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1.
Nutrients ; 13(12)2021 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-34959868

RESUMO

Declines in physiological functions are the predominant risk factors for age-related diseases, such as cancers and neurodegenerative diseases. Therefore, delaying the aging process is believed to be beneficial in preventing the onset of age-related diseases. Previous studies have demonstrated that Graptopetalum paraguayense (GP) extract inhibits liver cancer cell growth and reduces the pathological phenotypes of Alzheimer's disease (AD) in patient IPS-derived neurons. Here, we show that GP extract suppresses ß-amyloid pathology in SH-SYS5Y-APP695 cells and APP/PS1 mice. Moreover, AMP-activated protein kinase (AMPK) activity is enhanced by GP extract in U87 cells and APP/PS1 mice. Intriguingly, GP extract enhances autophagy in SH-SYS5Y-APP695 cells, U87 cells, and the nematode Caenorhabditis elegans, suggesting a conserved molecular mechanism by which GP extract might regulate autophagy. In agreement with its role as an autophagy activator, GP extract markedly diminishes mobility decline in polyglutamine Q35 mutants and aged wild-type N2 animals in C. elegans. Furthermore, GP extract significantly extends lifespan in C. elegans.

2.
Biology (Basel) ; 10(11)2021 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-34827109

RESUMO

The efficient discovery of anticancer targets with minimal side effects is a major challenge in drug discovery and development. Early prediction of side effects is key for reducing development costs, increasing drug efficacy, and increasing drug safety. This study developed a fuzzy optimization framework for Identifying AntiCancer Targets (IACT) using constraint-based models. Four objectives were established to evaluate the mortality of treated cancer cells and to minimize side effects causing toxicity-induced tumorigenesis on normal cells and smaller metabolic perturbations. Fuzzy set theory was applied to evaluate potential side effects and investigate the magnitude of metabolic deviations in perturbed cells compared with their normal counterparts. The framework was applied to identify not only gene regulator targets but also metabolite- and reaction-centric targets. A nested hybrid differential evolution algorithm with a hierarchical fitness function was applied to solve multilevel IACT problems. The results show that the combination of a carbon metabolism target and any one-target gene that participates in the sphingolipid, glycerophospholipid, nucleotide, cholesterol biosynthesis, or pentose phosphate pathways is more effective for treatment than one-target inhibition is. A clinical antimetabolite drug 5-fluorouracil (5-FU) has been used to inhibit synthesis of deoxythymidine-5'-triphosphate for treatment of colorectal cancer. The computational results reveal that a two-target combination of 5-FU and a folate supplement can improve cell viability, reduce metabolic deviation, and reduce side effects of normal cells.

3.
Biomedicines ; 9(11)2021 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-34829812

RESUMO

The multi-domain non-structural protein 3 (NSP3) is an oncogenic molecule that has been concomitantly implicated in the progression of coronavirus infection. However, its oncological role in lung cancer and whether it plays a role in modulating the tumor immune microenvironment is not properly understood. In the present in silico study, we demonstrated that NSP3 (SH2D3C) is associated with advanced stage and poor prognoses of lung cancer cohorts. Genetic alterations of NSP3 (SH2D3C) co-occurred inversely with Epidermal Growth Factor Receptor (EGFR) alterations and elicited its pathological role via modulation of various components of the immune and inflammatory pathways in lung cancer. Our correlation analysis suggested that NSP3 (SH2D3C) promotes tumor immune evasion via dysfunctional T-cell phenotypes and T-cell exclusion mechanisms in lung cancer patients. NSP3 (SH2D3C) demonstrated a high predictive value and association with therapy resistance in lung cancer, hence serving as an attractive target for therapy exploration. We evaluated the in silico drug-likeness and NSP3 (SH2D3C) target efficacy of six organosulfur small molecules from Allium sativum using a molecular docking study. We found that the six organosulfur compounds demonstrated selective cytotoxic potential against cancer cell lines and good predictions for ADMET properties, drug-likeness, and safety profile. E-ajoene, alliin, diallyl sulfide, 2-vinyl-4H-1,3-dithiin, allicin, and S-allyl-cysteine docked well into the NSP3 (SH2D3C)-binding cavity with binding affinities ranging from -4.3~-6.70 A and random forest (RF) scores ranging from 4.31~5.26 pKd. However, S-allyl-cysteine interaction with NSP3 (SH2D3C) is unfavorable and hence less susceptible to NSP3 ligandability. In conclusion, our study revealed that NSP3 is an important onco-immunological biomarker encompassing the tumor microenvironment, disease staging and prognosis in lung cancer and could serve as an attractive target for cancer therapy. The organosulfur compounds from A. sativum have molecular properties to efficiently interact with the binding site of NSP3 and are currently under vigorous preclinical study in our laboratory.

4.
Int J Mol Sci ; 22(22)2021 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-34830455

RESUMO

Chronic myeloid leukemia (CML) is a hematopoietic malignancy characterized by the presence of the BCR-ABL oncogene. Therapeutic regimens with tyrosine kinase inhibitors (TKIs) specifically targeting BCR-ABL have greatly improved overall survival of CML. However, drug intolerance and related toxicity remain. Combined therapy is effective in reducing drug magnitude while increasing therapeutic efficacy and, thus, lowers undesired adverse side effects. The p38 MAPK activity is critically linked to the pathogenesis of a number of diseases including hematopoietic diseases; however, the role of each isozyme in CML and TKI-mediated effects is still elusive. In this study, we used specific gene knockdown to clearly demonstrate that the deficiency of p38α greatly enhanced the therapeutic efficacy in growth suppression and cytotoxicity of TKIs, first-generation imatinib, and second generation dasatinib by approximately 2.5-3.0-fold in BCR-ABL-positive CML-derived leukemia K562 and KMB5 cells. Knockdown of p38ß, which displays the most sequence similarity to p38α, exerted distinct and opposite effects on the TKI-mediated therapeutic efficacy. These results show the importance of isotype-specific intervention in enhancing the therapeutic efficacy of TKI. A highly specific p38α inhibitor, TAK715, also significantly enhanced the imatinib- and dasatinib-mediated therapeutic efficacy, supporting the feasibility of p38α deficiency in future clinic application. Taken together, our results demonstrated that p38α is a promising target for combined therapy with BCR-ABL-targeting tyrosine kinase inhibitors for future application to increase therapeutic efficacy.

5.
Biomedicines ; 9(8)2021 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-34440089

RESUMO

Cholangiocarcinoma is the most common primary malignant tumor of the bile duct. The current standard first-line treatment for advanced or metastatic cholangiocarcinoma is gemcitabine and cisplatin. However, few effective treatment choices exist for refractory cholangiocarcinoma, and additional therapeutic drugs are urgently required. Our previous work demonstrated that the ALDH isoform 1A3 plays a vital role in the malignant behavior of cholangiocarcinoma and may serve as a new therapeutic target. In this study, we found a positive correlation between ALDH1A3 protein expression levels and the cell migration abilities of three cholangiocarcinoma cell lines, which was verified using ALDH1A3-overexpressing and ALDH1A3-knockdown clones. We also used ALDH1A3-high and ALDH1A3-low populations of cholangiocarcinoma cell lines from the library of integrated network-based cellular signatures (LINCS) program and assessed the effects of ruxolitinib, a commercially available JAK2 inhibitor. Ruxolitinib had a higher cytotoxic effect when combined with gemcitabine. Furthermore, the nuclear translocation STAT1 and STAT3 heterodimers were markedly diminished by ruxolitinib treatment, possibly resulting in decreased ALDH1A3 activation. Notably, ruxolitinib alone or combined with gemcitabine led to significantly reduced tumor size and weight. Collectively, our studies suggest that ruxolitinib might suppress the ALDH1A3 activation through the JAK2/STAT1/3 pathway in cholangiocarcinoma, and trials should be undertaken to evaluate its efficacy in clinical therapy.

6.
Antioxidants (Basel) ; 10(6)2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34204966

RESUMO

Nonarteritic anterior ischemic optic neuropathy (NAION) is the most common cause of acute vision loss in older people, and there is no effective therapy. The effect of the systemic or local application of steroids for NAION patients remains controversial. Oroxylin A (OA) (5,7-dihydroxy-6-methoxyflavone) is a bioactive flavonoid extracted from Scutellariae baicalensis Georgi. with various beneficial effects, including anti-inflammatory and neuroprotective effects. A previous study showed that OA promotes retinal ganglion cell (RGC) survival after optic nerve (ON) crush injury. The purpose of this research was to further explore the potential actions of OA in ischemic injury in an experimental anterior ischemic optic neuropathy (rAION) rat model induced by photothrombosis. Our results show that OA efficiently attenuated ischemic injury in rats by reducing optic disc edema, the apoptotic death of retinal ganglion cells, and the infiltration of inflammatory cells. Moreover, OA significantly ameliorated the pathologic changes of demyelination, modulated microglial polarization, and preserved visual function after rAION induction. OA activated nuclear factor E2 related factor (Nrf2) signaling and its downstream antioxidant enzymes NAD(P)H:quinone oxidoreductase (NQO-1) and heme oxygenase 1 (HO-1) in the retina. We demonstrated that OA activates Nrf2 signaling, protecting retinal ganglion cells from ischemic injury, in the rAION model and could potentially be used as a therapeutic approach in ischemic optic neuropathy.

7.
Stem Cell Res ; 54: 102419, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34119955

RESUMO

Atrial fibrillation is the most common heart disease in the world, with around 35 million patients in 2020. Here we reported the generation of IBMS-iPSC-015-06, IBMS-iPSC-016-06, and IBMS-iPSC-017-02 as human induced pluripotent stem cell (iPSC) lines from patients' peripheral blood mononuclear cells (PBMCs) with atrial fibrillation. The cell lines expressed properties of pluripotent stem cells, including pluripotent markers and the ability to differentiate into three germ layers. These cell lines served as suitable models for studying alternative therapies of atrial fibrillation.


Assuntos
Fibrilação Atrial , Células-Tronco Pluripotentes Induzidas , Células-Tronco Pluripotentes , Diferenciação Celular , Linhagem Celular , Humanos , Leucócitos Mononucleares
8.
Stem Cell Res ; 54: 102416, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34118567

RESUMO

ALDH2 gene is coded for the aldehyde dehydrogenase (ALDH), which is an enzyme involved in alcohol metabolism. Compared to normal aldehyde dehydrogenases, a homozygous point mutation on exon 12 from G to A significantly reduces its efficiency. In this study, we have reported the generation of IBMS-iPSC-021-04, IBMS-iPSC-022-01, and IBMS-iPSC-023-03 as induced pluripotent stem cell (iPSC) lines carrying the homozygous form of ALDH2 with the rs671 genetic polymorphism (E487K mutation). These cell lines were characterized in terms of pluripotency and differentiation potential. They serve as useful platforms to study alcohol metabolism and other chronic diseases associated with alcohol consumption.


Assuntos
Células-Tronco Pluripotentes Induzidas , Aldeído-Desidrogenase Mitocondrial/genética , Diferenciação Celular , Linhagem Celular , Humanos , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único/genética
9.
Life (Basel) ; 11(5)2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34069945

RESUMO

Therapeutic resistance in recurrent glioblastoma multiforme (GBM) after concurrent chemoradiotherapy (CCRT) is a challenging issue. Although standard fractionated radiation is essential to treat GBM, it has led to local recurrence along with therapy-resistant cells in the ionizing radiation (IR) field. Lines of evidence showed cancer stem cells (CSCs) play a vital role in therapy resistance in many cancer types, including GBM. However, the molecular mechanism is poorly understood. Here, we proposed that autophagy could be involved in GSC induction for radioresistance. In a clinical setting, patients who received radiation/chemotherapy had higher LC3II expression and showed poor overall survival compared with those with low LC3 II. In a cell model, U87MG and GBM8401 expressed high level of stemness markers CD133, CD44, Nestin, and autophagy marker P62/LC3II after receiving standard fractionated IR. Furthermore, Wnt/ß-catenin proved to be a potential pathway and related to P62 by using proteasome inhibitor (MG132). Moreover, pharmacological inhibition of autophagy with BAF and CQ inhibit GSC cell growth by impairing autophagy flux as demonstrated by decrease Nestin, CD133, and SOX-2 levels. In conclusion, we demonstrated that fractionated IR could induce GSCs with the stemness phenotype by P62-mediated autophagy through the Wnt/ß-catenin for radioresistance. This study offers a new therapeutic strategy for targeting GBM in the future.

10.
Int J Mol Sci ; 22(11)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34072831

RESUMO

Although histone deacetylase 8 (HDAC8) plays a role in glioblastoma multiforme (GBM), whether its inhibition facilitates the treatment of temozolomide (TMZ)-resistant GBM (GBM-R) remains unclear. By assessing the gene expression profiles from short hairpin RNA of HDAC8 in the new version of Connectivity Map (CLUE) and cells treated by NBM-BMX (BMX)-, an HDAC8 inhibitor, data analysis reveals that the Wnt signaling pathway and apoptosis might be the underlying mechanisms in BMX-elicited treatment. This study evaluated the efficacy of cotreatment with BMX and TMZ in GBM-R cells. We observed that cotreatment with BMX and TMZ could overcome resistance in GBM-R cells and inhibit cell viability, markedly inhibit cell proliferation, and then induce cell cycle arrest and apoptosis. In addition, the expression level of ß-catenin was reversed by proteasome inhibitor via the ß-catenin/ GSK3ß signaling pathway to reduce the expression level of c-Myc and cyclin D1 in GBM-R cells. BMX and TMZ cotreatment also upregulated WT-p53 mediated MGMT inhibition, thereby triggering the activation of caspase-3 and eventually leading to apoptosis in GBM-R cells. Moreover, BMX and TMZ attenuated the expression of CD133, CD44, and SOX2 in GBM-R cells. In conclusion, BMX overcomes TMZ resistance by enhancing TMZ-mediated cytotoxic effect by downregulating the ß-catenin/c-Myc/SOX2 signaling pathway and upregulating WT-p53 mediated MGMT inhibition. These findings indicate a promising drug combination for precision personal treating of TMZ-resistant WT-p53 GBM cells.


Assuntos
Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Glioblastoma/tratamento farmacológico , Histona Desacetilases/genética , Proteínas Repressoras/genética , Proteína Supressora de Tumor p53/genética , Proteínas Supressoras de Tumor/genética , beta Catenina/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Proteínas Repressoras/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Temozolomida/efeitos adversos , Temozolomida/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Biomolecules ; 11(3)2021 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-33805672

RESUMO

Mitochondrial fission and fusion cycles are integrated with cell cycle progression. Here we first re-visited how mitochondrial ETC inhibition disturbed mitosis progression, resulting in multipolar spindles formation in HeLa cells. Inhibitors of ETC complex I (rotenone, ROT) and complex III (antimycin A, AA) decreased the phosphorylation of Plk1 T210 and Aurora A T288 in the mitotic phase (M-phase), especially ROT, affecting the dynamic phosphorylation status of fission protein dynamin-related protein 1 (Drp1) and the Ser637/Ser616 ratio. We then tested whether specific Drp1 inhibitors, Mdivi-1 or Dynasore, affected the dynamic phosphorylation status of Drp1. Similar to the effects of ROT and AA, our results showed that Mdivi-1 but not Dynasore influenced the dynamic phosphorylation status of Ser637 and Ser616 in Drp1, which converged with mitotic kinases (Cdk1, Plk1, Aurora A) and centrosome-associated proteins to significantly accelerate mitotic defects. Moreover, our data also indicated that evoking mito-Drp1-Ser637 by protein kinase A (PKA) rather than Drp1-Ser616 by Cdk1/Cyclin B resulted in mitochondrial fission via the PINK1/Parkin pathway to promote more efficient mitophagy and simultaneously caused multipolar spindles. Collectively, this study is the first to uncover that mito-Drp1-Ser637 by PKA, but not Drp1-Ser616, drives mitophagy to exert multipolar spindles formation during M-phase.


Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Dinaminas/metabolismo , Dinâmica Mitocondrial , Mitofagia , Mitose , Proteínas Quinases/metabolismo , Fuso Acromático/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Antimicina A/farmacologia , Aurora Quinase A/metabolismo , Pontos de Checagem do Ciclo Celular , Proteínas de Ciclo Celular/metabolismo , Centrossomo/metabolismo , Transporte de Elétrons/efeitos dos fármacos , Células HeLa , Humanos , Hidrazonas/metabolismo , Mitocôndrias/metabolismo , Modelos Biológicos , Estresse Oxidativo , Fosforilação , Fosfosserina/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Quinazolinonas/metabolismo , Rotenona/farmacologia
12.
Viruses ; 13(2)2021 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-33669264

RESUMO

Honeysuckle (Lonicera japonica Thunb) is a traditional Chinese medicine (TCM) with an antipathogenic activity. MicroRNAs (miRNAs) are small non-coding RNA molecules that are ubiquitously expressed in cells. Endogenous miRNA may function as an innate response to block pathogen invasion. The miRNA expression profiles of both mice and humans after the ingestion of honeysuckle were obtained. Fifteen overexpressed miRNAs overlapped and were predicted to be capable of targeting three viruses: dengue virus (DENV), enterovirus 71 (EV71) and SARS-CoV-2. Among them, let-7a was examined to be capable of targeting the EV71 RNA genome by reporter assay and Western blotting. Moreover, honeysuckle-induced let-7a suppression of EV71 RNA and protein expression as well as viral replication were investigated both in vitro and in vivo. We demonstrated that let-7a targeted EV71 at the predicted sequences using luciferase reporter plasmids as well as two infectious replicons (pMP4-y-5 and pTOPO-4643). The suppression of EV71 replication and viral load was demonstrated in two cell lines by luciferase activity, RT-PCR, real-time PCR, Western blotting and plaque assay. Furthermore, EV71-infected suckling mice fed honeysuckle extract or inoculated with let-7a showed decreased clinical scores and a prolonged survival time accompanied with decreased viral RNA, protein expression and virus titer. The ingestion of honeysuckle attenuates EV71 replication and related pathogenesis partially through the upregulation of let-7a expression both in vitro and in vivo. Our previous report and the current findings imply that both honeysuckle and upregulated let-7a can execute a suppressive function against the replication of DENV and EV71. Taken together, this evidence indicates that honeysuckle can induce the expression of let-7a and that this miRNA as well as 11 other miRNAs have great potential to prevent and suppress EV71 replication.


Assuntos
Antivirais/farmacologia , Enterovirus Humano A/efeitos dos fármacos , Lonicera/química , MicroRNAs/metabolismo , Extratos Vegetais/farmacologia , Replicação Viral/efeitos dos fármacos , Animais , Linhagem Celular , Enterovirus Humano A/fisiologia , Infecções por Enterovirus/tratamento farmacológico , Humanos , Camundongos , Camundongos Endogâmicos ICR
13.
Free Radic Biol Med ; 167: 307-320, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33731308

RESUMO

Lung cancer is the leading cause of cancer-related deaths worldwide. Identifying genetic risk factors and understanding their mechanisms will help reduce lung cancer incidence. The p53 apoptosis effect is related to PMP-22 (PERP), a tetraspan membrane protein, and an apoptotic effector protein downstream of p53. Although historically considered a tumor suppressor, PERP is highly expressed in lung cancers. Stable knockdown of PERP expression induces CL1-5 and A549 lung cancer cell death, but transient knockdown has no effect. Interestingly, relative to the PERP-428GG genotype, PERP-428CC was associated with the highest lung cancer risk (OR = 5.38; 95% CI = 2.12-13.65, p < 0.001), followed by the PERP-428CG genotype (OR = 2.34; 95% CI = 1.55-3.55, p < 0.001). Ectopic expression of PERP-428G, but not PERP-428C, protects lung cancer cells against ROS-induced DNA damage. Mechanistically, PERP-428 SNPs differentially regulate p53 protein stability. p53 negatively regulates the expression of the antioxidant enzymes catalase (CAT) and glutathione reductase (GR), thereby modulating redox status. p53 protein stability is higher in PERP-428C-expressing cells than in PERP-428G-expressing cells because MDM2 expression is decreased and p53 Ser20 phosphorylation is enhanced in PERP-428C-expressing cells. The MDM2 mRNA level is decreased in PERP-428C-expressing cells via PTEN-mediated downregulation of the MDM2 constitutive p1 promoter. This study reveals that in individuals with PERP-428CC, CAT/GR expression is decreased via the PTEN/MDM2/p53 pathway. These individuals have an increased lung cancer risk. Preventive antioxidants and avoidance of ROS stressors are recommended to prevent lung cancer or other ROS-related chronic diseases.


Assuntos
Neoplasias Pulmonares , Proteína Supressora de Tumor p53 , Antioxidantes , Apoptose , Genes Supressores de Tumor , Humanos , Neoplasias Pulmonares/genética , Proteínas de Membrana , PTEN Fosfo-Hidrolase/genética , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteína Supressora de Tumor p53/genética
14.
Biochim Biophys Acta Mol Basis Dis ; 1867(5): 166088, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33515676

RESUMO

Point mutation in alcohol dehydrogenase 2 (ALDH2), ALDH2*2 results in decreased catalytic enzyme activity and has been found to be associated with different human pathologies. Whether ALDH2*2 would induce cardiac remodeling and increase the attack of atrial fibrillation (AF) remains poorly understood. The present study evaluated the effect of ALDH2*2 mutation on AF susceptibility and unravelled the underlying mechanisms using a multi-omics approach including whole-genome gene expression and proteomics analysis. The in-vivo electrophysiological study showed an increase in the incidence and reduction in the threshold of AF for the mutant mice heterozygous for ALDH2*2 as compared to the wild type littermates. The microarray analysis revealed a reduction in the retinoic acid signals which was accompanied by a downstream reduction in the expression of voltage-gated Na+ channels (SCN5A). The treatment of an antagonist for retinoic acid receptor resulted in a decrease in SCN5A transcript levels. The integrated analysis of the transcriptome and proteome data showed a dysregulation of fatty acid ß-oxidation, adenosine triphosphate synthesis via electron transport chain, and activated oxidative responses in the mitochondria. Oral administration of Coenzyme Q10, an essential co-factor known to meliorate mitochondrial oxidative stress and preserve bioenergetics, conferred a protection against AF attack in the mutant ALDH2*2 mice. The multi-omics approach showed the unique pathophysiology mechanisms of concurrent dysregulated SCN5A channel and mitochondrial bioenergetics in AF. This inspired the development of a personalized therapeutic agent, Coenzyme Q10, to protect against AF attack in humans characterized by ALDH2*2 genotype.


Assuntos
Aldeído-Desidrogenase Mitocondrial/fisiologia , Fibrilação Atrial/patologia , Metabolismo Energético , Mitocôndrias/patologia , Mutação , Canais de Sódio/metabolismo , Transcriptoma , Animais , Fibrilação Atrial/etiologia , Fibrilação Atrial/metabolismo , Redes Reguladoras de Genes , Masculino , Camundongos , Mitocôndrias/metabolismo , Transdução de Sinais , Canais de Sódio/genética
15.
Front Oncol ; 10: 561936, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33312947

RESUMO

P-glycoprotein (also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1) plays a crucial role in determining response against medications, including cancer therapeutics. It is now well established that p-glycoprotein acts as an ATP dependent pump that pumps out small molecules from cells. Ample evidence exist that show p-glycoprotein expression levels correlate with drug efficacy, which suggests the rationale for developing p-glycoprotein inhibitors for treatment against cancer. Preclinical and clinical studies have investigated this possibility, but mostly were limited by substantial toxicities. Repurposing FDA-approved drugs that have p-glycoprotein inhibition activities is therefore a potential alternative approach. In this review, we searched the Drugbank Database (https://www.drugbank.ca/drugs) and identified 98 FDA-approved small molecules that possess p-glycoprotein inhibition properties. Focusing on the small molecules approved with indications against non-cancer diseases, we query the scientific literature for studies that specifically investigate these therapeutics as cancer treatment. In light of this analysis, potential development opportunities will then be thoroughly investigated for future efforts in repositioning of non-cancer p-glycoprotein inhibitors in single use or in combination therapy for clinical oncology treatment.

16.
Cancers (Basel) ; 12(10)2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33036162

RESUMO

Analysis of various public databases revealed that HRAS gene mutation frequency and mRNA expression are higher in bladder urothelial carcinoma. Further analysis revealed the roles of oncogenic HRAS, autophagy, and cell senescence signaling in bladder cancer cells sensitized to the anticancer drug cisplatin using the phytochemical pterostilbene. A T24 cell line with the oncogenic HRAS was chosen for further experiments. Indeed, coadministration of pterostilbene increased stronger cytotoxicity on T24 cells compared to HRAS wild-type E7 cells, which was paralleled by neither elevated apoptosis nor induced cell cycle arrest, but rather a marked elevation of autophagy and cell senescence in T24 cells. Pterostilbene-induced autophagy in T24 cells was paralleled by inhibition of class I PI3K/mTOR/p70S6K as well as activation of MEK/ERK (a RAS target) and class III PI3K pathways. Pterostilbene-induced cell senescence on T24 cells was paralleled by increased pan-RAS and decreased phospho-RB expression. Coadministration of PI3K class III inhibitor 3-methyladenine or MEK inhibitor U0126 suppressed pterostilbene-induced autophagy and reversed pterostilbene-enhanced cytotoxicity, but did not affect pterostilbene-elevated cell senescence in T24 cells. Animal study data confirmed that pterostilbene enhanced cytotoxicity of cisplatin plus gemcitabine. These results suggest a therapeutic application of pterostilbene in cisplatin-resistant bladder cancer with oncogenic HRAS.

17.
J Ovarian Res ; 13(1): 95, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32825834

RESUMO

BACKGROUND: Ovarian cancer is the leading cause of cancer-related death among women. Complete cytoreductive surgery followed by platinum-taxene chemotherapy has been the gold standard for a long time. Various compounds have been assessed in an attempt to combine them with conventional chemotherapy to improve survival rates or even overcome chemoresistance. Many studies have shown that an antidiabetic drug, metformin, has cytotoxic activity in different cancer models. However, the synergism of metformin as a neoadjuvant formula plus chemotherapy in clinical trials and basic studies remains unclear for ovarian cancer. METHODS: We applied two clinical databases to survey metformin use and ovarian cancer survival rate. The Cancer Genome Atlas dataset, an L1000 microarray with Gene Set Enrichment Analysis (GSEA) analysis, Western blot analysis and an animal model were used to study the activity of the AKT/mTOR pathway in response to the synergistic effects of neoadjuvant metformin combined with chemotherapy. RESULTS: We found that ovarian cancer patients treated with metformin had significantly longer overall survival than patients treated without metformin. The protein profile induced by low- concentration metformin in ovarian cancer predominantly involved the AKT/mTOR pathway. In combination with chemotherapy, the neoadjuvant metformin protocol showed beneficial synergistic effects in vitro and in vivo. CONCLUSIONS: This study shows that neoadjuvant metformin at clinically relevant dosages is efficacious in treating ovarian cancer, and the results can be used to guide clinical trials.


Assuntos
Antineoplásicos/administração & dosagem , Carboplatina/administração & dosagem , Metformina/administração & dosagem , Neoplasias Ovarianas/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Carboplatina/farmacologia , Sinergismo Farmacológico , Feminino , Humanos , Metformina/farmacologia , Camundongos , Terapia Neoadjuvante , Neoplasias Ovarianas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Análise de Sobrevida , Serina-Treonina Quinases TOR/metabolismo , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Front Immunol ; 11: 1075, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32547560

RESUMO

Immunotherapy using checkpoint blockade has revolutionized cancer treatment, improving patient survival and quality of life. Nevertheless, the clinical outcomes of such immunotherapy are highly heterogeneous between patients. Depending on the cancer type, the patient response rates to this immunotherapy are limited to 20-30%. Based on the mechanism underlying the antitumor immune response, new therapeutic strategies have been designed with the aim of increasing the effectiveness and specificity of the antitumor immune response elicited by checkpoint blockade agents. The activation of toll-like receptor 9 (TLR9) by its synthetic agonists induces the antitumor response within the innate immunity arm, generating adjuvant effects and priming the adaptive immune response elicited by checkpoint blockade during the effector phase of tumor-cell killing. This review first describes the underlying mechanisms of action and current status of monotherapy using TLR9 agonists and immune checkpoint inhibitors for cancer immunotherapy. The rationale for combining these two agents is discussed, and evidence indicating the current status of such combination therapy as a novel cancer treatment strategy is presented.


Assuntos
Ilhas de CpG/genética , Inibidores de Checkpoint Imunológico , Imunoterapia/métodos , Neoplasias/terapia , Oligodesoxirribonucleotídeos/genética , Receptor Toll-Like 9/metabolismo , Adjuvantes Imunológicos , Animais , Antineoplásicos/uso terapêutico , Humanos , Neoplasias/genética , Neoplasias/imunologia , Transdução de Sinais , Microambiente Tumoral
19.
R Soc Open Sci ; 7(3): 191241, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32269785

RESUMO

Cancer cells are known to exhibit unusual metabolic activity, and yet few metabolic cancer driver genes are known. Genetic alterations and epigenetic modifications of cancer cells result in the abnormal regulation of cellular metabolic pathways that are different when compared with normal cells. Such a metabolic reprogramming can be simulated using constraint-based modelling approaches towards predicting oncogenes. We introduced the tri-level optimization problem to use the metabolic reprogramming towards inferring oncogenes. The algorithm incorporated Recon 2.2 network with the Human Protein Atlas to reconstruct genome-scale metabolic network models of the tissue-specific cells at normal and cancer states, respectively. Such reconstructed models were applied to build the templates of the metabolic reprogramming between normal and cancer cell metabolism. The inference optimization problem was formulated to use the templates as a measure towards predicting oncogenes. The nested hybrid differential evolution algorithm was applied to solve the problem to overcome solving difficulty for transferring the inner optimization problem into the single one. Head and neck squamous cells were applied as a case study to evaluate the algorithm. We detected 13 of the top-ranked one-hit dysregulations and 17 of the top-ranked two-hit oncogenes with high similarity ratios to the templates. According to the literature survey, most inferred oncogenes are consistent with the observation in various tissues. Furthermore, the inferred oncogenes were highly connected with the TP53/AKT/IGF/MTOR signalling pathway through PTEN, which is one of the most frequently detected tumour suppressor genes in human cancer.

20.
Invest New Drugs ; 38(2): 264-273, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-30993588

RESUMO

Background Thiostrepton, a natural antibiotic, has recently been shown to be a potential anticancer drug for certain cancers, but its study in nasopharyngeal carcinoma (NPC) is still limited. The aims of this study were to investigate the anticancer effect of thiostrepton on NPC cells and to explore its underlying mechanism. Methods The effects of thiostrepton on the proliferation, migration, and invasion of NPC cells were investigated by a WST-1 assay, wound healing assay, and cell invasion assay, respectively. Microarrays were conducted and further analyzed by Ingenuity Pathways Analysis (IPA) to determine the molecular mechanism by which thiostrepton affects NPC cells. Results Our results showed that thiostrepton reduced NPC cell viability in a dose-dependent manner. Thiostrepton inhibited the migration and invasion of NPC cells in wound healing and cell invasion assays. The microarray data analyzed by IPA indicated the top 5 ingenuity canonical pathways, which were unfolded protein response, NRF2-mediated oxidative stress response, retinoate biosynthesis I, choline biosynthesis III, and pancreatic adenocarcinoma signaling. Conclusion Thiostrepton effectively suppressed NPC cell proliferation, migration, and invasion, likely by several mechanisms. Thiostrepton may be a potential therapeutic agent for treating NPC in the future.


Assuntos
Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Tioestreptona/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética
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