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1.
Anticancer Res ; 40(1): 67-73, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892553

RESUMO

BACKGROUND/AIM: Aberrant expression of the SEI1 oncogene has been prevalently found in a variety of human cancers, including oral squamous cell carcinoma (OSCC). Recent studies have shown that cisplatin up-regulates the expression of SEI1 in breast and bladder cancer cells, thus inhibiting apoptosis and cell death in these cells. In the present study, we investigated the impact of cisplatin on the expression of SEI1 in OSCC cells. MATERIALS AND METHODS: Four OSCC cell lines, CAL27, SCC4, SCC15, and SCC22A were treated with cisplatin and 5-fluorouracil, and changes in SEI1 expression in these cells were evaluated using quantitative Reverse Transcription-Polymerase Chain Reaction (qRT-PCR) analyses. RESULTS: Cisplatin significantly induced SEI1 expression in the tested OSCC cells. Contrarily, cisplatin treatment did not affect the expression of gankyrin and BMI1, two oncogenes frequently overexpressed in a coordinate manner with SEI1 in OSCC. Additionally, 5-fluorouracil did not bring about any detectable changes in SEI1 expression in these cells. CONCLUSION: Cisplatin-induced up-regulation of SEI1 expression in OSCC is specific, and such induction could underlie the development of resistance to cisplatin in OSCC.


Assuntos
Carcinoma de Células Escamosas/genética , Cisplatino/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Bucais/genética , Oncogenes , Fatores de Transcrição/genética , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Fluoruracila/farmacologia , Humanos
2.
Anticancer Res ; 40(1): 169-176, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892565

RESUMO

BACKGROUND/AIM: Cancer stem cells (CSCs) are considered to be one of the causes of tumor recurrence after chemotherapy. The purpose of our study was to isolate CSCs from human colorectal cancer cell (CRC) lines. MATERIALS AND METHODS: Nine CRC lines were screened based on the expression level of potential CSC markers to identify putative CSCs. Tumor formation capacity in immunodeficient mice was compared with that of their counterparts. Stemness, differentiation potency and sensitivity to 5-fluorouracil (5-FU), in vitro, were also assessed. Microarray analysis was used to characterize the features of the putative CSCs. RESULTS: COLO 201 cells were separated into two populations based on CD44 expression. CD44 positive (CD44+) cells showed significantly higher tumor formation capacity than CD44- cells in immunodeficient mice. CD44+ cells also possessed stemness properties and lower sensitivity to 5-FU in vitro. Moreover, cancer stemness and chemoresistance-related genes were highly up-regulated in CD44+ cells. CONCLUSION: CD44+ COLO 201 cells possessed the features of CSCs; therefore, the present CSC model could serve as a valuable tool to accelerate CSC research.


Assuntos
Receptores de Hialuronatos/metabolismo , Células-Tronco Neoplásicas/metabolismo , Animais , Biomarcadores , Biomarcadores Tumorais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Modelos Animais de Doenças , Citometria de Fluxo , Fluoruracila/farmacologia , Xenoenxertos , Humanos , Receptores de Hialuronatos/genética , Camundongos
3.
Anticancer Res ; 39(12): 6463-6470, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31810910

RESUMO

BACKGROUND/AIM: The aim of the present study was to determine the efficacy of trabectedin combined with FOLFIRI (irinotecan, leucovorin and 5-fluorouracil) on a colorectal cancer (CRC) patient-derived orthotopic xenograft (iPDOX) mouse model. MATERIALS AND METHODS: A CRC tumor from a patient previously established in nude mice was implanted subcutaneously in transgenic green fluorescence protein (GFP)-expressing nude mice in order to label the tumor stromal cells with GFP. Mice were randomized into four groups: Group 1, untreated control; group 2, FOLFIRI; group 3, trabectedin alone; group 4, trabectedin plus FOLFIRI. Tumor width, length, and mouse body weight was measured twice every week. RESULTS: All three treatment groups showed inhibited tumor growth compared to the untreated control group. Only the combination of FOLFIRI and trabectedin arrested tumor growth. No significant changes was observed in body weight in any group. CONCLUSION: These findings suggest that the combination of trabectedin plus FOLFIRI has clinical potential for patients with CRC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Camptotecina/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Trabectedina/administração & dosagem , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Peso Corporal/efeitos dos fármacos , Camptotecina/administração & dosagem , Camptotecina/farmacologia , Neoplasias Colorretais/metabolismo , Fluoruracila/administração & dosagem , Fluoruracila/farmacologia , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Leucovorina/administração & dosagem , Leucovorina/farmacologia , Camundongos , Camundongos Nus , Camundongos Transgênicos , Distribuição Aleatória , Trabectedina/farmacologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Anticancer Res ; 39(12): 6555-6565, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31810921

RESUMO

BACKGROUND/AIM: Honokiol is a biphenolic component of the bark of Magnolia, and has been shown to exert several activities, including anti-depressant, anti-emetic, anti-oxidative, anti-thrombotic, anti-angiogenesis, anti-anxiolytic, anti-inflammatory and anti-tumor effects. MATERIALS AND METHODS: The anti-tumor activities of honokiol and its synergistic effect with 5-fluorouracil (5-FU) in human urothelial cell carcinoma (UCC) cells were investigated. RESULTS: Honokiol significantly suppressed the proliferation of UCC cells in a dose- and time-dependent manner. Moreover, honokiol inhibited the tumorigenesis of UCC cells in vitro. In addition, honokiol induced cell cycle arrest at G0/G1 phase and caused apoptosis of UCC cells through the intrinsic pathway. Importantly, we demonstrated that honokiol potentiated the cytotoxic effect of 5-FU, and displayed a synergistic effect with 5-FU in UCC cells. CONCLUSION: Honokiol causes growth inhibition, tumorigenesis suppression, cell cycle arrest, apoptosis, and importantly has a synergistic effect with 5-FU in human UCC cells. Therefore, this agent displays a therapeutic potential for treating human UCC.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Compostos de Bifenilo/farmacologia , Fluoruracila/farmacologia , Lignanas/farmacologia , Neoplasias da Bexiga Urinária/metabolismo , Caspase 3/metabolismo , Caspase 9/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Poli(ADP-Ribose) Polimerases/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico
5.
Anticancer Res ; 39(12): 6673-6684, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31810932

RESUMO

BACKGROUND/AIM: The aim of the study was to evaluate the antitumor potential and combination effects of chemotherapeutic drugs. MATERIALS AND METHODS: The cytotoxicity of 20 drip-type classical and molecular-targeted anticancer drugs was examined against 4 human oral squamous cell carcinoma cell lines and 5 human oral normal mesenchymal and epithelial cells. Cell cycle progression was monitored by a cell sorter. Combination effect was evaluated by combination index. RESULTS: Most of the classical anticancer drugs showed much higher antitumor activity than molecular-targeted drugs, except bortezomib. Among 12 classical anticancer drugs, taxanes and gemsitabine showed the highest tumor-specificity (TS) and potency-selectivity expression (PSE) values, whereas platinum analogs showed the least TS value. Combination of two classical or a classical and a molecular-targeted drug showed mostly additive or antagonistic effect. 5-FU and cisplatin did not produce a subG1 population, but induced G2/M or G1/S arrest, regardless of the addition of cetuximab. Cetuximab, nibolumab and bortezomib showed potent keratinocyte toxicity. CONCLUSION: The present TS monitoring system may provide useful information for building up the treatment regimens of anticancer drugs.


Assuntos
Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Células Epiteliais/efeitos dos fármacos , Terapia de Alvo Molecular , Neoplasias Bucais/tratamento farmacológico , Bortezomib/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cetuximab/farmacologia , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Fibroblastos/efeitos dos fármacos , Fluoruracila/farmacologia , Hormese , Humanos , Técnicas In Vitro , Queratinócitos/efeitos dos fármacos , Mucosa Bucal/citologia , Nivolumabe/farmacologia , Compostos de Platina/farmacologia , Taxoides/farmacologia
6.
Biochemistry (Mosc) ; 84(11): 1424-1432, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31760928

RESUMO

A large body of evidence suggests that cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT), as well as expression and function of retinoid receptors, are pivotal features of tumor initiation, progression, and chemoresistance. This is also true for pancreatic ductal adenocarcinoma (PDAC), which represents a clinical challenge due to poor prognosis and increasing incidence. Understanding the above features of cancer cells could open new avenues for PDAC treatment strategies. The aim of this study was to investigate the relation between CSCs, EMT, and retinoid receptors in PDAC after treatment with the chemotherapeutic agents - gemcitabine and 5-fluorouracil. First, we demonstrated the difference in the expression levels of CSC and EMT markers and retinoid receptors in the untreated Mia PaCa-2 and Panc1 cells that also differed in the frequency of spontaneous apoptosis and distribution between the cell cycle phases. Chemotherapy reduced the number of cancer cells in the S phase. Gemcitabine and 5-fluorouracil modulated expression of CSC markers, E-cadherin, and RXRß in Panc1 but not in Mia PaCa-2 cells. We suggest that these effects could be attributed to the difference in the basal levels of expression of the investigated genes. The obtained data could be interesting in the context of future preclinical research.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Receptor X Retinoide beta/metabolismo , Apoptose/efeitos dos fármacos , Caderinas/genética , Caderinas/metabolismo , Linhagem Celular Tumoral , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Fluoruracila/farmacologia , Humanos , Células-Tronco Neoplásicas/citologia , Células-Tronco Neoplásicas/metabolismo , Receptor X Retinoide beta/genética , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos
7.
Anticancer Res ; 39(11): 6041-6047, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704830

RESUMO

BACKGROUND/AIM: We have previously reported that alternate-day S-1 had comparable effects and milder adverse events than the respective consecutive-day regimen in head and neck cancer (HNC) patients. The aim of this study was to investigate the anticancer effects of both regimens and underlying mechanisms in vitro. MATERIALS AND METHODS: Two head and neck squamous cell carcinoma (HNSCC) cell lines were treated with 5-FU given on an alternate-day or consecutive-day schedule. The relative inhibition (RI) of tumor growth was calculated. Cell cycle distributions and cyclin expression following 5-FU treatment were analyzed. RESULTS: The RI of both regimens was almost identical. The percentage of cells in S phase was significantly increased in the alternate-day group compared to the consecutive-day group (p<0.001). CONCLUSION: The cytotoxic effect of alternate-day was equivalent to that of consecutive-day. S-phase arrest was more prominently observed with the alternate-day regimen, which may help maintain 5-FU sensitivity in head and neck cancer cells.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Fluoruracila/farmacologia , Neoplasias de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Esquema de Medicação , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Técnicas In Vitro , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Células Tumorais Cultivadas
8.
Int J Nanomedicine ; 14: 6661-6678, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31695362

RESUMO

Background: Cancer treatments are being continually developed. Increasingly more effective and better-targeted treatments are available. As treatment has developed, the outcomes have improved. Purpose: In this work, polyethylene glycol (PEG), layered double hydroxide (LDH) and 5-fluorouracil (5-FU) were used as a stabilizing agent, a carrier and an anticancer active agent, respectively. Characterization and methods: Magnetite nanoparticles (Fe3O4) coated with polyethylene glycol (PEG) and co-coated with 5-fluorouracil/Mg/Al- or Zn/Al-layered double hydroxide were synthesized by co-precipitation technique. Structural, magnetic properties, particle shape, particle size and drug loading percentage of the magnetic nanoparticles were investigated by XRD, TGA, FTIR, DLS, FESEM, TEM, VSM, UV-vis spectroscopy and HPLC techniques. Results: XRD, TGA and FTIR studies confirmed the formation of Fe3O4 phase and the presence of iron oxide nanoparticles, polyethylene glycol, LDH and the drug for all the synthesized samples. The size of the nanoparticles co-coated with Mg/Al-LDH is about 27 nm compared to 40 nm when they were co-coated with Zn/Al-LDH, with both showings near uniform spherical shape. The iron oxide nanoparticles retain their superparamagnetic property when they were coated with polyethylene glycol, polyethylene glycol co-coated with Mg/Al-LDH and polyethylene glycol co-coated with Zn/Al-LDH with magnetic saturation value of 56, 40 and 27 emu/g, respectively. The cytotoxicity study reveals that the anticancer nanodelivery system has better anticancer activity than the free drug, 5-FU against liver cancer HepG2 cells and at the same time, it was found to be less toxic to the normal fibroblast 3T3 cells. Conclusion: These are unique core-shell nanoparticles synthesized with the presence of multiple functionalities are hoped can be used as a multifunctional nanocarrier with the capability of targeted delivery using an external magnetic field and can also be exploited as hypothermia for cancer cells in addition to the chemotherapy property.


Assuntos
Fluoruracila/farmacologia , Hidróxidos/química , Fenômenos Magnéticos , Polietilenoglicóis/química , Nanomedicina Teranóstica , Células 3T3 , Animais , Antineoplásicos/farmacologia , Morte Celular/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Difusão Dinâmica da Luz , Células Hep G2 , Humanos , Concentração Inibidora 50 , Nanopartículas de Magnetita/química , Nanopartículas de Magnetita/ultraestrutura , Camundongos , Tamanho da Partícula , Espectroscopia de Infravermelho com Transformada de Fourier , Temperatura Ambiente , Difração de Raios X
9.
Cancer Sci ; 110(12): 3677-3688, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31646712

RESUMO

5-Fluorouracil (5-FU) is a chemotherapeutic agent commonly used to treat esophageal squamous cell carcinoma (ESCC), but acquisition of chemoresistance frequently occurs and the underlying mechanisms are not fully understood. We found that microRNA (miR)-338-5p was underexpressed in ESCC cells with acquired 5-FU chemoresistance. Forced expression of miR-338-5p in these cells resulted in downregulation of Id-1, and restoration of both in vitro and in vivo sensitivity to 5-FU treatment. The effects were abolished by reexpression of Id-1. In contrast, miR-338-5p knockdown induced 5-FU resistance in chemosensitive esophageal cell lines, and knockdown of both miR-338-5p and Id-1 resensitized the cells to 5-FU. In addition, miR-338-5p had suppressive effects on migration and invasion of ESCC cells. Luciferase reporter assay confirmed a direct interaction between miR-338-5p and the 3'-UTR of Id-1. We also found that miR-338-5p was significantly downregulated in tumor tissue and serum samples of patients with ESCC. Notably, low serum miR-338-5p expression level was associated with poorer survival and poor response to 5-FU/cisplatin-based neoadjuvant chemoradiotherapy. In summary, we found that miR-338-5p can modulate 5-FU chemoresistance and inhibit invasion-related functions in ESCC by negatively regulating Id-1, and that serum miR-338-5p could be a novel noninvasive prognostic and predictive biomarker in ESCC.


Assuntos
Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Proteína 1 Inibidora de Diferenciação/genética , MicroRNAs/fisiologia , Adulto , Idoso , Animais , Linhagem Celular Tumoral , Movimento Celular , Resistencia a Medicamentos Antineoplásicos , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/mortalidade , Carcinoma de Células Escamosas do Esôfago/patologia , Feminino , Fluoruracila/farmacologia , Humanos , Masculino , Camundongos , MicroRNAs/sangue , Pessoa de Meia-Idade , Invasividade Neoplásica
10.
Nat Med ; 25(10): 1607-1614, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31591597

RESUMO

Rectal cancer (RC) is a challenging disease to treat that requires chemotherapy, radiation and surgery to optimize outcomes for individual patients. No accurate model of RC exists to answer fundamental research questions relevant to patients. We established a biorepository of 65 patient-derived RC organoid cultures (tumoroids) from patients with primary, metastatic or recurrent disease. RC tumoroids retained molecular features of the tumors from which they were derived, and their ex vivo responses to clinically relevant chemotherapy and radiation treatment correlated with the clinical responses noted in individual patients' tumors. Upon engraftment into murine rectal mucosa, human RC tumoroids gave rise to invasive RC followed by metastasis to lung and liver. Importantly, engrafted tumors displayed the heterogenous sensitivity to chemotherapy observed clinically. Thus, the biology and drug sensitivity of RC clinical isolates can be efficiently interrogated using an organoid-based, ex vivo platform coupled with in vivo endoluminal propagation in animals.


Assuntos
Quimiorradioterapia , Organoides/patologia , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/radioterapia , Animais , Fluoruracila/farmacologia , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/radioterapia , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/secundário , Camundongos , Metástase Neoplásica , Organoides/efeitos dos fármacos , Organoides/efeitos da radiação , Neoplasias Retais/patologia
11.
Lett Appl Microbiol ; 69(5): 353-357, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31508840

RESUMO

The ability of chemotherapeutic agents to affect the growth of common bacterial pathogens and the relationship between the effects of chemotherapeutics and antimicrobials is largely unknown. The purpose of this study was to describe the susceptibility of canine bacterial isolates to chemotherapeutic agents and to compare these results to their antimicrobial susceptibility. The effects of bleomycin, doxorubicin, cytarabine, cyclophosphamide, methotrexate, 5-fluorouracil and gemcitabine on the growth of 33 Staphylococcus pseudintermedius isolates and 32 Escherichia coli isolates from dogs was determined by agar dilution. In addition to MICs, the lowest drug concentration associated with a decreased colony size was recorded. Results were compared to the MICs of a panel of antimicrobial agents. Bleomycin consistently inhibited bacterial growth of S. pseudintermedius and E. coli. Doxorubicin inhibited S. pseudintermedius but not E. coli while the opposite was seen for gemcitabine. Reduction in colony size on exposure to 5-fluorouracil for both organisms, and methotrexate for S. pseudintermedius was seen. No observable effect of cyclophosphamide or cytarabine was observed. Associations between elevated MICs to chemotherapeutic drugs and antimicrobial resistance were not found. These results indicate that chemotherapeutic agents affect the growth of bacteria, but do not support a role in the selection of antimicrobial resistance. SIGNIFICANCE AND IMPACT OF THE STUDY: This study shows that chemotherapy drugs commonly used in veterinary oncology have an effect of the growth of canine isolates of Escherichia coli and Staphylococcus pseudintermedius. No associations between susceptibility to chemotherapeutic drugs and antibiotics were found, which does not support selection of antimicrobial resistance by chemotherapy drugs.


Assuntos
Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Bleomicina/farmacologia , Doenças do Cão/microbiologia , Escherichia coli/efeitos dos fármacos , Fluoruracila/farmacologia , Staphylococcus/efeitos dos fármacos , Animais , Cães , Escherichia coli/crescimento & desenvolvimento , Testes de Sensibilidade Microbiana , Staphylococcus/crescimento & desenvolvimento , Staphylococcus/isolamento & purificação
12.
Cancer Sci ; 110(11): 3520-3532, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31505062

RESUMO

Cancer stem cells (CSC) are a subpopulation of tumor cells with properties of high tumorigenicity and drug resistance, which lead to recurrence and poor prognosis. Although a better understanding of CSC is essential for developing cancer therapies, scarcity of the CSC population has hindered such analyses. The aim of the present study was to elucidate whether the E-cadherin-Fc chimera protein (E-cad-Fc) enhances cancer stem-like properties because studies show that soluble E-cadherin stimulates human epithelial growth factor receptor (EGFR) and downstream signaling pathways that are reported to play a crucial role in CSC. For this purpose, we used ornithine decarboxylase (ODC)-degron-transduced (Degron(+)) KM12SM cells as a CSC model that retains relatively low CSC properties. Compared to cultures without E-cad-Fc treatment, we found that E-cad-Fc treatment further suppressed proteasome activity and largely enhanced cancer stem-like properties of ODC-degron-transduced KM12SM cells. These results include increased expression of stem cell markers Lgr5, Bmi-1, SOX9, CD44, and CD44v9, aldehyde dehydrogenase (ALDH), and enhancement of robust spheroid formation, and chemoresistance to 5-fluorouracil (5-FU) and oxaliplatin (L-OHP). These effects could be attributed to activation of the EGFR pathway as identified by extensive phosphorylation of EGFR, ERK, PI3K, AKT, and mTOR. In SW480 cells, E-cad-Fc matrix induced some CSC markers such as CD44v9 and ALDH. We also found that E-cad-Fc matrix showed high efficiency of inducing mesenchymal changes in colon cancer cells. Our data suggest that the E-cad-Fc matrix may enhance CSC properties such as enhancement of chemoresistance and sphere formation.


Assuntos
Neoplasias do Colo/patologia , Receptores ErbB , Fragmentos Fc das Imunoglobulinas , Células-Tronco Neoplásicas/patologia , Proteínas Recombinantes de Fusão/metabolismo , Aldeído Desidrogenase/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Neoplasias do Colo/metabolismo , Resistencia a Medicamentos Antineoplásicos , Fluoruracila/farmacologia , Humanos , Receptores de Hialuronatos/metabolismo , Células-Tronco Neoplásicas/metabolismo , Ornitina Descarboxilase , Oxaliplatina/farmacologia , Complexo Repressor Polycomb 1/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Fatores de Transcrição SOX9/metabolismo , Esferoides Celulares
13.
Eur J Med Chem ; 183: 111706, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31553932

RESUMO

A series of twenty-three parthenolide-5-fluorouracil (5-FU) conjugates ware synthesized and evaluated for their anti-cancer activities against human hepatocellular carcinoma cell line Bel-7402 and 5-fluorouracil resistant human hepatocellular carcinoma cell line Bel-7402/5-FU. The preliminary structure-activity relationships were discussed. The most active compound 15d showed high activity against Bel-7402/5-FU cell line with IC50 value of 2.25 µM, which demonstrated 5.8-fold improvement compared to that of the parent compound parthenolide (IC50 = 12.98 µM). The investigation of preliminary molecular mechanism of 15d revealed that 15d could reverse drug resistance by inhibiting MDR1, ABCC1 and ABCG2 to increase the intracellular drug accumulation and induce apoptosis of Bel-7402/5-FU cells through mitochondria mediated pathway. On the base of these results, compound 15d is deserved to be further investigated as a potential anti-HCC lead compound for ultimate discovery of pathenolide-based anti-cancer drug.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Desenho de Drogas , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Fluoruracila/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Sesquiterpenos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Núcleo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Fluoruracila/química , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Estrutura Molecular , Sesquiterpenos/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
14.
Int J Mol Sci ; 20(18)2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31491980

RESUMO

5-Fluorouracil (5-FU) is an important chemotherapeutic agent for the systemic treatment of colorectal cancer (CRC), but its effectiveness against CRC is limited by increased 5-FU resistance caused by the hypoxic tumor microenvironment. The purpose of our study was to assess the feasibility of using quinacrine (QC) to increase the efficacy of 5-FU against CRC cells under hypoxic conditions. QC reversed the resistance to 5-FU induced by hypoxia in CRC cell lines, as determined using ATP-Glo cell viability assays and clonogenic survival assays. Treatment of cells with 5-FU under hypoxic conditions had no effect on the expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a regulator of cellular resistance to oxidative stress, whereas treatment with QC alone or in combination with 5-FU reduced Nrf2 expression in all CRC cell lines tested. Overexpression of Nrf2 effectively prevented the increase in the number of DNA double-strand breaks induced by QC alone or in combination with 5-FU. siRNA-mediated c-Jun N-terminal kinase-1 (JNK1) knockdown inhibited the QC-mediated Nrf2 degradation in CRC cells under hypoxic conditions. The treatment of CRC xenografts in mice with the combination of QC and 5-FU was more effective in suppressing tumor growth than QC or 5-FU alone. QC increases the susceptibility of CRC cells to 5-FU under hypoxic conditions by enhancing JNK1-dependent Nrf2 degradation.


Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Fluoruracila/farmacologia , Hipóxia/genética , Hipóxia/metabolismo , Fator 2 Relacionado a NF-E2/genética , Quinacrina/farmacologia , Animais , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Modelos Animais de Doenças , Fluoruracila/uso terapêutico , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Modelos Biológicos , Fator 2 Relacionado a NF-E2/metabolismo , Estadiamento de Neoplasias , Proteólise , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Ann Clin Lab Sci ; 49(4): 481-487, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31471337

RESUMO

BACKGROUND: Chemotherapy resistance reduces the effectiveness of chemotherapeutic drugs greatly, resulting in treatment failure. Therefore, exploring chemoresistance-related genes and the corresponding mechanism is extremely important. The central role of CD44v6 in colorectal cancer has been previously reported. However, the effects of CD44v6 gene knockdown on the chemosensitivity of colorectal cancer cells are not conclusive. MATERIAL AND METHODS: A stable CD44v6 knockdown cell model in HT29 cells (HT29-KD) was established via lentiviral transduction. A quantitative real-time polymerase chain reaction (PCR) was carried out to confirm the knockdown efficiency. The chemosensitivity of cells to 5-fluorouracil (5-FU) was determined by a cell counting kit (CCK)-8 assay. Cell apoptosis and the cell cycle were assessed by flow cytometry. RESULTS: The CD44v6 knockdown cell model was successfully constructed by using lentiviral transduction. Upon treatment with 5-FU, the inhibitory rate for cell activity of HT29-KD cells was significantly higher than that of the control group (HT29-NC). CD44v6 gene knockdown did not significantly affect HT-29 cell proliferation, according to the CCK-8 assay and cell cycle analysis. The cell apoptosis assay revealed that CD44v6 gene knockdown promoted HT-29 cell apoptosis. Without 5-FU treatment, there was no significant difference in terms of the relative expression level of the autophagy-related gene BECN1 between the two groups. However, with 5-FU treatment, the relative expression level of BECN1 in HT29-KD cells was much lower than that in HT29-NC cells. CONCLUSION: Our study confirms that CD44v6 gene knockdown can enhance chemosensitivity in HT29 cells by promoting apoptosis and inhibiting autophagy, thus affirming the effects of CD44v6 on the chemosensitivity of colorectal cancer.


Assuntos
Apoptose , Autofagia , Neoplasias Colorretais/genética , Regulação para Baixo/genética , Receptores de Hialuronatos/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/genética , Autofagia/efeitos dos fármacos , Autofagia/genética , Proteína Beclina-1/genética , Proteína Beclina-1/metabolismo , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/patologia , Fluoruracila/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HCT116 , Células HT29 , Humanos , Modelos Biológicos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
16.
J Exp Clin Cancer Res ; 38(1): 353, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31412953

RESUMO

BACKGROUND: Tubeimoside-I (TBM), a plant-derived bioactive compound, shows antitumor activity in different tumors and can enhance the efficacy of chemotherapeutic agents. However, the detail mechanism underlying remains to be elucidated. METHODS: The cytotoxic potential of TBM towards CRC cells was examined by CCK8 assay, colony formation, LDH release assay, flow cytometry method and Western blots. The ROS levels, autophagy, apoptosis, chemosensitivity to 5-FU or DOX, etc. were determined between control and TBM-treated CRC cells. RESULTS: In this study, we found that TBM could inhibit proliferation and induce apoptosis in colorectal cancer (CRC) cells. Intriguingly, TBM treatment could either promote autophagy initiation by ROS-induced AMPK activation, or block autophagy flux through inhibiting lysosomal hydrolytic enzymes, which leaded to massive impaired autophagylysosomes accumulation. Administration of autophagy initiation inhibitor (3-MA or selective ablation of autophagy related proteins) relieves TBM-induced CRC suppression, while combination use of autophagy flux inhibitor chloroquine (CQ) slightly augments TBM-induced cell death, suggesting that impaired autophagylysosomes accumulation contributes to TBM-induced growth inhibition in CRC cells. Notably, as an autophagy flux inhibitor, TBM works synergistically with 5-fluorouracil (5-FU) or doxorubicin (DOX) in CRC suppression. CONCLUSION: Together, our study provides new insights regarding the anti-tumor activity of TBM against CRC, and established potential applications of TBM for CRC combination therapies in clinic.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Fagossomos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Saponinas/farmacologia , Triterpenos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Fluoruracila/farmacologia , Humanos , Lisossomos/metabolismo , Proteólise/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
17.
Nat Commun ; 10(1): 3667, 2019 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-31413255

RESUMO

Receptor type protein tyrosine phosphatase-sigma (PTPσ) is primarily expressed by adult neurons and regulates neural regeneration. We recently discovered that PTPσ is also expressed by hematopoietic stem cells (HSCs). Here, we describe small molecule inhibitors of PTPσ that promote HSC regeneration in vivo. Systemic administration of the PTPσ inhibitor, DJ001, or its analog, to irradiated mice promotes HSC regeneration, accelerates hematologic recovery, and improves survival. Similarly, DJ001 administration accelerates hematologic recovery in mice treated with 5-fluorouracil chemotherapy. DJ001 displays high specificity for PTPσ and antagonizes PTPσ via unique non-competitive, allosteric binding. Mechanistically, DJ001 suppresses radiation-induced HSC apoptosis via activation of the RhoGTPase, RAC1, and induction of BCL-XL. Furthermore, treatment of irradiated human HSCs with DJ001 promotes the regeneration of human HSCs capable of multilineage in vivo repopulation. These studies demonstrate the therapeutic potential of selective, small-molecule PTPσ inhibitors for human hematopoietic regeneration.


Assuntos
Apoptose/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/antagonistas & inibidores , Regeneração/efeitos dos fármacos , Regulação Alostérica , Animais , Antimetabólitos Antineoplásicos/farmacologia , Apoptose/efeitos da radiação , Fluoruracila/farmacologia , Células-Tronco Hematopoéticas/efeitos da radiação , Humanos , Camundongos , Radiação , Regeneração/efeitos da radiação , Proteína bcl-X/efeitos dos fármacos , Proteína bcl-X/metabolismo , Proteínas rac1 de Ligação ao GTP/efeitos dos fármacos , Proteínas rac1 de Ligação ao GTP/metabolismo , Proteínas rho de Ligação ao GTP/efeitos dos fármacos , Proteínas rho de Ligação ao GTP/metabolismo
18.
Nanoscale ; 11(34): 15958-15970, 2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31418432

RESUMO

Oral drug delivery systems (ODDSs) have attracted considerable attention in relation to orthotopic colon cancer therapy due to certain popular advantages. Unfortunately, their clinical applications are generally limited by the side-effects caused by systemic drug exposure and poor real-time monitoring capabilities. Inspired by the characteristics of pH changes of the gastrointestinal tract (GIT) and specific enzymes secreted by the colonic microflora, we anchored polyacrylic acid (PAA) and chitosan (CS) on Gd3+-doped mesoporous hydroxyapatite nanoparticles (Gd-MHAp NPs) to realize programmed drug release and magnetic resonance imaging (MRI) at the tumor sites. In particular, the grafted PAA, as a pH-responsive switch, could effect controlled drug release in the colon. Further, CS is functionalized as the enzyme-sensitive moiety, which could be degraded by ß-glycosidase in the colon. Gadolinium is a paramagnetic lanthanide element used in chelates, working as a contrast medium agent for an MRI system. Interestingly, after oral administration, CS and PAA could protect the drug-loaded nanoparticles (NPs) against variable physiological conditions in the GIT, allowing the drug to reach the colon tumor sites, preventing premature drug release. Enhanced drug concentrations at the colon tumor sites were achieved via this programmed drug release, which subsequently ameliorated the therapeutic effect. In addition, encapsulating both chemotherapeutic (5-fluorouracil, 5-FU) and targeted therapy drug (gefitinib, Gef) within Gd-MHAp NPs produced a synergistic therapeutic effect. In summary, this study demonstrated that such a novel drug system (Gd-MHAp/5-FU/Gef/CS/PAA NPs) could protect, transport, and program drug release locally within the colonic environment; further, this system exhibited a worthwhile therapeutic effect, providing a promising novel treatment strategy for orthotopic colon cancer.


Assuntos
Neoplasias do Colo , Meios de Contraste , Fluoruracila , Gadolínio , Gefitinibe , Imagem por Ressonância Magnética , Nanopartículas , Resinas Acrílicas/química , Resinas Acrílicas/farmacocinética , Resinas Acrílicas/farmacologia , Administração Oral , Animais , Quitosana/química , Quitosana/farmacocinética , Quitosana/farmacologia , Neoplasias do Colo/diagnóstico por imagem , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Meios de Contraste/química , Meios de Contraste/farmacocinética , Meios de Contraste/farmacologia , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Durapatita/química , Durapatita/farmacocinética , Durapatita/farmacologia , Fluoruracila/química , Fluoruracila/farmacocinética , Fluoruracila/farmacologia , Gadolínio/química , Gadolínio/farmacocinética , Gadolínio/farmacologia , Gefitinibe/química , Gefitinibe/farmacocinética , Gefitinibe/farmacologia , Células HT29 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/química , Nanopartículas/uso terapêutico
19.
Int J Mol Sci ; 20(17)2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31438649

RESUMO

The transforming growth factor-beta (TGF-ß) plays an important role in pathological fibrosis and cancer transformation. Therefore, the inhibition of the TGF-ß signaling pathway has therapeutic potential in the treatment of cancer. In this study, the binding modes between 47 molecules with a pyrrolotriazine-like backbone structure and transforming growth factor-beta type 1 receptor (TßR1) were simulated by molecular docking using Discovery Studio software, and their structure-activity relationships were analyzed. On the basis of the analysis of the binding modes of ligands in the active site and the structure-activity relationships, 29,254 new compounds were designed for virtual screening. According to the aforementioned analyses and Lipinski's rule of five, five new compounds (CQMU1901-1905) with potential activity were screened through molecular docking. Among them, CQMU1905 is an attractive molecule composed of 5-fluorouracil (5-FU), 6-mercaptopurine (6-MP), and 5-azacytosine. Interestingly, 5-FU, 6-MP, and 5-azacytidine are often used as anti-metabolic agents in cancer treatment. Compared with existing compounds, CQMU1901-1905 can interact with target proteins more effectively and have good potential for modification, making them worthy of further study.


Assuntos
Receptor do Fator de Crescimento Transformador beta Tipo I/antagonistas & inibidores , Citosina/análogos & derivados , Citosina/química , Citosina/farmacologia , Fluoruracila/química , Fluoruracila/farmacologia , Humanos , Mercaptopurina/química , Mercaptopurina/farmacologia , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade
20.
Int J Mol Sci ; 20(15)2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31374834

RESUMO

One of the current developments in drug research is the controlled release formulation of drugs, which can be released in a controlled manner at a specific target in the body. Due to the diverse physical and chemical properties of various drugs, a smart drug delivery system is highly sought after. The present study aimed to develop a novel drug delivery system using magnetite nanoparticles as the core and coated with polyvinyl alcohol (PVA), a drug 5-fluorouracil (5FU) and Mg-Al-layered double hydroxide (MLDH) for the formation of FPVA-FU-MLDH nanoparticles. The existence of the coated nanoparticles was supported by various physico-chemical analyses. In addition, the drug content, kinetics, and mechanism of drug release also were studied. 5-fluorouracil (5FU) was found to be released in a controlled manner from the nanoparticles at pH = 4.8 (representing the cancerous cellular environment) and pH = 7.4 (representing the blood environment), governed by pseudo-second-order kinetics. The cytotoxicity study revealed that the anticancer delivery system of FPVA-FU-MLDH nanoparticles showed much better anticancer activity than the free drug, 5FU, against liver cancer and HepG2 cells, and at the same time, it was found to be less toxic to the normal fibroblast 3T3 cells.


Assuntos
Hidróxido de Alumínio/química , Antimetabólitos Antineoplásicos/administração & dosagem , Preparações de Ação Retardada/química , Fluoruracila/administração & dosagem , Hidróxido de Magnésio/química , Nanopartículas de Magnetita/química , Álcool de Polivinil/química , Células 3T3 , Animais , Antimetabólitos Antineoplásicos/farmacologia , Combinação de Medicamentos , Sistemas de Liberação de Medicamentos , Fluoruracila/farmacologia , Células Hep G2 , Humanos , Camundongos , Neoplasias/tratamento farmacológico
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