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1.
Biomed Pharmacother ; 153: 113428, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36076548

RESUMO

Ligand-based targeting of the receptors that are overexpressed explicitly on cancer cells represents an effective drug delivery approach to enhance the chemotherapeutic efficacy. Proprotein convertase subtilisin/kexin type 9 (PCSK9) which is a serine protease enzyme primarily produced by the liver cells, can potentially be used as a targeting ligand. PCSK9 binds to the LDL-r on hepatocytes' surface, leading to endocytosis and endosomal degradation. High LDL-r expression, which is believed to meet the higher demand of the cholesterol and phospholipids to build proliferating cancer cell membrane, ensures selective uptake of the PCSK9 conjugated liposomes. In the present work, the PCSK9 conjugated liposomal system was developed to deliver paclitaxel (PTX) to cancer cells. The protein was conjugated by EDC and NHS in a two-step coupling reaction to the liposomes containing COOH-PEG2000-COOH lipid. Conjugation was confirmed by NMR, and liposomes were further characterized by SEM and zeta sizer. PCSK9-conjugated liposomes showed high encapsulation efficiency of 69.1% with a diameter of 90.0 ± 4.9 nm. Long-term stability (30 days) study (Zeta potential: -9.88) confirmed excellent constancy and significant drug retention (58.2%). Invitro cytotoxicity and targeting efficiency was explored using MTS assay in human embryonic kidney cells (HEK293), liver hepatocellular cells (HEPG2), and a human colon cancer cell line (HCT116) for 24 h. PCSK9 conjugated liposomes exhibited significantly higher growth inhibition than the unconjugated (control) liposomes in HCT116 cell line (p < 0.001). The novel PCSK9 conjugated liposomes presented potent and precise in vitro anticancer activity and, therefore, are suggested for the first time as a promising targeted delivery system for cancer treatment.


Assuntos
Neoplasias , Pró-Proteína Convertase 9 , Células HEK293 , Humanos , Ligantes , Lipossomos , Neoplasias/tratamento farmacológico , Paclitaxel/farmacologia , Pró-Proteína Convertase 9/metabolismo , Pró-Proteína Convertases/química , Pró-Proteína Convertases/metabolismo , Receptores de LDL/metabolismo
2.
Front Endocrinol (Lausanne) ; 13: 950345, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36120434

RESUMO

Due to the lack of symptoms and detection biomarkers at the early stage, most patients with ovarian cancer (OC) are diagnosed at an advanced stage and often face chemoresistance and relapse. Hence, defining detection biomarkers and mechanisms of chemoresistance is imperative. A previous report of a cDNA microarray analysis shows a potential association of carnitine O-octanoyltransferase (CROT) with taxane resistance but the biological function of CROT in OC remains unknown. The current study explored the function and regulatory mechanism of CROT on cellular behavior and paclitaxel (PTX)-resistance in OC. We found that CROT was downregulated in OC tissues and PTX-resistant cells. Furthermore, CROT expression was negatively correlated with the prognosis of OC patients. Overexpression of CROT inhibited the OC cell proliferation, migration, invasion, and colony formation, arrested the cell cycle at the G2/M phase, and promoted cell apoptosis. In addition, miR-33a-5p bound directly to the 3'UTR of CROT to negatively regulate the expression of CROT and promoted OC cell growth. Finally, overexpression of CROT decreased the phosphorylation of Smad2, whereas knockdown of CROT increased the nuclear translocation of Smad2 and Smad4, two transducer proteins of TGF-ß signaling, indicating that CROT is a tumor suppressor which mediates OC cell behaviors through the TGF-ß signaling pathway. Thus, targeting the miR-33a-5p/CROT axis may have clinical potential for the treatment of patients with OC.


Assuntos
MicroRNAs , Neoplasias Ovarianas , Regiões 3' não Traduzidas , Carnitina , Linhagem Celular Tumoral , DNA Complementar/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Recidiva Local de Neoplasia/genética , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Transdução de Sinais , Taxoides/uso terapêutico , Fator de Crescimento Transformador beta
3.
Molecules ; 27(17)2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-36080414

RESUMO

During a screening performed by the National Cancer Institute in the 1960s, the terpenoid paclitaxel was discovered. Paclitaxel expanded the treatment options for breast, lung, prostate and ovarian cancer. Paclitaxel is only present in minute amounts in the bark of Taxia brevifolia. A sustainable supply was ensured with a culture developed from Taxus chinensis, or with semi-synthesis from other taxanes. Paclitaxel is marketed under the name Taxol. An intermediate from the semi-synthesis docetaxel is also used as a drug and marketed as Taxotere. O-Methylated docetaxel is used for treatment of some paclitaxel-resistant cancer forms as cabazitaxel. The solubility problems of paclitaxel have been overcome by formulation of a nanoparticle albumin-bound paclitaxel (NAB-paclitaxel, Abraxane). The mechanism of action is affinity towards microtubules, which prevents proliferation and consequently the drug would be expected primarily to be active towards cancer cells proliferating faster than benign cells. The activity against slowly growing tumors such as solid tumors suggests that other effects such as oncogenic signaling or cellular trafficking are involved. In addition to terpenoids, recently discovered microtubule-targeting polyketide macrolides and non-ribosomal peptides have been discovered and marketed as drugs. The revolutionary improvements for treatment of cancer diseases targeting microtubules have led to an intensive search for other compounds with the same target. Several polyketide macrolides, terpenoids and non-ribosomal peptides have been investigated and a few marketed.


Assuntos
Macrolídeos , Neoplasias Ovarianas , Docetaxel/farmacologia , Feminino , Humanos , Macrolídeos/farmacologia , Masculino , Microtúbulos , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/farmacologia , Peptídeos/farmacologia
4.
Int J Mol Sci ; 23(17)2022 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-36077036

RESUMO

The incidence of melanoma is steadily increasing worldwide. Melanoma is the most lethal skin cancer, and new therapeutic methods are being sought. Our research aimed to investigate the cytotoxic and antiproliferative effects of betulinic acid in vitro, used alone and in combination with taxanes (paclitaxel, docetaxel) in four melanoma cell lines. Isobolographic analysis allowed us to assess the interactions between these compounds. Betulinic acid had no cytotoxic effect on normal human keratinocyte HaCaT cells; the amount of LDH released by them was significantly lower compared to melanoma cell lines. The present study shows that betulinic acid significantly inhibits the growth of melanoma cell lines in vitro. The IC50 values of betulinic acid ranged from 2.21 µM to 15.94 µM against the four melanoma lines. Co-treatment of betulinic acid with paclitaxel or docetaxel generated desirable drug-drug interactions, such as an additive and additive with a tendency to synergy interactions.


Assuntos
Antineoplásicos , Melanoma , Neoplasias Cutâneas , Antineoplásicos/farmacologia , Linhagem Celular , Docetaxel/farmacologia , Humanos , Técnicas In Vitro , Melanoma/metabolismo , Paclitaxel/farmacologia , Triterpenos Pentacíclicos , Taxoides/farmacologia
5.
Oncol Rep ; 48(4)2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36069232

RESUMO

Paclitaxel (PTX) is widely used in the treatment of non­small cell lung cancer (NSCLC). However, acquired PTX drug resistance is a major obstacle to its therapeutic efficacy and the underlying mechanisms are still unclear. The present study revealed a novel role of the SRY­box transcription factor 2 (SOX2)­chloride voltage­gated channel­3 (ClC­3) axis in PTX resistance of A549 NSCLC cells. The expression levels of SOX2 and ClC­3 were upregulated in PTX­resistant A549 NSCLC cells by RT­qPCR and western blotting. The drug resistance to PTX of A549 NSCLC cells were measured by detecting the cell viability and the expression of drug resistance markers. Knockdown of SOX2 or ClC­3 effectively decreased PTX resistance of A549 NSCLC cells, whereas SOX2 or ClC­3 overexpression promoted PTX resistance. Mechanistically, SOX2 bound to the promoter of ClC­3 and enhanced the transcriptional activation of ClC­3 expression by CUT&Tag assays, CUT&Tag qPCR and luciferase reporter. In summary, the present findings defined ClC­3 as an important downstream effector of SOX2 and ClC­3 and SOX2 contributed to PTX resistance. Targeting SOX2 and its downstream effector ClC­3 increased the sensitivity of NSCLC cells to PTX treatment, which provided potential therapeutic strategies for patients with NSCLC with PTX resistance.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Células A549 , Apoptose , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Fatores de Transcrição SOXB1/genética
6.
PLoS One ; 17(9): e0274607, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36108271

RESUMO

Mesenchymal stem cells can be obtained and multiplied from various sources and have a very high capacity to release exosomes. Exosomes are nano-sized extracellular vesicles containing biological signaling molecules. This study aimed to determine the effect of MSC-derived exosomes as a drug delivery system for paclitaxel in cervical cancer cells. In this study, human MSC were isolated from wharton jelly of umbilical cord tissue (WJ-MSC), and cells were characterized by CD44, CD90, CD105, and CD34 staining. Exosomes were released in WJ-MSC cells with serum-starved conditions for 48 hours, and particle sizes and structures were examined with zeta-sizer and TEM. In addition, exosomes CD9, CD63, and CD81 markers were checked by western blot. Paclitaxel was loaded into exosomes (Exo-PAC) by electroporation and then incubated with Hela cervical cancer cells for 24 hours. TGF-ß, SMAD, Snail, Slug, ß-catenin, Notch, Caspase-3, Caspase-9, Bax, Bcl-2 protein and gene expression levels were analyzed in Hela cells. As a result, low concentration Exo-PAC induced apoptosis, and suppressed epithelial-mesenchymal transition proteins in Hela cells. In this study, it has been demonstrated that WJ-MSCs can be used as drug delivery systems for cervical cancer if exosomes are produced scalably in the future.


Assuntos
Exossomos , Células-Tronco Mesenquimais , Neoplasias do Colo do Útero , Geleia de Wharton , Apoptose , Caspase 3/metabolismo , Caspase 9/metabolismo , Portadores de Fármacos/metabolismo , Exossomos/metabolismo , Feminino , Células HeLa , Humanos , Células-Tronco Mesenquimais/metabolismo , Paclitaxel/metabolismo , Paclitaxel/farmacologia , Fator de Crescimento Transformador beta/metabolismo , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/metabolismo , Geleia de Wharton/metabolismo , Proteína X Associada a bcl-2/metabolismo , beta Catenina/metabolismo
7.
Biomed Pharmacother ; 153: 113474, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36076499

RESUMO

Tumor cells can secret various cytokines and chemokines, which affect the tumor cells themselves and the neighboring cells. Here, we observed that human ovarian cancer (OC) cells developed resistance to paclitaxel treatment following culture with the conditioned medium (CM) derived from paclitaxel-resistant OC (OCTR) cells. A cytokine array revealed that both OCTR cells secreted large amounts of CC chemokine ligand 2 (CCL2). CCL2 and its receptor, CCR2, were overexpressed in OCTR cells. CCL2 expression was associated with worse progression-free survival in patients with ovarian cancer. The inhibition of the CCL2/CCR2 axis suppressed the chemoresistance induced by OCTR-CM. The enhanced expression and production of CCL2 in OC cells were mediated via the NF-κB pathway, and stimulated the activation of the PI3K/Akt pathway, which resulted in the development of paclitaxel resistance in OC cells. Additionally, the OCTR cells significantly increased the migration of macrophages, which was also associated with the overproduction of CCL2 in chemoresistant cancer cells. The macrophages stimulated by OCTR cells expressed high levels of markers of M2 phenotype, and their CM significantly decreased the paclitaxel responsiveness of OC cells. The administration of a CCR2 inhibitor to a murine model significantly improved the paclitaxel sensitivity. These data suggested that apart from inducing chemoresistance in OC cells by acting as an autocrine factor, CCL2 also functions as a chemokine that induces the chemotaxis of macrophages, which may contribute to chemoresistance. Therefore, targeting the CCL2/CCR2 signaling axis may improve the therapeutic response of patients with ovarian cancer to paclitaxel.


Assuntos
Comunicação Autócrina , Neoplasias Ovarianas , Animais , Carcinoma Epitelial do Ovário/metabolismo , Linhagem Celular Tumoral , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Quimiocinas/metabolismo , Citocinas/metabolismo , Feminino , Humanos , Ligantes , Macrófagos/metabolismo , Camundongos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Paclitaxel/metabolismo , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Fosfatidilinositol 3-Quinases/metabolismo
8.
Cells ; 11(17)2022 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-36078127

RESUMO

The emergence of drug resistance in cancer poses the greatest hurdle for successful therapeutic results and is associated with most cancer deaths. In triple negative breast cancer (TNBC), due to the lack of specific therapeutic targets, systemic chemotherapy is at the forefront of treatments, but it only benefits a fraction of patients because of the development of resistance. Cancer cells may possess an innate resistance to chemotherapeutic agents or develop new mechanisms of acquired resistance after long-term drug exposure. Such mechanisms involve an interplay between genetic, epigenetic and metabolic alterations that enable cancer cells to evade therapy. In this work, we generated and characterized a chemoresistant TNBC cell line to be used for the investigation of mechanisms that drive resistance to paclitaxel. Transcriptomic analysis highlighted the important role of metabolic-associated pathways in the resistant cells, prompting us to employ 1H-NMR to explore the metabolome and lipidome of these cells. We identified and described herein numerous metabolites and lipids that were significantly altered in the resistant cells. Integrated analysis of our omics data revealed MSMO1, an intermediate enzyme of cholesterol biosynthesis, as a novel mediator of chemoresistance in TNBC. Overall, our data provide a critical insight into the metabolic adaptations that accompany acquired resistance in TNBC and pinpoint potential new targets.


Assuntos
Antineoplásicos , Neoplasias de Mama Triplo Negativas , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo
9.
PLoS One ; 17(8): e0268307, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36001584

RESUMO

Peripheral artery disease (PAD) is a systemic vascular disease of the legs that results in a blockage of blood flow from the heart to the lower extremities. Now one of the most common causes of mortality in the U.S., the first line of therapy for PAD is to mechanically open the blockages using balloon angioplasty. Coating the balloons with antiproliferative agents can potentially reduce vessel re-narrowing, or restenosis after surgical intervention, but current drug-coated balloons releasing chemotherapy agents like paclitaxel have in some cases shown increased mortality long-term. Our aim was to design a novel drug-coated balloon using a polymeric nanodelivery system for a sustained release of polyphenols that reduce restenosis but with reduced toxicity compared to chemotherapy agents. Poly (lactic-co-glycolic acid) (PLGA) nanoparticles with entrapped quercetin, a dimethoxy quercetin (rhamnazin), as well as quercetin covalently attached to PLGA, were developed. Balloon catheters were coated with polymeric nanoparticles using an ultrasonic method, and nanoparticle characteristics, drug loading, coating uniformity and drug release were determined. The adhesion of nanoparticles to vascular smooth muscle cells and the antiproliferative effect of nano-delivered polyphenols were also assessed. Of the nanoparticle systems tested, those with covalently attached quercetin provided the most sustained release over a 6-day period. Although these particles adhered to cells to a smaller extent compared to other nanoparticle formulations, their attachment was resistant to washing. These particles also exhibited the greatest anti-proliferative effect. In addition, their attachment was not altered when the cells were grown in calcifying conditions, and in PAD tissue calcification is typically a condition that impedes drug delivery. Moreover, the ultrasonic coating method generated a uniform balloon coating. The polymeric nanoparticle system with covalently attached quercetin developed herein is thus proposed as a promising platform to reduce restenosis post-angioplasty.


Assuntos
Angioplastia com Balão , Nanopartículas , Doença Arterial Periférica , Angioplastia com Balão/métodos , Materiais Revestidos Biocompatíveis , Preparações de Ação Retardada , Humanos , Paclitaxel/farmacologia , Doença Arterial Periférica/terapia , Polímeros , Quercetina/farmacologia
10.
Int J Mol Sci ; 23(15)2022 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-35955892

RESUMO

Ovarian cancer is a carcinoma that affects women and that has a high mortality rate. Overcoming paclitaxel resistance is important for clinical application. However, the effect of amino acid metabolism regulation on paclitaxel-resistant ovarian cancer is still unknown. In this study, the effect of an amino acid-deprived condition on paclitaxel resistance in paclitaxel-resistant SKOV3-TR cells was analyzed. We analyzed the cell viability of SKOV3-TR in culture conditions in which each of the 20 amino acids were deprived. As a result, the cell viability of the SKOV3-TR was significantly reduced in cultures deprived of arginine, glutamine, and lysine. Furthermore, we showed that the glutamine-deprived condition inhibited mTORC1/S6K signaling. The decreased cell viability and mTORC1/S6K signaling under glutamine-deprived conditions could be restored by glutamine and α-KG supplementation. Treatment with PF-4708671, a selective S6K inhibitor, and the selective glutamine transporter ASCT2 inhibitor V-9302 downregulated mTOR/S6K signaling and resensitized SKOV3-TR to paclitaxel. Immunoblotting showed the upregulation of Bcl-2 phosphorylation and a decrease in Mcl-1 expression in SKOV3-TR via the cotreatment of paclitaxel with PF-4708671 and V-9302. Collectively, this study demonstrates that the inhibition of glutamine uptake can resensitize SKOV3-TR to paclitaxel and represents a promising therapeutic target for overcoming paclitaxel resistance in ovarian cancer.


Assuntos
Neoplasias Ovarianas , Paclitaxel , Carcinoma Epitelial do Ovário , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Feminino , Glutamina/farmacologia , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Neoplasias Ovarianas/patologia , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Proteínas Quinases S6 Ribossômicas/metabolismo , Transdução de Sinais
11.
Cell Death Dis ; 13(8): 751, 2022 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-36042202

RESUMO

There is a potential correlation between G-protein-coupled receptor-associated sorting protein 1 (GASP1) and breast tumorigenesis. However, its biological function and underlying molecular mechanism in breast cancer have not been clearly delineated. Here, we demonstrated that GASP1 was highly expressed in breast cancers, and patients harboring altered GASP1 showed a worse prognosis than those with wild-type GASP1. Functional studies showed that GASP1 knockout significantly suppressed malignant properties of breast cancer cells, such as inhibition of cell proliferation, colony formation, migration, invasion and xenograft tumor growth in nude mice as well as induction of G1-phase cell cycle arrest, and vice versa. Mechanistically, GASP1 inhibited proteasomal degradation of insulin-like growth factor 1 receptor (IGF1R) by competitively binding to IGF1R with ubiquitin E3 ligase MDM2, thereby activating its downstream signaling pathways such as NF-κB, PI3K/AKT, and MAPK/ERK pathways given their critical roles in breast tumorigenesis and progression. IGF1, in turn, stimulated GASP1 expression by activating the PI3K/AKT pathway, forming a vicious cycle propelling the malignant progression of breast cancer. Besides, we found that GASP1 knockout obviously improved the response of breast cancer cells to paclitaxel. Collectively, this study demonstrates that GASP1 enhances malignant behaviors of breast cancer cells and decreases their cellular response to paclitaxel by interacting with and stabilizing IGF1R, and suggests that it may serve as a valuable prognostic factor and potential therapeutic target in breast cancer.


Assuntos
Neoplasias da Mama , Fator de Crescimento Insulin-Like I , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células , Transformação Celular Neoplásica , Feminino , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Camundongos , Camundongos Nus , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Fenótipo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais
12.
Cell Mol Biol (Noisy-le-grand) ; 68(3): 314-321, 2022 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-35988184

RESUMO

This study aimed to investigate the effect of double-layer nano-infusion on restenosis in animal models of coronary atherosclerosis (CAD). For this purpose, forty Apolipoprotein E (APOE) gene mice (ApoE -/ -) were fed with 1.25% cholesterol, 10% fat, and 88.75% standard diet to establish CAD models. They were classified into the control group with paclitaxel nanoparticles (PTX-NPs) and the observation group with balloon infusion of PTX combined with vascular endothelial growth factor (VEGF) double-layer nanoparticles (V-P-NPs). The vascular endothelial healing and the occurrence of vascular restenosis were assessed. Results showed no significant differences in the particle size, distribution, and Zeta-potential between PTX-NPs and V-P-NPs (P>0.05). According to the transmission electron microscope (TEM), the nanoparticles had good dispersity, and the structure of the inner and outer layers of V-P-NPs was obvious. There were insignificant differences between the entrapment efficiency of PTX in PTX-PNS and the PTX and VEGF in V-P-NPs (94.32%, 95.66%, 97.89%) and drug-loading rate (28.91%, 30.12%, 29.91%) (P>0.05). The vascular endothelial healing degree of the observation group was better than that of the control group under optical coherence tomography (OCT). The restenosis, including the stenosis (6.91±7.59)%, proliferation (0.12±0.02), and the maximum intima thickness (0.07±0.09)mm of the observation group was decreased compared with the control group ((24.01±12.78)%, (0.28±0.01), (0.19±0.08)mm) (P<0.05). Then the double-layer nano-infusion therapy was conducive to healing vascular endothelial tissue and could effectively inhibit vascular restenosis, with clinical adoption value.


Assuntos
Doença da Artéria Coronariana , Sistemas de Liberação de Fármacos por Nanopartículas , Animais , Apolipoproteínas E/genética , Constrição Patológica/tratamento farmacológico , Doença da Artéria Coronariana/tratamento farmacológico , Camundongos , Modelos Animais , Sistemas de Liberação de Fármacos por Nanopartículas/química , Sistemas de Liberação de Fármacos por Nanopartículas/farmacologia , Nanopartículas/química , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Fator A de Crescimento do Endotélio Vascular
13.
Molecules ; 27(16)2022 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-36014500

RESUMO

Natural products represent an excellent source of unprecedented anticancer compounds. However, the identification of the mechanism of action remains a major challenge. Several techniques and methodologies have been considered, but with limited success. In this work, we explored the combination of live cell imaging and machine learning techniques as a promising tool to depict in a fast and affordable test the mode of action of natural compounds with antiproliferative activity. To develop the model, we selected the non-small cell lung cancer cell line SW1573, which was exposed to the known antimitotic drugs paclitaxel, colchicine and vinblastine. The novelty of our methodology focuses on two main features with the highest relevance, (a) meaningful phenotypic metrics, and (b) fast Fourier transform (FFT) of the time series of the phenotypic parameters into their corresponding amplitudes and phases. The resulting algorithm was able to cluster the microtubule disruptors, and meanwhile showed a negative correlation between paclitaxel and the other treatments. The FFT approach was able to group the samples as efficiently as checking by eye. This methodology could easily scale to group a large amount of data without visual supervision.


Assuntos
Antimitóticos , Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Antimitóticos/farmacologia , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Humanos , Neoplasias Pulmonares/metabolismo , Microtúbulos/metabolismo , Paclitaxel/metabolismo , Paclitaxel/farmacologia , Tubulina (Proteína)/metabolismo
14.
Int J Mol Sci ; 23(15)2022 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-35955813

RESUMO

Triple-negative breast cancer (TNBC) has the poorest prognosis of all breast cancer subtypes. Recently, the activation of NF-κB, which is involved in the growth and survival of malignant tumors, has been demonstrated in TNBC, suggesting that NF-κB may serve as a new therapeutic target. In the present study, we examined whether dimethyl fumarate (DMF), an NF-κB inhibitor, induces apoptosis in TNBC cells and enhances the apoptosis-inducing effect of paclitaxel and adriamycin. Cell survival was analyzed by the trypan blue assay and apoptosis assay. Protein detection was examined by immunoblotting. The activation of NF-κB p65 was correlated with poor prognosis in patients with TNBC. DMF induced apoptosis in MDA-MB-231 and BT-549 cells at concentrations that were non-cytotoxic to the normal mammary cell line MCF-10A. Furthermore, DMF inhibited NF-κB nuclear translocation and Survivin, XIAP, Bcl-xL, and Bcl-2 expression in MDA-MB-231 and BT-549 cells. Moreover, DMF enhanced the apoptosis-inducing effect of paclitaxel and adriamycin in MDA-MB-231 cells. These findings suggest that DMF may be an effective therapeutic agent for the treatment of TNBC, in which NF-κB is constitutively active. DMF may also be useful as an adjuvant therapy to conventional anticancer drugs.


Assuntos
NF-kappa B , Neoplasias de Mama Triplo Negativas , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Fumarato de Dimetilo/farmacologia , Fumarato de Dimetilo/uso terapêutico , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Humanos , NF-kappa B/metabolismo , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Transdução de Sinais , Neoplasias de Mama Triplo Negativas/patologia
15.
Pathol Oncol Res ; 28: 1610404, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35911442

RESUMO

Introduction: We aimed to explore the abnormal expression of dual-specificity protein phosphatase 1 (DUSP1) and its latent molecular mechanisms in ovarian carcinoma (OVCA). Materials and Methods: Two clinical cohorts collected from two different hospitals were used to evaluate the expression of DUSP1 protein in OVCA tissues. RNA-sequencing and microarray datasets were utilised to verify DUSP1 expression at mRNA levels in both OVCA tissues and in the peripheral blood of OVCA patients. Furthermore, an integrated calculation was performed to pool the standard mean difference (SMD) from each cohort in order to comprehensively assess the expression of DUSP1 in OVCA. Furthermore, we examined the relationship among DUSP1, tumour microenvironment (TME), and chemotherapy resistance in OVCA. Moreover, we used pathway enrichment analysis to explore the underlying mechanisms of DUSP1 in OVCA. Results: A pooled SMD of -1.19 (95% CI [-2.00, -0.38], p = 0.004) with 1,240 samples revealed that DUSP1 was downregulated in OVCA at both mRNA and protein levels. The area under the receiver operating characteristic curve of 0.9235 indicated the downregulated DUSP1 in peripheral blood may have a non-invasive diagnostic value in OVCA. Through six algorithms, we identified that DUSP1 may related to tumour-infiltrating T cells and cancer associated fibroblasts (CAFs) in OVCA. Pathway enrichment demonstrated that DUSP1 might participate in the mitogen-activated protein kinase (MAPK) signalling pathway. Furthermore, DUSP1 may have relations with chemotherapy resistance, and a favourable combining affinity was observed in the paclitaxel-DUSP1 docking model. Conclusion: DUSP1 was downregulated in OVCA, and this decreasing trend may affect the infiltration of CAFs. Finally, DUSP1 may have a targeting relation with paclitaxel and participate in MAPK signaling pathways.


Assuntos
Fosfatase 1 de Especificidade Dupla , Neoplasias Ovarianas , Carcinoma Epitelial do Ovário , Fosfatase 1 de Especificidade Dupla/metabolismo , Feminino , Humanos , Sistema de Sinalização das MAP Quinases , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , RNA Mensageiro/metabolismo , Microambiente Tumoral/genética
16.
Crit Rev Eukaryot Gene Expr ; 32(7): 67-76, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36004696

RESUMO

Tripartite motif-containing protein 11 (TRIM11) and family with sequence similarity 46B (FAM46B) have been demonstrated to play roles in prostate cancer development, but their function in paclitaxel resistance remains unclear. The role of TRIM11 and FAM46B in paclitaxel resistance in prostate cancer was estimated. The paclitaxel-resistant cells were established with gradually increasing concentrations of paclitaxel in prostate cancer cells. The sensitivity to paclitaxel of established cells was assessed by the value of the median inhibitory concentration in the presence of 0-1000 nM paclitaxel. The expression level of TRIM11 and FAM46B was evaluated by real-time quantitative polymerase chain reaction. The proliferation, migration, and invasion of established cells were evaluated by CCK8 and Tran-swell assay. TRIM11 was upregulated in paclitaxel-resistant cells and promoted the proliferation, migration, and invasion of established cells. The significant downregulation of FAM46B was observed in paclitaxel-resistant cells. Although the overexpression of FAM46B suppressed the viability and metastasis of paclitaxel-resistant cells, which was reversed by the upregulation of TRIM11. Both the knockdown of TRIM11 and overexpression of FAM46B could enhance paclitaxel sensitivity of established resistant cells. The promoted effect of FAM46B overexpression was alleviated by the elevation of TRIM11. TRIM11 could improve the sensitivity to paclitaxel of resistant prostate cancer cells via regulating FAM46B.


Assuntos
Paclitaxel , Neoplasias da Próstata , Linhagem Celular Tumoral , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Masculino , Paclitaxel/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Proteínas com Motivo Tripartido/genética , Ubiquitina-Proteína Ligases/genética
17.
Anticancer Drugs ; 33(8): 701-709, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-35946537

RESUMO

An increasing number of studies have confirmed that microRNAs (miRNAs) are involved in various biological processes, including tumor growth and drug resistance. MiR-4284 has been proved to be abnormally regulated in several cancers, but the function of miR-4284 in ovarian carcinoma (OC) is unclear. Paclitaxel resistance is a key obstacle in OC treatment. Here, the role of miR-4284 in cell sensitivity to paclitaxel in OC was investigated. Two OC cell lines (SKOV3ip1 and HeyA8) were utilized for the establishment of paclitaxel-resistant cell lines. Reverse transcription-quantitative PCR (RT-qPCR) was applied to analyze the levels of miR-4284 and potential mRNAs in OC cell lines. Western blotting was performed to evaluate the levels of DNA meiotic recombinase 1 (DMC1) protein and cell cycle-associated proteins. Identification of the relationship between miR-4284 and DMC1 was achieved by luciferase reporter assay. CCK-8 and flow cytometry assays were utilized for evaluating the impact of miR-4284 on the malignant characteristics of paclitaxel-resistant OC cells. MiR-4284 was upregulated in paclitaxel-resistant OC cell lines and correlated with an adverse prognosis in OC patients. Depletion of miR-4284 suppressed cell proliferation and cell cycle progression of paclitaxel-resistant OC. MiR-4284 targeted DMC1 which was downregulated in paclitaxel-resistant cells and reversed the inhibitory influence of miR-4284 silencing on the malignant characters of paclitaxel-resistant OC cells. MiR-4284 targets DMC1 to suppress sensitivity to paclitaxel in human OC cells.


Assuntos
Carcinoma , Proteínas de Ciclo Celular , Proteínas de Ligação a DNA , MicroRNAs , Neoplasias Ovarianas , Carcinoma/genética , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células , Proteínas de Ligação a DNA/genética , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Paclitaxel/farmacologia
18.
Colloids Surf B Biointerfaces ; 218: 112723, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35932558

RESUMO

Self-assembling prodrug nanotherapeutics have emerged as a promising nanoplatform for anticancer drug delivery. The specific and efficient activation of prodrug nanotherapeutics inside tumor cells is vital for the antitumor efficacy and security. Herein, a triple-activable prodrug polymer (TAP) is synthesized by conjugating polyethylene glycol-poly-(caprolactone)-paclitaxel (PTX) polymer with two tumor-responsive bonds, disulfide and acetal. TAP could self-assemble into nanotherapeutics (TAP NTs) free of surfactant with a high drug loading (32.6%). In blood circulation, TAP NTs could remain intact to efficiently accumulate in tumor sites. Thereafter, tumor cells would internalize TAP NTs through multiple endocytosis pathways. Inside tumor cells, TAP NTs could be activated to release PTX and induce tumor cell apoptosis in triple pathways: (i) lysosomal acidity rapid activation; (ii) ROS-acidity tandem activation and (iii) GSH-acidity tandem activation. Compared with Taxol and non-activable control, TAP NTs significantly potentiate the antitumor efficacy and security of PTX against solid tumors including breast cancer and colon cancer.


Assuntos
Antineoplásicos , Nanopartículas , Pró-Fármacos , Acetais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Dissulfetos , Portadores de Fármacos/química , Endocitose , Humanos , Nanopartículas/química , Paclitaxel/química , Paclitaxel/farmacologia , Polietilenoglicóis/química , Polímeros/química , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Espécies Reativas de Oxigênio , Tensoativos
19.
Free Radic Biol Med ; 190: 202-215, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35985562

RESUMO

The intrinsic link of ferroptosis to neurodegeneration, such as Parkinson's disease and Alzheimer's disease, has set promises to apply ferroptosis inhibitors for treatment of neurodegenerative disorders. Herein, we report that the natural small molecule hinokitiol (Hino) functions as a potent ferroptosis inhibitor to rescue neuronal damages in vitro and in vivo. The action mechanisms of Hino involve chelating irons and activating cytoprotective transcription factor Nrf2 to upregulate the antioxidant genes including solute carrier family 7 member 11, glutathione peroxidase 4 and Heme oxygenase-1. In vivo studies demonstrate that Hino rescues the deficits of locomotor activity and neurodevelopment in zebrafishes. In addition, Hino shows the efficient blood-brain barrier permeability in mice, supporting the application of Hino for brain disorders. Paclitaxel is one of the most widely used broad-spectrum antineoplastic agents. However, its neurotoxic side effect is a severe concern. We demonstrate that the neurotoxicity of paclitaxel is ferroptosis-related and Hino also alleviates the paclitaxel-induced neurotoxicity without compromising its cytotoxicity to cancer cells. Hino also salvages the neurobehavioral impairment by paclitaxel in zebrafishes. Collectively, the discovery of Hino as a novel ferroptosis inhibitor and disclosure of its action mechanisms establish a foundation for the further development of Hino as a neuroprotective agent.


Assuntos
Ferroptose , Síndromes Neurotóxicas , Animais , Camundongos , Monoterpenos , Fator 2 Relacionado a NF-E2/genética , Neuroproteção , Paclitaxel/farmacologia , Tropolona/análogos & derivados , Peixe-Zebra
20.
Cells ; 11(13)2022 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-35805152

RESUMO

Despite huge progress in biotechnological approaches to paclitaxel production, Taxus spp. in vitro culture productivity still remains a challenge. This could be solved by developing a new strategy engaging mechanisms of the primed defence response joined with subsequent elicitation treatment to circumvent limitations in paclitaxel biosynthesis. The hairy roots were primed by preincubation with ß-aminobutyric acid (BABA) for 24 h or 1 week, and then elicited with methyl jasmonate (MeJA) or a mixture of MeJA, sodium nitroprusside and L-phenylalanine (MIX). The effect of priming was evaluated on a molecular level by examination of the expression profiles of the four genes involved in paclitaxel biosynthesis, i.e., TXS (taxadiene synthase), BAPT (baccatin III: 3-amino, 3-phenylpropanoyltransferase), DBTNBT (3'-N-debenzoyl-2-deoxytaxol-N-benzoyltransferase) and PAM (phenylalanine aminomutase), as well as rolC (cytokinin-ß-glucosidase), originated from the T-DNA of Agrobacterium rhizogenes. The maximum paclitaxel yield was achieved in cultures primed with BABA for 1 week and elicited with MIX (3179.9 ± 212 µg/g dry weight), which corresponded to the highest expression levels of TXS and BAPT genes. Although BABA itself induced the investigated gene expression over control level, it was not translated into paclitaxel production. Nevertheless, preincubation with BABA essentially affected paclitaxel yield, and the duration of BABA pretreatment seemed to have the most pronounced impact on its productivity.


Assuntos
Taxus , Regulação da Expressão Gênica de Plantas , Paclitaxel/farmacologia , Fenilalanina/metabolismo , Taxus/genética , Taxus/metabolismo
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