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1.
Cancer Genomics Proteomics ; 18(5): 661-673, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34479918

RESUMO

BACKGROUND/AIM: Coronavirus disease 2019 (COVID-19) poses a great challenge for the treatment of cancer patients. It presents as a severe respiratory infection in aged individuals, including some lung cancer patients. COVID-19 may be linked to the progression of aggressive lung cancer. In addition, the side effects of chemotherapy, such as chemotherapy resistance and the acceleration of cellular senescence, can worsen COVID-19. Given this situation, we investigated the role of paclitaxel (a chemotherapy drug) in the cell proliferation, apoptosis, and cellular senescence of gefitinib-resistant non-small-cell lung cancer (NSCLC) cells (PC9-MET) to clarify the underlying mechanisms. MATERIALS AND METHODS: PC9-MET cells were treated with paclitaxel for 72 h and then evaluated by a cell viability assay, DAPI staining, Giemsa staining, apoptosis assay, a reactive oxygen species (ROS) assay, SA-ß-Gal staining, a terminal deoxynucleotidyl transferase dUTP nick-end labeling assay and Western blotting. RESULTS: Paclitaxel significantly reduced the viability of PC9-MET cells and induced morphological signs of apoptosis. The apoptotic effects of paclitaxel were observed by increased levels of cleaved caspase-3 (Asp 175), cleaved caspase-9 (Asp 330) and cleaved PARP (Asp 214). In addition, paclitaxel increased ROS production, leading to DNA damage. Inhibition of ROS production by N-acetylcysteine attenuates paclitaxel-induced DNA damage. Importantly, paclitaxel eliminated cellular senescence, as observed by SA-ß-Gal staining. Cellular senescence elimination was associated with p53/p21 and p16/pRb signaling inactivation. CONCLUSION: Paclitaxel may be a promising anticancer drug and offer a new therapeutic strategy for managing gefitinib-resistant NSCLC during the COVID-19 pandemic.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Gefitinibe/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
2.
Nat Commun ; 12(1): 4671, 2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34344863

RESUMO

Triple negative breast cancer (TNBC) remains challenging because of heterogeneous responses to chemotherapy. Incomplete response is associated with a greater risk of metastatic progression. Therefore, treatments that target chemotherapy-resistant TNBC and enhance chemosensitivity would improve outcomes for these high-risk patients. Breast cancer stem cell-like cells (BCSCs) have been proposed to represent a chemotherapy-resistant subpopulation responsible for tumor initiation, progression and metastases. Targeting this population could lead to improved TNBC disease control. Here, we describe a novel multi-kinase inhibitor, 108600, that targets the TNBC BCSC population. 108600 treatment suppresses growth, colony and mammosphere forming capacity of BCSCs and induces G2M arrest and apoptosis of TNBC cells. In vivo, 108600 treatment of mice bearing triple negative tumors results in the induction of apoptosis and overcomes chemotherapy resistance. Finally, treatment with 108600 and chemotherapy suppresses growth of pre-established TNBC metastases, providing additional support for the clinical translation of this agent to clinical trials.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Células-Tronco Neoplásicas/efeitos dos fármacos , Inibidores de Proteínas Quinases/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Caseína Quinase II/antagonistas & inibidores , Caseína Quinase II/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Camundongos , Células-Tronco Neoplásicas/patologia , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/química , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/química , Neoplasias de Mama Triplo Negativas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Int J Mol Sci ; 22(16)2021 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-34445264

RESUMO

The multidrug efflux transporter ABCB1 is clinically important for drug absorption and distribution and can be a determinant of chemotherapy failure. Recent structure data shows that three glutamines donate hydrogen bonds to coordinate taxol in the drug binding pocket. This is consistent with earlier drug structure-activity relationships that implicated the importance of hydrogen bonds in drug recognition by ABCB1. By replacing the glutamines with alanines we have tested whether any, or all, of Gln347, Gln725, and Gln990 are important for the transport of three different drug classes. Flow cytometric transport assays show that Q347A and Q990A act synergistically to reduce transport of Calcein-AM, BODIPY-verapamil, and OREGON GREEN-taxol bisacetate but the magnitude of the effect was dependent on the test drug and no combination of mutations completely abrogated function. Surprisingly, Q725A mutants generally improved transport of Calcein-AM and BODIPY-verapamil, suggesting that engagement of the wild-type Gln725 in a hydrogen bond is inhibitory for the transport mechanism. To test transport of unmodified taxol, stable expression of Q347/725A and the triple mutant was engineered and shown to confer equivalent resistance to the drug as the wild-type transporter, further indicating that none of these potential hydrogen bonds between transporter and transport substrate are critical for the function of ABCB1. The implications of the data for plasticity of the drug binding pocket are discussed.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Paclitaxel/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Substituição de Aminoácidos , Resistencia a Medicamentos Antineoplásicos/genética , Glutamina/genética , Glutamina/metabolismo , Células HEK293 , Humanos , Mutação de Sentido Incorreto
4.
Int J Mol Sci ; 22(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34360846

RESUMO

ATC is a very rare, but extremely aggressive form of thyroid malignancy, responsible for the highest mortality rate registered for thyroid cancer. In patients without known genetic aberrations, the current treatment is still represented by palliative surgery and systemic mono- or combined chemotherapy, which is often not fully effective for the appearance of drug resistance. Comprehension of the mechanisms involved in the development of the resistance is therefore an urgent issue to suggest novel therapeutic approaches for this very aggressive malignancy. In this study, we created a model of anaplastic thyroid cancer (ATC) cells resistant to paclitaxel and investigated the characteristics of these cells by analyzing the profile of gene expression and comparing it with that of paclitaxel-sensitive original ATC cell lines. In addition, we evaluated the effects of Dihydrotanshinone I (DHT) on the viability and invasiveness of paclitaxel-resistant cells. ATC paclitaxel-resistant cells highlighted an overexpression of ABCB1 and a hyper-activation of the NF-κB compared to sensitive cells. DHT treatment resulted in a reduction of viability and clonogenic ability of resistant cells. Moreover, DHT induces a decrement of NF-κB activity in SW1736-PTX and 8505C-PTX cells. In conclusion, to the best of our knowledge, the results of the present study are the first to demonstrate the antitumor effects of DHT on ATC cells resistant to Paclitaxel in vitro.


Assuntos
Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Furanos/farmacologia , Fenantrenos/farmacologia , Quinonas/farmacologia , Carcinoma Anaplásico da Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , NF-kappa B/metabolismo , Paclitaxel/farmacologia
5.
Anticancer Res ; 41(7): 3363-3370, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230132

RESUMO

BACKGROUND/AIM: The mechanisms through which cetuximab (cMab) coadministration with paclitaxel (PTX) enhances antitumor efficacy remain unclear. We examined the mechanism of the antitumor enhancing effect of cMab by determining changes in gene expression in the PI3K-AKT pathway. MATERIALS AND METHODS: Eight human oral squamous cell carcinoma (OSCC) cell lines were cultured three-dimensionally and exposed to PTX + cMab. The expression levels of PTEN mRNA in OSCC cell lines after anticancer drug treatment were assessed using real-time PCR. PTEN mRNA expression levels were also confirmed after administration of PTX + cMab in vivo. Western blot analysis was used to confirm the results at the protein level. RESULTS: PTEN mRNA and protein expression were significantly increased only in the cell lines with high sensitivity to PTX + cMab, and similar results were observed in vivo. CONCLUSION: PTEN activation may enhance the antitumor effect of PTX + cMab.


Assuntos
Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/genética , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/genética , PTEN Fosfo-Hidrolase/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Cetuximab/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Paclitaxel/farmacologia , Fosfatidilinositol 3-Quinases/genética
6.
Int J Mol Sci ; 22(12)2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34198613

RESUMO

Breast cancer is the most common cancer in females. The aim of this study was to determine the effect of paclitaxel (PTX) and doxorubicin (DOX) therapy on the ßIII-tubulin, carbonic anhydrase IX (CA IX), and survivin expression in chemically-induced rat mammary tumors. Animals with induced mammary carcinogenesis were randomly divided into treatment groups and an untreated group. The total proportion of tumors, the proportion of carcinoma in situ (CIS), and invasive carcinoma (IC) were evaluated. Protein expression in tumor tissue was determined using IHC. Statistical analysis of the data, evaluated by Fisher-exact test and unpaired t-test. Significantly increased levels of proteins in the tumor cells were confirmed using the IHC method for all studied proteins. The expression of ßIII-tubulin, CA IX, and survivin increased significantly after treatment with both cytostatics (PTX and DOX). Depending on the type of tumor, a significant increase in all proteins was observed in IC samples after PTX treatment, and CA IX expression after DOX treatment. In CIS samples, a significant increase of ßIII-tubulin and survivin expression was observed after a DOX treatment. The results suggest that ßIII-tubulin, survivin, and CA IX may be significant drug resistance markers and the clinical regulation of their activity may be an effective means of reversing this resistance.


Assuntos
Anidrase Carbônica IX/metabolismo , Doxorrubicina/uso terapêutico , Neoplasias Mamárias Animais/tratamento farmacológico , Neoplasias Mamárias Animais/metabolismo , Paclitaxel/uso terapêutico , Survivina/metabolismo , Tubulina (Proteína)/metabolismo , Animais , Doxorrubicina/farmacologia , Feminino , Paclitaxel/farmacologia , Ratos Sprague-Dawley
7.
Int J Mol Sci ; 22(14)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34299315

RESUMO

The absence of chemotherapeutic target hormone receptors in breast cancer is descriptive of the commonly known triple-negative breast cancer (TNBC) subtype. TNBC remains one of the most aggressive invasive breast cancers, with the highest mortality rates in African American women. Therefore, new drug therapies are continually being explored. Microtubule-targeting agents such as paclitaxel (Taxol) interfere with microtubules dynamics, induce mitotic arrest, and remain a first-in-class adjunct drug to treat TNBC. Recently, we synthesized a series of small molecules of substituted tetrahydroisoquinolines (THIQs). The lead compound of this series, with the most potent cytostatic effect, was identified as 4-Ethyl-N-(7-hydroxy-3,4-dihydroisoquinolin-2(1H)-yl) benzamide (GM-4-53). In our previous work, GM-4-53 was similar to paclitaxel in its capacity to completely abrogate cell cycle in MDA-MB-231 TNBC cells, with the former not impairing tubulin depolymerization. Given that GM-4-53 is a cytostatic agent, and little is known about its mechanism of action, here, we elucidate differences and similarities to paclitaxel by evaluating whole-transcriptome microarray data in MDA-MB-231 cells. The data obtained show that both drugs were cytostatic at non-toxic concentrations and caused deformed morphological cytoskeletal enlargement in 2D cultures. In 3D cultures, the data show greater core penetration, observed by GM-4-53, than paclitaxel. In concentrations where the drugs entirely blocked the cell cycle, the transcriptome profile of the 48,226 genes analyzed (selection criteria: (p-value, FDR p-value < 0.05, fold change -2< and >2)), paclitaxel evoked 153 differentially expressed genes (DEGs), GM-4-53 evoked 243 DEGs, and, of these changes, 52/153 paclitaxel DEGs were also observed by GM-4-53, constituting a 34% overlap. The 52 DEGS analysis by String database indicates that these changes involve transcripts that influence microtubule spindle formation, chromosome segregation, mitosis/cell cycle, and transforming growth factor-ß (TGF-ß) signaling. Of interest, both drugs effectively downregulated "inhibitor of DNA binding, dominant negative helix-loop-helix" (ID) transcripts; ID1, ID3 and ID4, and amphiregulin (AREG) and epiregulin (EREG) transcripts, which play a formidable role in cell division. Given the efficient solubility of GM-4-53, its low molecular weight (MW; 296), and capacity to penetrate a small solid tumor mass and effectively block the cell cycle, this drug may have future therapeutic value in treating TNBC or other cancers. Future studies will be required to evaluate this drug in preclinical models.


Assuntos
Citostáticos/farmacologia , Paclitaxel/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Antineoplásicos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Descoberta de Drogas , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Tetra-Hidroisoquinolinas/farmacologia , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
8.
Int J Mol Sci ; 22(14)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34299320

RESUMO

Chemotherapy is still widely used as a coadjutant in gastric cancer when surgery is not possible or in presence of metastasis. During tumor evolution, gatekeeper mutations provide a selective growth advantage to a subpopulation of cancer cells that become resistant to chemotherapy. When this phenomenon happens, patients experience tumor recurrence and treatment failure. Even if many chemoresistance mechanisms are known, such as expression of ATP-binding cassette (ABC) transporters, aldehyde dehydrogenase (ALDH1) activity and activation of peculiar intracellular signaling pathways, a common and universal marker for chemoresistant cancer cells has not been identified yet. In this study we subjected the gastric cancer cell line AGS to chronic exposure of 5-fluorouracil, cisplatin or paclitaxel, thus selecting cell subpopulations showing resistance to the different drugs. Such cells showed biological changes; among them, we observed that the acquired chemoresistance to 5-fluorouracil induced an endothelial-like phenotype and increased the capacity to form vessel-like structures. We identified the upregulation of thymidine phosphorylase (TYMP), which is one of the most commonly reported mutated genes leading to 5-fluorouracil resistance, as the cause of such enhanced vasculogenic ability.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Fluoruracila/farmacologia , Neovascularização Patológica/induzido quimicamente , Neoplasias Gástricas/irrigação sanguínea , Neoplasias Gástricas/tratamento farmacológico , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/patologia , Fluoruracila/metabolismo , Humanos , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Paclitaxel/farmacologia , Neoplasias Gástricas/patologia , Talidomida/farmacologia , Timidina Fosforilase/genética , Regulação para Cima/efeitos dos fármacos
9.
Biomed Pharmacother ; 138: 111536, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34311534

RESUMO

Ovarian cancer rates the highest mortality among all gynecological malignancies. The main reason for high mortality is the development of drug resistance. It can be related to changes in the expression of many drug resistance genes as well as expression of extracellular matrix proteins and cell density in the tumor. We developed a simple two-dimensional and three-dimensional model of drug sensitive A2780 and resistant to cisplatin and paclitaxel variants of ovarian cancer cell line. Using MTT assay, we compared drug resistance in two-dimensional and three-dimensional cell culture conditions. Real-time polymerase chain reaction analysis was used to compare the expression of drug resistance genes. The expression of proteins in spheroids was determined by immunohistochemistry. We observed a moderate increase in cisplatin resistance and a significant increase in paclitaxel resistance between two-dimensional and three-dimensional cell culture conditions. Our findings show that changes in the expression of drug resistance genes may play a crucial role in the drug resistance of cancer cells in traditional cell culture. On the other hand, the drug resistance in spheroids may result from different mechanisms such as cell density in the spheroid, extracellular matrix proteins expression and drug capacity to diffuse into the spheroid.


Assuntos
Antineoplásicos/farmacologia , Comunicação Celular , Técnicas de Cultura de Células , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia
10.
Int J Mol Sci ; 22(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34208987

RESUMO

Pancreatic Cancer (PC) is recognized as a highly thrombogenic tumor; thus, low-molecular-weight heparin (LMWH) such as tinzaparin is routinely used for PC patients. On the basis of combinatorial therapy approaches to treat highly malignant and refractory cancers such as PC, we hypothesized that tinzaparin can augment the effectiveness of traditional chemotherapeutic drugs and induce efficient antitumor activity. PANC-1 and MIAPaCa-2 were incubated alone or in combination with tinzaparin, nab-paclitaxel and gemcitabine. In vivo evaluation of these compounds was performed in a NOD/SCID mouse using a model injected with PANC-1. Tinzaparin enhances the anti-tumor effects of nab-paclitaxel and gemcitabine in mtKRAS PC cell lines via apoptosis in in vitro experiments. The triple combination power acts through the induction of apoptosis, reduction of the proliferative potential and angiogenesis; hence, contributing to a decrease in tumor volume observed in vivo. The triple regimen provided an extra 24.3% tumor reduction compared to the double combination (gemcitabine plus nab-paclitaxel). Combinatorial strategies can create novel therapeutic approaches for the treatment of patients with PC, achieving a better clinical outcome and prolonged survival. Further prospective randomized research is needed and the investigation of various concentrations of tinzaparin above 150 UI/Kg, would potentially provide a valuable synergistic effect to the conventional therapeutic compounds.


Assuntos
Albuminas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Desoxicitidina/análogos & derivados , Paclitaxel/administração & dosagem , Neoplasias Pancreáticas/tratamento farmacológico , Tinzaparina/administração & dosagem , Albuminas/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Desoxicitidina/administração & dosagem , Desoxicitidina/farmacologia , Relação Dose-Resposta a Droga , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Paclitaxel/farmacologia , Neoplasias Pancreáticas/metabolismo , Tinzaparina/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Nano Lett ; 21(14): 6031-6041, 2021 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-34240603

RESUMO

Triple-negative breast cancer (TNBC) is an aggressive disease with a high recurrence rate and poor outcomes in clinic. In this study, inspired by the enriched innate immune cell type tumor-associated macrophages (TAMs) in TNBC, we proposed a matrix metalloprotease 2 (MMP2) responsive integrated immunochemotherapeutic strategy to deliver paclitaxel (PTX) and anti-CD47 (aCD47) by detachable immune liposomes (ILips). In the TNBC microenvironment, the "two-in-one" ILips facilitated MMP2-responsive release of aCD47 to efficiently polarize M2 macrophages toward the M1 phenotype to enhance phagocytosis against tumor cells and activate the systemic T cell immune response. Together with the immune effect, the detached PTX-loaded liposomes were internalized in MDA-MB-231 cells to synergistically inhibit tumor cell proliferation and metastasis. In the TNBC-bearing mouse model, PTX-loaded ILips demonstrated superior antitumor efficacy against TNBC and inhibited tumor recurrence. Our integrated strategy represents a promising approach to synchronously enhance immune response and tumor-killing effects, improving the therapeutic efficacy against TNBC.


Assuntos
Neoplasias de Mama Triplo Negativas , Animais , Linhagem Celular Tumoral , Humanos , Lipossomos , Camundongos , Paclitaxel/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Microambiente Tumoral , Macrófagos Associados a Tumor
12.
Eur J Med Chem ; 222: 113605, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34126457

RESUMO

In this study, we designed and developed a novel asialoglycoprotein receptor (ASGPR)-targeted PEGylated paclitaxel (PTX) nanoliposome for hepatocellular carcinoma (HCC). N-acetylgalactosamine with α configuration (Tn) was synthesized and used as the active targeting ligand. Notably, Tn modified nanoliposomes loaded with PTX (Tn-Lipo-PTX) showed a narrow distribution (PDI = 0.18-0.20) with 74 ± 0.36 nm of average sizes. Tn-Lipo-PTX has a high encapsulation efficiency of more than 93.0% and 13% of drug loading (DL). Compared with no targeted Con-Lipo-PTX, Tn-Lipo-PTX showed lower and sustained release characteristic in PBS in vitro. Tn targeting ASGPR was confirmed by HepG-2 cells uptake experiment by fluorescence microscopy analysis. Tn-Lipo-PTX accumulated in HepG-2 cells and this process was inhibited by adding Tn ligand, supporting receptor-mediated endocytosis mechanism. MTT assays was implemented in four cell lines. Tn-Lipo-PTX exhibited superior inhibition against ASGPR on over-expressing HepG-2 (IC50 = 1.93 nM). The cell cycle experiments showed that Tn-Lipo-PTX could efficiently increase the percentage of cells arrest in the G2/M phase. Through western blotting analysis, the ß-tubulin and cyclin B1 expression in the Tn-Lipo-PTX group were significantly higher compared with other groups and the CDK1 was down-regulated compared with PTX group, which indicated that targeting liposome delivery system could not only change periodic proteins expression, but also improve the killing effect of PTX on hepatocarcinoma cell. Tn-installed PEGylated nanoliposomes have a great potential for targeted cancer chemotherapy.


Assuntos
Acetilgalactosamina/química , Antineoplásicos Fitogênicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Neoplasias Hepáticas/tratamento farmacológico , Nanopartículas/química , Paclitaxel/farmacologia , Antineoplásicos Fitogênicos/química , Carcinoma Hepatocelular/patologia , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Lipossomos/química , Neoplasias Hepáticas/patologia , Estrutura Molecular , Paclitaxel/química , Relação Estrutura-Atividade
13.
Nan Fang Yi Ke Da Xue Xue Bao ; 41(5): 760-766, 2021 May 20.
Artigo em Chinês | MEDLINE | ID: mdl-34134965

RESUMO

OBJECTIVE: To construct an ovarian cancer cell line stably overexpressing XAF1 gene and observe the effects of XAF1 gene overexpression on proliferation, apoptosis, cell cycle and sensitivity to paclitaxel of the cells. OBJECTIVE: Ovarian cancer A2780 cells were transfected with the plasmids pcDNA3.1(+) or pcDNA3.1(+)-XAF1, and the cells stably Over expressing XAF1 (A2780/XAF1 cells) were screened using G418. Cell clone formation assay and CCK8 assay were used to evaluate the changes in proliferation and paclitaxel sensitivity of the transfected cells, and cell cycle and apoptosis of the cells were analyzed using flow cytometry. OBJECTIVE: We successfully obtained A2780/XAF1 cells stably overexpressing XAF1, which exhibited no significant changes in cell morphology. Compared with the negative control cells (A2780/NC), A2780/XAF1 cells had lowered clone formation ability (P=0.0016) and attenuated proliferative activity on the first (P=0.009) and third (P=0.0035) days after cell adherence with also a significantly increased percentage of cells in G2-M phase (P < 0.001). A2780/XAF1 cells showed significantly higher apoptosis rates than A2780/NC cells in the absence of apoptotic stimulation, in serum-free culture or following paclitaxel induction (P < 0.001). The proliferative activity of A2780/XAF1 cells was significantly lower than that of A2780/NC cells after exposure to different paclitaxel concentrations (P < 0.001). The half inhibitory concentration of paclitaxel was significantly lower in A2780/XAF1 than in A2780/NC cells. OBJECTIVE: Overexpression of XAF1 significantly inhibits the proliferation, induces cell cycle arrest, promotes apoptosis, and increases paclitaxel sensitivity in ovarian cancer cells.


Assuntos
Neoplasias Ovarianas , Proteínas Adaptadoras de Transdução de Sinal , Apoptose/genética , Proteínas Reguladoras de Apoptose , Linhagem Celular Tumoral , Proliferação de Células/genética , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Neoplasias Ovarianas/genética , Paclitaxel/farmacologia
14.
J Interv Cardiol ; 2021: 9962313, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34121951

RESUMO

Objectives: The present study was designed to compare the characteristics and performance regarding drug delivery of a novel drug-coated balloon (DCB) to a benchmark device (Restore® versus SeQuent® Please) in an in vitro and in vivo model. Background: Although Restore® and SeQuent® are both paclitaxel-coated, they use different coating excipient, shellac-ammonium salt and iopromide, respectively. Preclinical study comparing these two different commercial DCBs regarding their characteristics and effects on early vascular response is sparse. Methods: Restore® and SeQuent® DCBs were scanned with electron microscopy for surface characteristic assessment. Both DCBs were transported in an in vitro vessel model for the evaluation of drug wash-off rate and particulate formation. Eighteen coronary angioplasties with either Restore® or SeQuent® DCBs were conducted in 6 swine (three coronary vessels each). Histopathological images of each vessel were evaluated for vessel injury. Results: The surface of Restore® DCB was smooth and evenly distributed with hardly visible crystal, while SeQuent® DCB showed a rougher surface with relatively larger apparent crystals. Restore® DCB had a lower drug wash-off rate and fewer large visible particles, compared to the SeQuent® DCB. No significant difference in mean injure score was found between Restore® and SeQuent® group. Conclusion: Our results suggest that Restore® is better in preclinical performance regarding less release of particles and lower drug wash-off rate as compared to SeQuent® Please. The Restore® DCB, using stable amorphous coating and shellac-ammonium salt as an excipient, appears to provide an advantage in drug delivery efficacy; however, further clinical studies are warranted.


Assuntos
Compostos de Amônio/farmacologia , Angioplastia Coronária com Balão/instrumentação , Cateteres Cardíacos , Vasos Coronários/cirurgia , Paclitaxel/farmacologia , Resinas Vegetais/farmacologia , Angioplastia Coronária com Balão/métodos , Animais , Antineoplásicos Fitogênicos/farmacologia , Materiais Revestidos Biocompatíveis/farmacologia , Sistemas de Liberação de Medicamentos , Teste de Materiais/métodos , Propriedades de Superfície , Suínos
15.
Acta Biochim Biophys Sin (Shanghai) ; 53(8): 1027-1036, 2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34109980

RESUMO

Targeted delivery and smart response of nanomedicine hold great promise for improving the therapeutic efficacy and alleviating the side effects of chemotherapy agents in cancer treatment. However, availability of only a few studies that discuss organic nanomedicines with these properties limits the development prospects of nanomedicines. In the present study, folic acid (FA)-targeted delivery and glutathione (GSH) smart responsive nanomedicine were rationally designed for paclitaxel (PTX) delivery for the treatment of lung cancer. Compared with other stimuli-responsive nanomedicines, this nanocarrier was not only sensitive to biologically relevant GSH for on-demand drug release but also biodegradable into biocompatible products after fulfilling its delivery task. The nanomedicine first entered tumor cells via FA and its receptor-mediated endocytosis. After the lysosomal escape, poly(lactic-co-glycolic acid) (PLGA) nanomedicine was triggered by a higher level of GSH and released its cargo into the tumor microenvironment. In vitro and in vivo results revealed that the PLGA nanomedicine not only inhibited the proliferation and promoted the apoptosis of lung cancer cells significantly but also possessed less toxic side effects when compared with free PTX. Therefore, the proposed drug delivery system demonstrates the potential of a multifunctional nano-platform to enhance bioavailability and reduce the side effects of chemotherapy agents.


Assuntos
Carcinoma Pulmonar de Lewis , Ácido Fólico , Glutationa/metabolismo , Neoplasias Pulmonares , Nanomedicina , Paclitaxel , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Animais , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Carcinoma Pulmonar de Lewis/metabolismo , Carcinoma Pulmonar de Lewis/patologia , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Ácido Fólico/química , Ácido Fólico/farmacocinética , Ácido Fólico/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Paclitaxel/química , Paclitaxel/farmacocinética , Paclitaxel/farmacologia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/farmacocinética , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/farmacologia
16.
J Med Chem ; 64(12): 8142-8160, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34086472

RESUMO

Salt-inducible kinases (SIKs) are key metabolic regulators. The imbalance in SIK function is associated with the development of diverse cancers, including breast, gastric, and ovarian cancers. Chemical tools to clarify the roles of SIK in different diseases are, however, sparse and are generally characterized by poor kinome-wide selectivity. Here, we have adapted the pyrido[2,3-d]pyrimidin-7-one-based p21-activated kinase (PAK) inhibitor G-5555 for the targeting of SIK, by exploiting differences in the back-pocket region of these kinases. Optimization was supported by high-resolution crystal structures of G-5555 bound to the known off-targets, MST3 and MST4, leading to a chemical probe, MRIA9, with dual SIK/PAK activity and excellent selectivity over other kinases. Furthermore, we show that MRIA9 sensitizes ovarian cancer cells to treatment with the mitotic agent paclitaxel, confirming earlier data from genetic knockdown studies and suggesting a combination therapy with SIK inhibitors and paclitaxel for the treatment of paclitaxel-resistant ovarian cancer.


Assuntos
Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Piridonas/farmacologia , Pirimidinas/farmacologia , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Desenho de Fármacos , Humanos , Simulação de Dinâmica Molecular , Estrutura Molecular , Paclitaxel/farmacologia , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Piridinas/síntese química , Piridinas/metabolismo , Piridonas/síntese química , Piridonas/metabolismo , Pirimidinas/síntese química , Pirimidinas/metabolismo , Ratos Sprague-Dawley , Relação Estrutura-Atividade
17.
J Med Chem ; 64(12): 8437-8446, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34097831

RESUMO

Paclitaxel (PTX) is a first-line treatment in breast cancer, though resistance develops quickly and frequently. Cytochrome P450 enzymes CYP3A4 and CYP2C8, which metabolically inactivate PTX in hepatic tissue, are overexpressed in malignant breast tissues. CYP3A4 expression correlates with PTX therapy failure and poor outcomes, though no direct evidence of CYP3A4 contributing to PTX sensitivity exists. Because CYP3A4/2C8 is susceptible to carbon monoxide (CO)-mediated inhibition and CO (a gaseous signaling molecule) has previously exhibited drug-sensitizing effects in cancer cells, we hypothesized that CO-mediated inhibition of CYP3A4/2C8 could lead to enhanced drug sensitivity. Using a photo-activated CO-releasing molecule, we have assessed the ability of CO to alter the pharmacokinetics of PTX in breast cancer cells via inhibition of CYP3A4/2C8 and determined that CO does enhance sensitivity of breast cancer cells to PTX. Inhibition of CYP3A4/2C8 by CO could therefore be a promising therapeutic strategy to enhance PTX response in breast cancer.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Monóxido de Carbono/farmacologia , Inibidores do Citocromo P-450 CYP2C8/farmacologia , Inibidores do Citocromo P-450 CYP3A/farmacologia , Paclitaxel/farmacologia , Antineoplásicos/farmacocinética , Monóxido de Carbono/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cloranfenicol/farmacologia , Complexos de Coordenação/farmacologia , Complexos de Coordenação/efeitos da radiação , Citocromo P-450 CYP2C8/metabolismo , Inibidores do Citocromo P-450 CYP2C8/efeitos da radiação , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A/efeitos da radiação , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Luz , Manganês/química , Paclitaxel/farmacocinética
18.
Cancer Sci ; 112(9): 3769-3783, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34181803

RESUMO

The large-conductance Ca2+ -activated K+ channel KCa 1.1 plays a pivotal role in tumor development and progression in several solid cancers. The three-dimensional (3D) in vitro cell culture system is a powerful tool for cancer spheroid formation, and mimics in vivo solid tumor resistance to chemotherapy in the tumor microenvironment (TME). KCa 1.1 is functionally expressed in osteosarcoma and chondrosarcoma cell lines. KCa 1.1 activator-induced hyperpolarizing responses were significantly larger in human osteosarcoma MG-63 cells isolated from 3D spheroid models compared with in those from adherent 2D monolayer cells. The present study investigated the mechanisms underlying the upregulation of KCa 1.1 and its role in chemoresistance using a 3D spheroid model. KCa 1.1 protein expression levels were significantly elevated in the lipid-raft-enriched compartments of MG-63 spheroids without changes in its transcriptional level. 3D spheroid formation downregulated the expression of the ubiquitin E3 ligase FBXW7, which is an essential contributor to KCa 1.1 protein degradation in breast cancer. The siRNA-mediated inhibition of FBXW7 in MG-63 cells from 2D monolayers upregulated KCa 1.1 protein expression. Furthermore, a treatment with a potent and selective KCa 1.1 inhibitor overcame the chemoresistance of the MG-63 and human chondrosarcoma SW-1353 spheroid models to paclitaxel, doxorubicin, and cisplatin. Among several multidrug resistance ATP-binding cassette transporters, the expression of the multidrug resistance-associated protein MRP1 was upregulated in both spheroids and restored by the inhibition of KCa 1.1. Therefore, the pharmacological inhibition of KCa 1.1 may be an attractive new strategy for acquiring resistance to chemotherapeutic drugs in the TME of KCa 1.1-positive sarcomas.


Assuntos
Neoplasias Ósseas/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/metabolismo , Osteossarcoma/metabolismo , Esferoides Celulares/metabolismo , Regulação para Cima/genética , Antineoplásicos/farmacologia , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/farmacologia , Doxorrubicina/farmacologia , Proteína 7 com Repetições F-Box-WD/genética , Proteína 7 com Repetições F-Box-WD/metabolismo , Humanos , Indóis/farmacologia , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/antagonistas & inibidores , Osteossarcoma/patologia , Paclitaxel/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , RNA Interferente Pequeno/genética , Transfecção , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética
19.
Nanoscale ; 13(23): 10536-10543, 2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34100041

RESUMO

The rational design of oral paclitaxel (PTX) preparations is still a challenge. Many studies focus on developing PTX-loaded nanoemulsions (NEs) for oral administration. Unfortunately, PTX has poor affinity with the commonly used oil phases, leading to low encapsulation efficiency, poor colloidal stability, and premature drug leakage of PTX-loaded NEs. Herein, three lipophilic PTX prodrugs are synthesized by conjugating PTX with citronellol (CIT), using different lengths of disulfide bond-containing linkages. Interestingly, compared with PTX, the prodrugs exhibit higher affinity with the oil phase, effectively improving the encapsulation efficiency, colloidal stability, and sustained-release behavior of NEs. In addition, the disulfide bond-bridged prodrugs could specifically release PTX in tumor cells, reducing unnecessary systemic exposure of PTX. As a result, all three prodrug NEs exhibited improved oral bioavailability and antitumor effects compared to oral Taxol. Moreover, the length of disulfide bond-containing linkages exhibits great impacts on the oral absorption, drug release, and antitumor behaviors of NEs. It is found that the prodrug NEs with the shortest linkages show comparable antitumor effects with intravenous Taxol, but with less systemic and gastrointestinal toxicity.


Assuntos
Antineoplásicos Fitogênicos , Pró-Fármacos , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Dissulfetos , Portadores de Fármacos , Paclitaxel/farmacologia , Pró-Fármacos/farmacologia
20.
Molecules ; 26(9)2021 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-34064416

RESUMO

The objective of this study was to synthesize and characterize a set of biodegradable block copolymers based on TPGS-block-poly(ε-caprolactone) (TPGS-b-PCL) and to assess their self-assembled structures as a nanodelivery system for paclitaxel (PAX). The conjugation of PCL to TPGS was hypothesized to increase the stability and the drug solubilization characteristics of TPGS micelles. TPGS-b-PCL copolymer with various PCL/TPGS ratios were synthesized via ring opening bulk polymerization of ε-caprolactone using TPGS, with different molecular weights of PEG (1-5 kDa), as initiators and stannous octoate as a catalyst. The synthesized copolymers were characterized using 1H NMR, GPC, FTIR, XRD, and DSC. Assembly of block copolymers was achieved via the cosolvent evaporation method. The self-assembled structures were characterized for their size, polydispersity, and CMC using dynamic light scattering (DLS) technique. The results from the spectroscopic and thermal analyses confirmed the successful synthesis of the copolymers. Only copolymers that consisted of TPGS with PEG molecular weights ≥ 2000 Da were able to self-assemble and form nanocarriers of ≤200 nm in diameter. Moreover, TPGS2000-b-PCL4000, TPGS3500-b-PCL7000, and TPGS5000-b-PCL15000 micelles enhanced the aqueous solubility of PAX from 0.3 µg/mL up to 88.4 ug/mL in TPGS5000-b-PCL15000. Of the abovementioned micellar formulations, TPGS5000-b-PCL15000 showed the slowest in vitro release of PAX. Specifically, the PAX-loaded TPGS5000-b-PCL15000 micellar formulation showed less than 10% drug release within the first 12 h, and around 36% cumulative drug release within 72 h compared to 61% and 100% PAX release, respectively, from the commercially available formulation (Ebetaxel®) at the same time points. Our results point to a great potential for TPGS-b-PCL micelles to efficiently solubilize and control the release of PAX.


Assuntos
Portadores de Fármacos/química , Nanopartículas/química , Paclitaxel/farmacologia , Poliésteres/química , Vitamina E/química , Varredura Diferencial de Calorimetria , Cromatografia em Gel , Preparações de Ação Retardada , Liberação Controlada de Fármacos , Micelas , Nanopartículas/ultraestrutura , Tamanho da Partícula , Poliésteres/síntese química , Espectroscopia de Prótons por Ressonância Magnética , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Vitamina E/síntese química , Água/química , Difração de Raios X
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