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1.
Anticancer Res ; 41(9): 4505-4513, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475076

RESUMO

BACKGROUND: The tumor vascular microenvironment has an important role in tumor progression and metastasis. The objective of this study was to assess the significance of metastatic hepatic tumor vascular microenvironment in relation to the response to systemic fluorouracil-based chemotherapy [folinic acid/fluorouracil/oxaliplatin (FOLFOX) or folinic acid/fluorouracil/irinotecan (FOLFIRI)]. PATIENTS AND METHODS: A total of 48 consecutive patients with colorectal cancer (CRC) with hepatic metastasis were retrospectively reviewed, and factors such as metastatic tumor vascular microenvironment, chemotherapy response and hepatic resection, were analyzed. Tumor angiogenesis was microscopically evaluated by microvessel density (MVD) in sections stained immunochemically with antibody to CD34 in patients with hepatic resection. Angiogenesis in the tumor microenvironment in association with ring enhancement (RE) on computed tomography (CT) was also examined. RESULTS: Microscopic examination revealed that peripheral RE on CT of the metastatic tumor was associated with tumor angiogenesis by MVD. The overall response rate after six courses of first-line chemotherapy for liver metastasis with RE on CT was 64% (23/36), whereas the response rate for those without RE was 25% (3/12), which was significantly lower, although the survival of patients with RE-positive and RE-negative tumors did not differ significantly. CONCLUSION: Peripheral RE of metastatic hepatic tumor on CT was associated with angiogenesis in the tumor microenvironment and higher chemotherapy response.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD34/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Camptotecina/uso terapêutico , Neoplasias Colorretais/diagnóstico por imagem , Neoplasias Colorretais/metabolismo , Angiografia por Tomografia Computadorizada , Feminino , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Humanos , Leucovorina/farmacologia , Leucovorina/uso terapêutico , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/metabolismo , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/farmacologia , Compostos Organoplatínicos/uso terapêutico , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento , Microambiente Tumoral/efeitos dos fármacos
2.
Molecules ; 26(16)2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34443689

RESUMO

Effective intracerebral delivery is key for glioma treatment. However, the drug delivery system within the brain is largely limited by its own adverse physical and chemical properties, low targeting efficiency, the blood-brain barrier and the blood-brain tumor barrier. Herein, we developed a simple, safe and efficient biomimetic nanosuspension. The C6 cell membrane (CCM) was utilized to camouflaged the 10-hydroxycamptothecin nanosuspension (HCPT-NS) in order to obtain HCPT-NS/CCM. Through the use of immune escape and homotypic binding of the cancer cell membrane, HCPT-NS/CCM was able to penetrate the blood-brain barrier and target tumors. The HCPT-NS is only comprised of drugs, as well as a small amount of stabilizers that are characterized by a simple preparation method and high drug loading. Similarly, the HCPT-NS/CCM is able to achieve targeted treatment of glioma without any ligand modification, which leads it to be stable and efficient. Cellular uptake and in vivo imaging experiments demonstrated that HCPT-NS/CCM is able to effectively cross the blood-brain barrier and was concentrated at the glioma site due to the natural homing pathway. Our results reveal that the glioma cancer cell membrane is able to promote drug transport into the brain and enter the tumor via a homologous targeting mechanism.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Membrana Celular/patologia , Glioma/tratamento farmacológico , Glioma/patologia , Nanopartículas/química , Animais , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/patologia , Camptotecina/efeitos adversos , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Camptotecina/uso terapêutico , Linhagem Celular Tumoral , Endocitose/efeitos dos fármacos , Feminino , Humanos , Masculino , Camundongos Endogâmicos ICR , Nanopartículas/ultraestrutura , Ratos , Suspensões , Distribuição Tecidual/efeitos dos fármacos , Resultado do Tratamento
3.
Molecules ; 26(16)2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34443490

RESUMO

Hydroxycamptothecin (SN38) is a natural plant extract isolated from Camptotheca acuminate. It has a broad spectrum of anticancer activity through inhibition of DNA topoisomerase I, which could affect DNA synthesis and lead to DNA damage. Thus, the action of SN38 against cancers could inevitably affect endogenous levels of ribonucleotide (RNs) and deoxyribonucleotide (dRNs) that play critical roles in many biological processes, especially in DNA synthesis and repair. However, the exact impact of SN38 on RNs and dRNs is yet to be fully elucidated. In this study, we evaluated the anticancer effect and associated mechanism of SN38 in human colorectal carcinoma HCT 116 cells. As a result, SN38 could decrease the cell viability and induce DNA damage in a concentration-dependent manner. Furthermore, cell cycle arrest and intracellular nucleotide metabolism were perturbed due to DNA damage response, of which ATP, UTP, dATP, and TTP may be the critical metabolites during the whole process. Combined with the expression of deoxyribonucleoside triphosphates synthesis enzymes, our results demonstrated that the alteration and imbalance of deoxyribonucleoside triphosphates caused by SN38 was mainly due to the de novo nucleotide synthesis at 24 h, and subsequently the salvage pathways at 48 h. The unique features of SN38 suggested that it might be recommended as an effective supplementary drug with an anticancer effect.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Camptotecina/análogos & derivados , Neoplasias Colorretais/metabolismo , DNA/metabolismo , Ribonucleotídeos/metabolismo , Camptotecina/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA , Células HCT116 , Humanos , Irinotecano/farmacologia , Ribonucleosídeo Difosfato Redutase/metabolismo , Ribonucleotídeo Redutases/metabolismo
4.
Nat Commun ; 12(1): 4373, 2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34272385

RESUMO

Although homologous recombination (HR) is indicated as a high-fidelity repair mechanism, break-induced replication (BIR), a subtype of HR, is a mutagenic mechanism that leads to chromosome rearrangements. It remains poorly understood how cells suppress mutagenic BIR. Trapping of Topoisomerase 1 by camptothecin (CPT) in a cleavage complex on the DNA can be transformed into single-ended double-strand breaks (seDSBs) upon DNA replication or colliding with transcriptional machinery. Here, we demonstrate a role of Abraxas in limiting seDSBs undergoing BIR-dependent mitotic DNA synthesis. Through counteracting K63-linked ubiquitin modification, Abraxas restricts SLX4/Mus81 recruitment to CPT damage sites for cleavage and subsequent resection processed by MRE11 endonuclease, CtIP, and DNA2/BLM. Uncontrolled SLX4/MUS81 loading and excessive end resection due to Abraxas-deficiency leads to increased mitotic DNA synthesis via RAD52- and POLD3- dependent, RAD51-independent BIR and extensive chromosome aberrations. Our work implicates Abraxas/BRCA1-A complex as a critical regulator that restrains BIR for protection of genome stability.


Assuntos
Proteínas de Transporte/metabolismo , Cromatina/metabolismo , Dano ao DNA/efeitos dos fármacos , DNA Topoisomerases Tipo I/metabolismo , Proteínas de Ligação a DNA/metabolismo , Endonucleases/metabolismo , Recombinases/metabolismo , Animais , Camptotecina/farmacologia , Proteínas de Transporte/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Cromatina/genética , Quebras de DNA de Cadeia Dupla , Dano ao DNA/genética , DNA Polimerase III/metabolismo , Replicação do DNA/genética , Proteínas de Ligação a DNA/genética , Endonucleases/genética , Recombinação Homóloga , Humanos , Proteína Homóloga a MRE11/metabolismo , Camundongos , RNA Interferente Pequeno , Proteína Rad52 de Recombinação e Reparo de DNA/genética , Proteína Rad52 de Recombinação e Reparo de DNA/metabolismo , Recombinases/genética , Inibidores da Topoisomerase I/farmacologia , Ubiquitinação
5.
Int J Mol Sci ; 22(14)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34299325

RESUMO

Extramammary Paget's disease (EMPD) is a rare skin cancer arising in the apocrine gland-rich areas. Most EMPD tumors are dormant, but metastatic lesions are associated with poor outcomes owing to the lack of effective systemic therapies. Trophoblast cell surface antigen 2 (Trop2), a surface glycoprotein, has drawn attention as a potential therapeutic target for solid tumors. Sacituzumab govitecan, an antibody-drug conjugate of Trop2, has recently entered clinical use for the treatment of various solid cancers. However, little is known about the role of Trop2 in EMPD. In this study, we immunohistochemically examined Trop2 expression in 116 EMPD tissue samples and 10 normal skin tissues. In normal skin, Trop2 was expressed in the epidermal keratinocytes, inner root sheaths, and infundibulum/isthmus epithelium of hair follicles, eccrine/apocrine glands, and sebaceous glands. Most EMPD tissues exhibited homogeneous and strong Trop2 expression, and high Trop2 expression was significantly associated with worse disease-free survival (p = 0.0343). These results suggest the potential use of Trop2-targeted therapy for EMPD and improve our understanding of the skin-related adverse effects of current Trop2-targeted therapies such as sacituzumab govitecan.


Assuntos
Antígenos de Neoplasias/biossíntese , Moléculas de Adesão Celular/biossíntese , Doença de Paget Extramamária/metabolismo , Neoplasias Cutâneas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/farmacologia , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Glândulas Apócrinas/metabolismo , Biomarcadores Tumorais , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Feminino , Expressão Gênica/genética , Regulação da Expressão Gênica/genética , Folículo Piloso/metabolismo , Humanos , Imunoconjugados/farmacologia , Queratinócitos/metabolismo , Masculino , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Doença de Paget Extramamária/tratamento farmacológico , Doença de Paget Extramamária/genética , Doença de Paget Extramamária/patologia , Glândulas Sebáceas/metabolismo , Pele/metabolismo , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia
6.
Colloids Surf B Biointerfaces ; 206: 111966, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34293577

RESUMO

The release and biodistribution of drugs in the body have an important impact on tumor diagnosis and treatment. Near-infrared (NIR) fluorescent active fluorophores with good photostability are used to detect drug release and perform in vivo imaging. Here, we developed a glutathione-responsive NIR prodrug POEGMA-b-P(CPT-CyOH) (PCC) for effective cancer diagnosis and treatment, whereby the camptothecin (CPT) and NIR fluorophore CyOH in PCC are connected by disulfide bonds. In vitro experiments confirmed that PCC was quickly taken up by cells. The high concentration of tumor intracellular glutathione caused the cleavage of the PCC disulfide bonds, leading to the release of the chemotherapeutic drug CPT, indicating that PCC can promote apoptosis. Moreover, owing to the fluorescent properties of CyOH, PCC was successfully used for in vivo imaging to observe the drug penetration and enrichment capabilities in tumors. Finally, PCC successfully inhibited tumor growth, indicating that the prodrug has a good anti-tumor effect. This work provides new strategies for chemical drug delivery and precise cancer treatment.


Assuntos
Nanopartículas , Neoplasias , Pró-Fármacos , Animais , Camptotecina/farmacologia , Linhagem Celular Tumoral , Feminino , Citometria de Fluxo , Glutationa/metabolismo , Células HeLa , Humanos , Camundongos Endogâmicos BALB C , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Imagem Óptica , Pró-Fármacos/farmacologia , Distribuição Tecidual
7.
Nano Lett ; 21(13): 5730-5737, 2021 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-34142834

RESUMO

Mitochondrion-targeting therapy exhibits great potential in cancer therapy but significantly suffers from limited therapeutic efficiency. Here we report on mitochondrion-targeting supramolecular antagonist-inducing tumor cell death via simultaneously promoting cellular apoptosis and preventing survival. The supramolecular antagonist was created via coassembly of a mitochondrion-targeting pentapeptide with its two derivatives functionalized with a BH3 domain or the drug camptothecin (CPT). While drug CPT released from the antagonist induced cellular apoptosis via decreasing the mitochondrial membrane potential, the BH3 domain prevented cellular survival through facilitating the association between the supramolecular antagonists and antiapoptotic proteins, thereby initiating mitochondrial permeabilization. Both in vitro and in vivo studies confirmed the combinatorial therapeutic effect arising from the BH3 domain and CPT drug within the supramolecular antagonist on cell death and thereby inhibiting tumor growth. Our findings demonstrate an efficient combinatorial mechanism for mitochondrial dysfunction, thus potentially serving as novel organelle-targeting medicines.


Assuntos
Apoptose , Camptotecina , Camptotecina/farmacologia , Mitocôndrias
8.
Eur J Med Chem ; 223: 113639, 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34175539

RESUMO

Nature represents a rich source of compounds used for the treatment of many diseases. Camptothecin (CPT), isolated from the bark of Camptotheca acuminata, is a cytotoxic alkaloid that attenuates cancer cell replication by inhibiting DNA topoisomerase 1. Despite its promising and wide spectrum antiproliferative activity, its use is limited due to low solubility, instability, acquired tumour cell resistance, and remarkable toxicity. This has led to the development of numerous CPT analogues with improved pharmacodynamic and pharmacokinetic profiles. Three natural product-inspired drugs, namely, topotecan, irinotecan, and belotecan, are clinically approved and prescribed drugs for the treatment of several types of cancer, whereas other derivatives are in clinical trials. In this review, which covers literature from 2015 to 2020, we aim to provide a comprehensive overview and describe efforts that led to the development of a variety of CPT analogues. These efforts have led to the discovery of potent, first-in-class chemotherapeutic agents inspired by CPT. In addition, the mechanism of action, SAR studies, and recent advances of novel CPT drug delivery systems and antibody drug conjugates are discussed.


Assuntos
Antineoplásicos Fitogênicos/química , Camptotecina/análogos & derivados , Antineoplásicos Fitogênicos/metabolismo , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Camptotheca/química , Camptotheca/metabolismo , Camptotecina/metabolismo , Camptotecina/farmacologia , Camptotecina/uso terapêutico , Sobrevivência Celular/efeitos dos fármacos , Portadores de Fármacos/química , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Relação Estrutura-Atividade , Inibidores da Topoisomerase I/química , Inibidores da Topoisomerase I/metabolismo , Inibidores da Topoisomerase I/farmacologia , Inibidores da Topoisomerase I/uso terapêutico , Organização Mundial da Saúde
9.
Cell Chem Biol ; 28(6): 743-745, 2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-34143956

RESUMO

Topoisomerase I is the target for a number of widely prescribed anticancer drugs that are based on camptothecin. In this issue of Cell Chemical Biology, Flor et al. (2020) demonstrate that the cellular response to camptothecin is mediated by lipid-derived electrophiles that are generated as a result of drug-induced oxidative stress.


Assuntos
DNA Topoisomerases Tipo I , Venenos , Camptotecina/farmacologia , DNA Topoisomerases Tipo I/metabolismo , Inibidores da Topoisomerase I
10.
Int J Mol Sci ; 22(9)2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33946310

RESUMO

HER2 targeted therapies have significantly improved prognosis of HER2-positive breast and gastric cancer. HER2 overexpression and mutation is the pathogenic driver in non-small cell lung cancer (NSCLC) and colorectal cancer, however, to date, there are no approved HER2-targeted therapies with these indications. Trastuzumab deruxtecan (T-DXd) is a novel HER2-directed antibody drug conjugate showing significant anti-tumor activity in heavily pre-treated HER2-positive breast and gastric cancer patients. Preliminary data have shown promising objective response rates in patients with HER2-positive NSCLC and colorectal cancer. T-DXd has an acceptable safety profile, however with concerns regarding potentially serious treatment-emergent adverse events. In this review we focus on the pharmacologic characteristics and toxicity profile of T-Dxd, and provide an update on the most recent results of clinical trials of T-DXd in solid tumors. The referenced papers were selected through a PubMed search performed on 16 March 2021 with the following searching terms: T-DXd and breast cancer, or gastric cancer, or non-small cell lung cancer (NSCLC), or colorectal cancer. Oral presentation, abstracts, and posters presented at the American Society of Clinical Oncology (ASCO, Alexandria, VA, USA) 2020 and the European Society for Medical Oncology (ESMO, Lugano, Switzerland) 2020 annual meetings were retrieved for data on T-DXd. We also overview ongoing research and data of combination therapies currently under investigation, which will impact on future therapeutic strategies. Clinicaltrials.gov was searched to identify ongoing clinical trials of T-DXd alone or in combination in solid tumors.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Camptotecina/análogos & derivados , Imunoconjugados/uso terapêutico , Neoplasias/tratamento farmacológico , Receptor ErbB-2/análise , Trastuzumab/uso terapêutico , Animais , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/farmacologia , Camptotecina/efeitos adversos , Camptotecina/farmacologia , Camptotecina/uso terapêutico , Ensaios Clínicos como Assunto , Humanos , Imunoconjugados/efeitos adversos , Imunoconjugados/farmacologia , Neoplasias/patologia , Trastuzumab/efeitos adversos , Trastuzumab/farmacologia
11.
BMC Genomics ; 22(1): 391, 2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-34039281

RESUMO

BACKGROUND: Spodoptera frugiperda is a serious pest that causes devastating losses to many major crops, including corn, rice, sugarcane, and peanut. Camptothecin (CPT) is a bioactive secondary metabolite of the woody plant Camptotheca acuminata, which has shown high toxicity to various pests. However, the effect of CPT against S. frugiperda remains unknown. RESULTS: In this study, bioassays have been conducted on the growth inhibition of CPT on S. frugiperda larvae. Histological and cytological changes were examined in the midgut of larvae fed on an artificial diet supplemented with 1.0 and 5.0 µg/g CPT. The potential molecular mechanism was explored by comparative transcriptomic analyses among midgut samples obtained from larvae under different treatments. A total of 915 and 3560 differentially expressed genes (DEGs) were identified from samples treated with 1.0 and 5.0 µg/g CPT, respectively. Among the identified genes were those encoding detoxification-related proteins and components of peritrophic membrane such as mucins and cuticle proteins. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses indicated that part of DEGs were involved in DNA replication, digestion, immunity, endocrine system, and metabolism. CONCLUSIONS: Our results provide useful information on the molecular basis for the impact of CPT on S. frugiperda and for future studies on potential practical application.


Assuntos
Camptotecina , Transcriptoma , Animais , Camptotecina/farmacologia , Sistema Digestório , Larva/genética , Spodoptera/genética
12.
Front Immunol ; 12: 619761, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33868235

RESUMO

Microglia, the main immune cells in the brain, participate in the innate immune response in the central nervous system (CNS). Studies have shown that microglia can be polarized into pro-inflammatory M1 and anti-inflammatory M2 phenotypes. Accumulated evidence suggests that over-activated M1 microglia release pro-inflammatory mediators that damage neurons and lead to Parkinson's disease (PD). In contrast, M2 microglia release neuroprotective factors and exert the effects of neuroprotection. Camptothecin (CPT), an extract of the plant Camptotheca acuminate, has been reported to have anti-inflammation and antitumor effects. However, the effect of CPT on microglia polarization and microglia-mediated inflammation responses has not been reported. In our study we found that CPT improved motor performance of mice and reduced the loss of neurons in the substantia nigra (SN) of the midbrain in LPS-injected mice. In the mechanism study, we found that CPT inhibited M1 polarization of microglia and promotes M2 polarization via the AKT/Nrf2/HO-1 and NF-κB signals. Furthermore, CPT protected the neuroblastoma cell line SH-SY5Y and dopaminergic neuron cell line MN9D from damage mediated by microglia activation. In conclusion, our results demonstrate that CPT regulates the microglia polarization phenotype via activating AKT/Nrf2/HO-1 and inhibiting NF-κB pathways, inhibits neuro-inflammatory responses, and exerts neuroprotective effects in vivo and in vitro.


Assuntos
Camptotecina/farmacologia , Heme Oxigenase-1/metabolismo , Microglia/efeitos dos fármacos , Microglia/fisiologia , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Citocinas/metabolismo , Citotoxicidade Imunológica , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos/imunologia , Masculino , Camundongos
13.
Curr Top Med Chem ; 21(10): 908-919, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33902420

RESUMO

BACKGROUND: In the present study, we have explored the utility of QSAR modelling, in silico ADMET, docking, chemical semi-synthesis, and in vitro evaluation studies for the identification of active camptothecin (CPT) derivatives against cancer-targeting human liver (HepG2) and lung (A549) cancer cell lines. METHODS: Two QSAR models were developed as screenings tools using the multiple linear regression (MLR) method followed by ADMET and docking studies. The regression coefficient (r2) and cross-validation regression coefficients (rCV2T) of the QSAR model for the HepG2 cell line was 0.95 and 0.90, respectively, and for the A549 cell line, it was 0.93 and 0.81, respectively. RESULTS: In silico studies show that CPT derivatives (CPT-1 and CPT-6) possess drug-like properties. Docking performed on DNA Topoisomerase-I showed significant binding affinity. Finally, predicted active derivatives were chemically semi synthesized, spectroscopically characterized, and evaluated in-vitro for cytotoxic/anticancer activity against HepG2 and A549 cell lines. CONCLUSION: The experimental results are consistent with the predicted results. These findings may be of immense importance in the anticancer drug development from an inexpensive and widely available natural product, camptothecin.


Assuntos
Antineoplásicos/isolamento & purificação , Produtos Biológicos/isolamento & purificação , Camptotecina/isolamento & purificação , Magnoliopsida/química , Extratos Vegetais/isolamento & purificação , Células A549 , Antineoplásicos/farmacologia , Produtos Biológicos/farmacologia , Camptotecina/farmacologia , DNA Topoisomerases Tipo I/química , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Modelos Lineares , Simulação de Acoplamento Molecular/métodos , Extratos Vegetais/farmacologia , Ligação Proteica , Relação Quantitativa Estrutura-Atividade , Transdução de Sinais
14.
Mater Sci Eng C Mater Biol Appl ; 123: 111979, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33812607

RESUMO

The present study demonstrates the extraction and identification of phospholipids (PLs) from peanut seed for formulation of liposomes for pH and thermo-sensitive delivery and release of folic acid (FA), levodopa (DOPA) and, camptothecin (CPT). The TLC, FTIR and GC-MS based characterization of extracted peanut PLs showed phosphatidylethanolamine, cardiolipin and phosphatidic acid as major PLs and palmitic acid and oleic acid as major fatty acids. Liposomes (LSMs) of size 1-2 µm formulated by optimized thin-film hydration method were found to entrap FA, DOPA and CPT with 58, 61.4 and 52.12% efficiency, respectively with good stability. The effect of external stimuli like pH and temperature on the release pattern of FA, DOPA and CPT indicated that FA was optimally released at pH 10 and 57 °C, DOPA at pH 2 and 37 °C, while CPT was best released at pH 6 and 47 °C. When tested for the in vitro activity, DOPA released by DOPA@LSMs showed lower toxicity to 3T3 than to SH-SY5Y cells. Similarly, CPT released by CPT@LSMs showed remarkable anticancer activity against MCF-7 cells with an IC50 value of 17.99 µg/mL. Thus peanut PLs can be efficiently used for liposomal formulations for pH and thermo-sensitive release of drugs.


Assuntos
Camptotecina , Lipossomos , Arachis , Camptotecina/farmacologia , Ácido Fólico , Humanos , Concentração de Íons de Hidrogênio , Levodopa , Fosfolipídeos , Temperatura
15.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(2): 363-368, 2021 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-33812400

RESUMO

OBJECTIVE: To investigate the effect of Bmi-1 expression on the chemosensitivity of THP-1 cells and its relative mechanism. METHODS: The pGenesil-2-Bmi-1 1 siRNA, p-MSCV-Bmi-1 plasmid was transfected into THP-1 cells to reduce or increase the expression of Bmi-1. The expression of Bmi-1 mRNA and protein was verified by PCR and Western blot. The effect of camptothecin (CPT) on the proliferation and chemosensitivity of THP-1 cells affected by Bmi-1 gene were detected by MTT assay. The expression of DNA double-strand breaks marker-γ-H2AX was detected by immunofluorescence assay. Mitochondrial membrane potential and apoptosis were observed by flow cytometry. The expression of Cytochrome C, Caspase 3, Bax and BCL-2 was detected by Western blot. RESULTS: Silencing Bmi-1 could inhibit proliferation and enhance the sensitivity of THP-1 cells to CPT, while overexpressed Bmi-1 could promote the cell proliferation and attenucate sensitivity of THP-1 cells to CPT. Silencing Bmi-1 could enhance CPT-induced DNA double-strand breaks, decrease mitochondrial membrane potential and promote CPT-induced apoptosis. While increasing Bmi-1 gene expression could attenuate CPT-induced DNA double-strand breaks, enhamce mitochondrial membrane potential and significantly reduce CPT-induced apoptosis of cells. CONCLUSION: Bmi-1 expression could influence the sensitivity of THP-1 cells to CPT, and its relative mechanism may relate to DNA double-strand breaks and endogenous apoptotic pathways.


Assuntos
Apoptose , Camptotecina , Camptotecina/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Células THP-1
16.
Biochem Biophys Res Commun ; 550: 166-170, 2021 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-33706100

RESUMO

In the present study the role of poly(ADP)ribosylation on rubitecan induced caspase dependent cell death was evaluated. We show that Top1 poisoning by rubitecan induces caspase mediated apoptosis which was reduced by PARP inhibitor olaparib in zebrafish embryo. Collectively our data introduces zebrafish as a valuable model for PARP related biomedical research.


Assuntos
Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , DNA Topoisomerases Tipo I/metabolismo , Poli(ADP-Ribose) Polimerase-1/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores da Topoisomerase I/farmacologia , Peixe-Zebra/embriologia , Animais , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Sinergismo Farmacológico , Ftalazinas/farmacologia , Piperazinas/farmacologia , Poli(ADP-Ribose) Polimerase-1/análise , Poli(ADP-Ribose) Polimerase-1/química
17.
Food Chem Toxicol ; 151: 112113, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33722602

RESUMO

Camptothecin (CPT), a well-known monoterpenoid indole alkaloid with broad-spectrum anti-cancer activity, is produced from plants and endophytes. In view of the limitations of plants as sources of camptothecin in productivity and efficiency, endophytes serve as the fast growth, high cost-effectiveness, good reproducibility, and feasible genetic manipulation, so they have the potential to meet the huge market demand of the pharmaceutical industry. In this review, we summarized the isolation, identification and fermentation of CPT-producing endophytes, as well as the biosynthesis, extraction and detection of camptothecin from endophytes. Among them, we put emphasis on increasing the production of camptothecin in endophytes through different strategies such as changing the proportion of carbon, nitrogen and phosphate source, adding the precursors, elicitors or adsorbent resin, utilizing co-culture fermentation or fermenter culture. However, cell subculture and metabolic reprogramming affect the expression of camptothecin biosynthetic genes in CPT-producing endophytes, which poses a challenge to the industrial production of camptothecin. Therefore, it will be useful to gain insights through the review of these researches and provide alternative approaches to develop economical, eco-friendly and reliable natural products.


Assuntos
Antineoplásicos Fitogênicos/biossíntese , Camptotecina/biossíntese , Endófitos/metabolismo , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Reatores Biológicos , Camptotecina/química , Camptotecina/farmacologia , Fermentação , Regulação da Expressão Gênica/efeitos dos fármacos , Transcrição Genética/efeitos dos fármacos
18.
DNA Repair (Amst) ; 101: 103099, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33740539

RESUMO

Inhibitors of Chk1 kinase, a key effector of the DNA damage response pathway, are currently undergoing Phase 1 and 2 clinical trials as single agents and in combination with cytotoxic chemotherapy. Understanding the biological effects of Chk1 inhibitors on cancer cells is critical for their continued clinical development. Treatment of adherent HT29 or HCC1937 cancer cells or suspension Jurkat or THP1 cells with a Chk1 inhibitor increased γH2AX in these cells. Chk1i pre-treated HCC1937 or HT29 cells resulted in γH2AX induction in cocultured Jurkat or THP1 cells despite these cells never being treated with a Chk1i. Pre-treatment of HT29 cells with camptothecin or gemcitabine followed by a Chk1i increased the DNA damage bystander effect in naïve cocultured THP1 cells compared to camptothecin or gemcitabine alone. This bystander effect appeared to occur through soluble factors via ATR, ATM, and DNA-PKcs activation in the bystander cells. Chk1 silencing by siRNA in HCC1937 or HT29 cells induced a DNA damage bystander effect in cocultured THP1 cells. However, this bystander effect induced by siRNA appeared mechanistically different to that induced by the Chk1 inhibitor. This work suggests that a Chk1 inhibitor-induced bystander effect may increase the clinical effectiveness of Chk1 inhibitors by inducing additional DNA damage or replication stress in cancer cells not directly exposed to the inhibitor. Conversely, it may also contribute to Chk1 inhibitor toxicity by increasing DNA damage in non-tumour cells.


Assuntos
Efeito Espectador , Quinase 1 do Ponto de Checagem/antagonistas & inibidores , Dano ao DNA , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Camptotecina/farmacologia , Linhagem Celular Tumoral , Quinase 1 do Ponto de Checagem/metabolismo , Técnicas de Cocultura , DNA/metabolismo , Proteína Quinase Ativada por DNA/metabolismo , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Células HT29 , Histonas/análise , Histonas/metabolismo , Humanos , Células Jurkat , Neoplasias/enzimologia , Neoplasias/metabolismo , Neoplasias/fisiopatologia , Inibidores de Proteínas Quinases/uso terapêutico
19.
Mater Sci Eng C Mater Biol Appl ; 122: 111796, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33641933

RESUMO

Biocompatible polymer-coated magnetic nanoparticles are designed with an objective to sharp-shoot cancer by loading anticancer drugs on them and delivering to the target site. In this work, novel biocompatible polymers of poly(dl-lactic-co-glycolide), functionalized with ß-cyclodextrin and ß-cyclodextrin-folate conjugate are synthesized and characterized by spectroscopic techniques. Magnetic ytterbium ferrite nanoparticles are prepared, and the synthesized polymers are coated on them. The polymer-coated nanoparticles are intended to be employed as magnetic nanocarriers that transport the anticancer drug, camptothecin. The ferrite nanoparticles are superparamagnetic in nature. Camptothecin was loaded in the nanocarriers and the adsorption percentage was near or above 90%. Study of the in vitro release of camptothecin from the nanocarrier reveals its sustained nature, i.e. a cumulative release of about 50% at 72 h and a pH of 7.4. A pH-dependent enhanced release of 60% is observed, i.e. at a more acidic pH of 6.8. In vitro anti-cancer studies on breast cancer cell lines (MCF7) were carried out. The cell inhibition is enhanced in the case of camptothecin-loaded nanocarrier. The enhanced efficacy of the camptothecin, its sustained release, and the size of the nanocarrier in the range that is considered suitable for magnetic field-assisted drug delivery reveal the magnetic nanocarrier promising for transport of the drug.


Assuntos
Nanopartículas , beta-Ciclodextrinas , Camptotecina/farmacologia , Portadores de Fármacos , Compostos Férricos , Ácido Fólico , Humanos , Nanopartículas Magnéticas de Óxido de Ferro , Itérbio
20.
Nanoscale ; 13(9): 5094-5102, 2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33650607

RESUMO

Tyroservatide (YSV) belongs to a class of bioactive peptides that have drawn considerable attention in the field of drug discovery, yet it displays limited potency and often requires a millimolar concentration to execute its cellular functions. To enhance the potency of the drug through a self-assembling strategy, we designed and synthesized a series of octapeptides through conjugation of YSV with a pentapeptide sequence bearing alternating hydrophobic and hydrophilic amino acids to promote their self-assembling capabilities. Initial screening for hydrogelation gave a novel octapeptide (denoted as 1-YSV hereafter) that was capable of self-assembling under physiological conditions to afford supramolecular nanofibers with enhanced anti-cancer efficacy compared to YSV itself. Interestingly, 1-YSV formed a robust co-assembly with the anticancer drug hydroxycamptothecin (HCPT) to afford 1-YSV/HCPT hydrogel, which not only greatly improved the viscoelastic properties of hydrogels, but also stabilized HCPT in the hydrogel matrix and avoided the agglomeration of drug molecules. Compared to HCPT solution, the hydrogel formulation of 1-YSV/HCPT demonstrated better efficacy against the proliferation of non-small cell lung cancer A549 cells both in vitro and in vivo. Finally, thanks to the pure amino acid-based composition, the 1-YSV/HCPT formulation exhibited excellent biocompatibility, giving a low hemolytic rate to red blood cells, with mild local tissue reactions and negligible systematic toxicities in mice.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Animais , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Linhagem Celular Tumoral , Neoplasias Pulmonares/tratamento farmacológico , Camundongos , Oligopeptídeos
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