufanolídeos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Gânglios Espinais/metabolismo , NF-kappa B/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Venenos de Anfíbios/administração & dosagem , Animais , Células Cultivadas , Relação Dose-Resposta a Droga , Feminino , Gânglios Espinais/efeitos dos fármacos , Camundongos , NF-kappa B/antagonistas & inibidores , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologiaRESUMO
Resibufogenin (RB), one of the major active compounds of the traditional Chinese medicine Chansu, has received considerable attention for its potency in cancer therapy. However, the anticancer effects and the underlying mechanisms of RB on pancreatic cancer remain elusive. Here, we found that RB inhibited the viability and induces caspase-dependent apoptosis in human pancreatic cancer cells Panc-1 and Aspc. Resibufogenin-induced apoptosis was through inhibition of constitutive nuclear factor-κB (NF-κB) activity and its target genes' expression, which was caused by downregulation of transforming growth factor-ß-activated kinase 1 (TAK1) levels and suppression of IκB kinase activity in Panc-1 and Aspc cells. This induction of TAK1-mediated NF-κB inactivation by RB was associated with increased glycogen synthase kinase-3 (GSK-3) phosphorylation and subsequent suppression of its activity. Moreover, RB-induced GSK-3 phosphorylation/inactivation acted through activation of protein kinase C but not Akt. Finally, RB suppressed human pancreatic tumor xenograft growth in athymic nude mice. Thus, our findings reveal a novel mechanism by which RB suppresses TAK1-mediated NF-κB activity through protein kinase C-dependent inhibition of GSK-3. Our findings provide a rationale for the potential application of RB in pancreatic cancer therapy.
Assuntos
Bufanolídeos/administração & dosagem , Proteínas I-kappa B/metabolismo , NF-kappa B/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Bufanolídeos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , MAP Quinase Quinase Quinases/genética , MAP Quinase Quinase Quinases/metabolismo , Camundongos , Camundongos Nus , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Aim of the study was to observe and analyze the clinical effect of intravenous infusion of zoledronic acid combined with oral medication of cinobufagin in treating metastatic bone tumors. The 120 patients who have been treated in the hospital for metastatic bone tumor from June 2014 to June 2017 were selected as research objects. They were randomly divided into research group and control group, each containing 60. The research group was treated with intravenous infusion of zoledronic acid combined with oral medication of cinobufagin. In the control group, only zoledronic acid intravenous infusion was administered. The overall treatment effect of the two groups was observed. The pain of two groups was evaluated using numerical rating scale (NRS). The results showed that compared with the control group, the research group achieved better clinical effect and had a higher quality of life, and the intergroup difference was of statistical significance, P<0.05. There was no difference in rate of adverse reactions between the two groups, P>0.05, without statistical significance. The combined therapy of intravenous infusion of zoledronic acid and oral medication of cinobufagin can obtain better therapeutic effect in treating metastatic bone tumors.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Bufanolídeos/uso terapêutico , Ácido Zoledrônico/uso terapêutico , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Conservadores da Densidade Óssea/administração & dosagem , Conservadores da Densidade Óssea/efeitos adversos , Conservadores da Densidade Óssea/uso terapêutico , Neoplasias Ósseas/secundário , Bufanolídeos/administração & dosagem , Bufanolídeos/efeitos adversos , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/efeitos adversos , Medicamentos de Ervas Chinesas/uso terapêutico , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Medição da Dor/efeitos dos fármacos , Qualidade de Vida , Ácido Zoledrônico/administração & dosagem , Ácido Zoledrônico/efeitos adversosRESUMO
Sorafenib inhibits tumor growth primarily by inhibiting vessel formation, however, its efficacy requires improvement, therefore, the development of strategies which augment its antiangiogenic effect are of primary concern. Bufalin inhibits tumor cell proliferation and metastasis, and induces apoptosis. In our previous study, it was demonstrated that the antiangiogenic effect of sorafenib was improved by bufalin in human umbilical vein endothelial cells (HUVECs). However, whether bufalin synergizes with sorafenib by affecting the tumor vascular microenvironment remains to be elucidated. In the present study, it was found that hepatocellular carcinoma (HCC) cell proliferation was inhibited by either bufalin or sorafenib following incubation for 24 h, and the inhibition was enhanced upon treatment with a combination of the two. Conditioned medium (CM), comprising supernatant from HCC cells was collected from each of the treatment groups. The migration and tubule formation were suppressed the most in the combination-CM treated HUVECs. The secretion of vascular endothelial growth factor (VEGF) was decreased in HCC cells treated with the combination-CM, as determined by an angiogenesis array, enzyme-linked immunosorbent assay (ELISA) and western blot analysis. The inhibition of tube formation in HUVECs treated with the combination-CM was reversed by incubation with VEGF. The in vivo experiments demonstrated that subcutaneous HCC cell tumors from mice treated with the combination treatment expressed the lowest levels of VEGF, as evidenced by immunohistochemistry and ELISA. Additionally, the level of phosphorylated mechanistic target of rapamycin (mTOR) was reduced in HUVECs pretreated with the phosphoinositide 3-kinase inhibitor PI103. Furthermore, the migration of HCC cells and HUVEC tube formation were attenuated by PI103 pretreatment. In conclusion, the results revealed a synergistic anti-hepatoma effect of bufalin combined with sorafenib via affecting the tumor vascular microenvironment by targeting mTOR/VEGF signaling.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bufanolídeos/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Niacinamida/análogos & derivados , Compostos de Fenilureia/administração & dosagem , Serina-Treonina Quinases TOR/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Bufanolídeos/farmacologia , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular , Meios de Cultivo Condicionados/farmacologia , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/metabolismo , Camundongos , Niacinamida/administração & dosagem , Niacinamida/farmacologia , Compostos de Fenilureia/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sorafenibe , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
OBJECTIVE: To discuss and assess the clinical value of treating lung cancer cachexia with thalidomide combined with cinobufagin.s. METHODS: A cohort of 54 patients, who were diagnosed with lung carcinoma, was randomly divided into two groups, a trial group and a control group, respectively. The trial group was given 150 mg/day thalidomide and 2700 mg/day cinobufagin; the control group only received 2,700 mg/day cinobufagin. The therapy lasted for 12 weeks, and the nutritional status, quality of life, survival, and side effects in patients in the two groups were recorded. RESULTS: The nutritional status, quality of life, and survival of patients with lung cancer cachexia in the trial group were significantly improved compared to the control group. The trial group received 150 mg thalidomide, which by contrast reduced the incidence of side effect and increased tolerance. CONCLUSION: Using thalidomide combined with cinobufagin to treat patients with lung cancer cachexia will significantly improve their nutritional status and quality of life. This therapy is better than that using cinobufagin alone and is well tolerated.