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1.
Nat Commun ; 11(1): 3288, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620753

RESUMO

The prognostic and therapeutic relevance of molecular subtypes for the most aggressive isocitrate dehydrogenase 1/2 (IDH) wild-type glioblastoma (GBM) is currently limited due to high molecular heterogeneity of the tumors that impedes patient stratification. Here, we describe a distinct binary classification of IDH wild-type GBM tumors derived from a quantitative proteomic analysis of 39 IDH wild-type GBMs as well as IDH mutant and low-grade glioma controls. Specifically, GBM proteomic cluster 1 (GPC1) tumors exhibit Warburg-like features, neural stem-cell markers, immune checkpoint ligands, and a poor prognostic biomarker, FKBP prolyl isomerase 9 (FKBP9). Meanwhile, GPC2 tumors show elevated oxidative phosphorylation-related proteins, differentiated oligodendrocyte and astrocyte markers, and a favorable prognostic biomarker, phosphoglycerate dehydrogenase (PHGDH). Integrating these proteomic features with the pharmacological profiles of matched patient-derived cells (PDCs) reveals that the mTORC1/2 dual inhibitor AZD2014 is cytotoxic to the poor prognostic PDCs. Our analyses will guide GBM prognosis and precision treatment strategies.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Isocitrato Desidrogenase/genética , Proteogenômica/métodos , Proteômica/métodos , Benzamidas/farmacologia , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Glioblastoma/genética , Glioblastoma/terapia , Humanos , Isocitrato Desidrogenase/classificação , Isocitrato Desidrogenase/metabolismo , Estimativa de Kaplan-Meier , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Alvo Mecanístico do Complexo 2 de Rapamicina/antagonistas & inibidores , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Morfolinas/farmacologia , Mutação , Prognóstico , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia
2.
Public Health Nutr ; 23(9): 1507-1514, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32172710

RESUMO

OBJECTIVE: To propose a new anthropometric index that can be employed to better predict percent body fat (PBF) among young adults and to compare with current anthropometric indices. DESIGN: Cross-sectional. SETTING: All measurements were taken in a controlled laboratory setting in Seoul (South Korea), between 1 December 2015 and 30 June 2016. PARTICIPANTS: Eighty-seven young adults (18-35 years) who underwent dual-energy x-ray absorptiometry (DXA) were used for analysis. Multiple regression analyses were conducted to develop a body fat index (BFI) using simple demographic and anthropometric information. Correlations of DXA measured PBF (DXA_PBF) with previously developed anthropometric indices and the BFI were analysed. Receiver operating characteristic curve analyses were conducted to compare the ability of anthropometric indices to identify obese individuals. RESULTS: BFI showed a strong correlation with DXA_PBF (r = 0·84), which was higher than the correlations of DXA_PBF with the traditional (waist circumference, r = 0·49; waist to height ratio, r = 0·68; BMI, r = 0·36) and alternate anthropometric indices (a body shape index, r = 0·47; body roundness index, r = 0·68; body adiposity index, r = 0·70). Moreover, the BFI showed higher accuracy at identifying obese individuals (area under the curve (AUC) = 0·91), compared with the other anthropometric indices (AUC = 0·71-0·86). CONCLUSIONS: The BFI can accurately predict DXA_PBF in young adults, using simple demographic and anthropometric information that are commonly available in research and clinical settings. However, larger representative studies are required to build on our findings.

3.
Cell ; 173(4): 864-878.e29, 2018 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-29681454

RESUMO

Diversity in the genetic lesions that cause cancer is extreme. In consequence, a pressing challenge is the development of drugs that target patient-specific disease mechanisms. To address this challenge, we employed a chemistry-first discovery paradigm for de novo identification of druggable targets linked to robust patient selection hypotheses. In particular, a 200,000 compound diversity-oriented chemical library was profiled across a heavily annotated test-bed of >100 cellular models representative of the diverse and characteristic somatic lesions for lung cancer. This approach led to the delineation of 171 chemical-genetic associations, shedding light on the targetability of mechanistic vulnerabilities corresponding to a range of oncogenotypes present in patient populations lacking effective therapy. Chemically addressable addictions to ciliogenesis in TTC21B mutants and GLUT8-dependent serine biosynthesis in KRAS/KEAP1 double mutants are prominent examples. These observations indicate a wealth of actionable opportunities within the complex molecular etiology of cancer.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Proliferação de Células/efeitos dos fármacos , Neoplasias Pulmonares/patologia , Bibliotecas de Moléculas Pequenas/farmacologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Família 4 do Citocromo P450/deficiência , Família 4 do Citocromo P450/genética , Descoberta de Drogas , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Glucocorticoides/farmacologia , Proteínas Facilitadoras de Transporte de Glucose/antagonistas & inibidores , Proteínas Facilitadoras de Transporte de Glucose/genética , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Mutação , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptor Notch2/genética , Receptor Notch2/metabolismo , Receptores de Glucocorticoides/antagonistas & inibidores , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/metabolismo
4.
Anticancer Res ; 36(11): 5849-5858, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27793908

RESUMO

Clinical trials are in progress on AZD5363, an inhibitor of protein kinase B (AKT), to assess its effects on the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway. Cells treated with AKT inhibitors have been reported to activate alternative pathways in order to escape growth inhibition. AZD5363-sensitized Hs578T breast cancer cells displayed reduced levels of phosphorylated glycogen synthase kinase 3 beta (pGSK3ß). Interestingly, in AZD5363-treated cells, the level of phosphorylated (activated) AKT (pAKT) increased. Since pAKT positively correlates with cancer growth and survival, we aimed to identify conditions that could reduce AZD5363-induction of pAKT. We examined whether AZD5363 induction of pAKT could be reduced by co-treatment with inhibitors of the PI3K/AKT/mTOR pathway (LY294002, MK-2206, wortmannin, perifosine, rapamycin, everolimus, and temsirolimus). We observed that co-treatment of LY294002 or MK-2206 with AZD5363 reduced the level of pAKT. Since MK-2206 is clinically used, we propose that co-treatment using MK-2206 with AZD5363 would prove beneficial in blocking the AZD5363-induced pAKT signaling pathway. Our findings contribute to the development of AZD5363-based sensitization therapies for patients with cancer.


Assuntos
Inibidores Enzimáticos/farmacologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirimidinas/farmacologia , Pirróis/farmacologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Cromonas , Sinergismo Farmacológico , Humanos , Morfolinas , Fosforilação
5.
Anticancer Res ; 36(11): 5859-5866, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27793909

RESUMO

BACKGROUND/AIM: Colchicine (COL) is a well-known and potent microtubule targeting anticancer agent. The purpose of our study was to identify conditions that increase sensitization of COL-resistant cancer cells that overexpress P-glycoprotein (P-gp). MATERIALS AND METHODS: The anti-malarial drugs chloroquine (CHL), mefloquine (MEF) and primaquine (PRI) have been shown to increase sensitization in drug-resistant KBV20C cells via P-gp inhibition. Therefore, we tested whether co-treatment of COL with PRI, CHL or MEF increases sensitivity in COL-resistant KBV20C cells over that of cells treated with COL alone and whether these effects are attributable to P-gp activity. RESULTS: Interestingly, we found that both CHL and PRI, but not MEF, reduced cytotoxicity in KBV20C cells receiving high concentrations of COL, suggesting that the effects of CHL and PRI have specific mechanisms among the anti-malarial drugs. The effects of CHL and PRI were specific to COL-resistant cells, since we did not detect a reduction in cytotoxicity in drug-sensitive parent KB cells. These data suggest that CHL and PRI inhibit the signaling pathways of COL-treated-resistant cells without P-gp inhibition. Furthermore, we studied the molecular mechanisms underlying the effects of COL-CHL co-treatment in KBV20C cells. FACS analysis, annexin V staining and western blot analysis revealed that G2 arrest and apoptosis were lower in cells co-treated with COL and CHL than in cells treated with COL alone. We also found that pH2AX, pHistone H3 and pRb expression was highly reduced in COL-CHL co-treated cells but not in COL-VIB co-treated cells. In addition, expression of the p21 protein, which correlates with drug-resistant phenotypes, increased in cells receiving COL-CHL co-treatment over that of COL-treated cells. CONCLUSION: These results suggest that reduced G2 arrest and apoptosis resulting from COL-CHL co-treatment was attributable to DNA damage and reduced cell cycle progression. These findings provide important information regarding the prevention of COL toxicity in COL-resistant cells and indicate that CHL, PRI and MEF may contribute to sensitization in COL-resistant cells.


Assuntos
Antimaláricos/farmacologia , Colchicina/toxicidade , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Histonas/metabolismo , Humanos
7.
Anticancer Res ; 36(4): 1641-8, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27069141

RESUMO

The purpose of this study was to identify conditions that would increase the sensitivity of drug-resistant cancer cells. Previously, two anti-malarial drugs, chloroquine (CHL) and primaquine (PRI), showed different sensitization effects for vinblastine (VIB)-resistant cancer cells. Herein, we tested co-treatment of cells with CHL or PRI and other microtubule-targeting cancer drugs, namely, vinorelbine (VIO), paclitaxel (PAC), docetaxel (DOC), vincristine (VIC), or halaven (HAL). We found that PRI sensitized P-glycoprotein (P-gp)-overexpressing drug-resistant KBV20C cells to all six anti-mitotic drugs to a similar extent. CHL had a similar sensitization effect only for co-treatment with PAC, DOC, VIC, and HAL, while the sensitization effect was less marked for co-treatment with VIB or VIO. FACS analysis and western blot analysis revealed that G2arrest and apoptosis showed only a slight increase on co-treatment with VIB or VIO and CHL. We also found that phospho-histone H3 and pRb were markedly increased only by PRI-VIB co-treatment, but not by CHL-VIB co-treatment. This suggests that reduction in the expression of these proteins correlates with decreased G2arrest in CHL-VIB co-treatment. We further compared the effect of another anti-malarial drug, mefloquine (MEF), in combination with the six anti-mitotic drugs. We found that MEF and PRI had similar sensitization effects in co-treatment with these anti-mitotic drugs. PRI and MEF had generally similar sensitization effects in co-treatment with anti-mitotic drugs, suggesting that they do not have any preferred anti-mitotic drug partner in co-treatment. This indicates that only CHL shows specificity in co-treatment with anti-mitotic drugs in resistant cancer cells. Our results may contribute to the choice of anti-mitotic drugs to be used in co-treatment of resistant cancer cells with the anti-malarial drugs, CHL, PRI, and MEF.


Assuntos
Antimaláricos/farmacologia , Antineoplásicos/farmacologia , Cloroquina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Mitose/efeitos dos fármacos , Primaquina/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Linhagem Celular Tumoral , Docetaxel , Humanos , Paclitaxel/farmacologia , Taxoides , Vimblastina/análogos & derivados , Vimblastina/farmacologia , Vinorelbina
9.
PLoS One ; 10(9): e0136698, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26335687

RESUMO

Undesirable toxicity is one of the main reasons for withdrawing drugs from the market or eliminating them as candidates in clinical trials. Although numerous studies have attempted to identify biomarkers capable of predicting pharmacotoxicity, few have attempted to discover robust biomarkers that are coherent across various species and experimental settings. To identify such biomarkers, we conducted meta-analyses of massive gene expression profiles for 6,567 in vivo rat samples and 453 compounds. After applying rigorous feature reduction procedures, our analyses identified 18 genes to be related with toxicity upon comparisons of untreated versus treated and innocuous versus toxic specimens of kidney, liver and heart tissue. We then independently validated these genes in human cell lines. In doing so, we found several of these genes to be coherently regulated in both in vivo rat specimens and in human cell lines. Specifically, mRNA expression of neuronal regeneration-related protein was robustly down-regulated in both liver and kidney cells, while mRNA expression of cathepsin D was commonly up-regulated in liver cells after exposure to toxic concentrations of chemical compounds. Use of these novel toxicity biomarkers may enhance the efficiency of screening for safe lead compounds in early-phase drug development prior to animal testing.


Assuntos
Biomarcadores/análise , Catepsina D/análise , Proteínas do Tecido Nervoso/análise , Proteínas Oncogênicas/análise , Toxicogenética , Animais , Linhagem Celular , Expressão Gênica , Humanos
11.
Anticancer Res ; 35(9): 4741-7, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26254364

RESUMO

AZD5363, an inhibitor of protein kinase B (AKT), is currently in clinical trials assessing the potential of the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway. The purpose of the present study was to identify conditions that increase the sensitivity of cancer cells to AZD5363. Microscopic examination revealed that treatment of cancer cells with a low concentration of salinomycin reduced cellular growth of AZD5363-treated breast cancer cells. Furthermore, fluorescence-activated cell sorting (FACS) analysis, Hoechst staining, and annexin V staining revealed that co-treatment with salinomycin sensitizes AZD5363-treated cancer cells via increased apoptosis with S-phase arrest. These results suggest that salinomycin can be applied to increase treatment efficacy for AZD5363-treated cancer cells. Our findings may contribute to improving the efficacy of the development of AZD5363-based sensitization therapies for patients with cancer.


Assuntos
Apoptose , Neoplasias da Mama/tratamento farmacológico , Ensaios de Seleção de Medicamentos Antitumorais , Piranos/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Piranos/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Fase S
12.
Biomed Res Int ; 2014: 295760, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25114899

RESUMO

MK-2206 is an inhibitor of Akt activation. It has been investigated as an anticancer drug in clinical trials assessing the potential of pAkt targeting therapy. The purpose of this study was to identify conditions that increase the sensitivity of cancer cells to MK-2206. We found that the treatment of cancer cells with a high concentration of salinomycin (Sal) reduced total Akt protein levels but increased activated Akt levels. When cancer cells were cotreated with MK-2206 and Sal, both pAkt and total Akt levels were reduced. Using microscopic observation, an assessment of cleaved PARP, FACS analysis of pre-G1 region, and Hoechst staining, we found that Sal increased apoptosis of MK-2206-treated cancer cells. These results suggest that cotreatment with MK-2206 and Sal sensitizes cancer cells via reduction of both pAkt and total Akt. Furthermore, cotreatment of cancer cells with Sal and MK-2206 reduced pp70S6K, pmTOR, and pPDK1 levels. In addition, Sal-induced activation of GSK3ß, TSC2, and 4EBP1 was abolished by MK-2206 cotreatment. These results suggest that cotreatment using MK-2206 and Sal could be used as a therapeutic method to sensitize cancer cells through targeting of the PI3K/Akt/mTOR pathway. Our findings may contribute to the development of MK-2206-based sensitization therapies for cancer patients.


Assuntos
Antineoplásicos/farmacologia , Regulação para Baixo/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Piranos/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/análise , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Apoptose/efeitos dos fármacos , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Quinase 3 da Glicogênio Sintase/análise , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Humanos , Fosfoproteínas/análise , Fosfoproteínas/metabolismo , Proteínas Proto-Oncogênicas c-akt/análise , Proteína 2 do Complexo Esclerose Tuberosa , Proteínas Supressoras de Tumor/análise , Proteínas Supressoras de Tumor/metabolismo
13.
Tumour Biol ; 35(10): 9831-8, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24989930

RESUMO

This study was designed to identify conditions that induce an increase in the sensitivity of drug-resistant cancer cells compared to sensitive cells. Using cell proliferation assays and microscopic observation, thioridazine (THIO) was found to induce higher sensitization in drug-resistant KBV20C cancer cells compared to sensitive KB parent cells. By studying cleaved PARP, annexin V staining, and Hoechst staining, we found that THIO largely increased apoptosis specifically in KBV20C cells, suggesting that the difference in sensitization between the resistant and sensitive cells can be attributed to the ability of THIO to induce apoptosis. THIO could also inhibit p-glycoprotein (P-gp) activity in the resistant KBV20C cells. These observations suggest that the mechanisms underlying THIO sensitization in resistant KBV20C cells involve both apoptosis and P-gp inhibition. Furthermore, co-treatment with THIO and vinblastine (VIB) induces higher sensitization in KBV20C cells than KB cells. As observed in a single treatment with THIO, the sensitization mechanism induced by the co-treatment also involves both apoptosis and P-gp inhibition. These results suggest that the THIO sensitization mechanism is generally conserved. Our findings may contribute to the development of THIO-based therapies for patients presenting resistance to antimitotic drugs.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Bucais/metabolismo , Tioridazina/farmacologia , Apoptose/efeitos dos fármacos , Western Blotting , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/fisiologia , Citometria de Fluxo , Humanos , Neoplasias Bucais/patologia
14.
Eur J Pharmacol ; 723: 141-7, 2014 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-24333214

RESUMO

The purpose of this study was to identify conditions that increase the sensitivity of resistant cancer cells to antimitotic drugs. Using MTS assays, microscopic observation, assessment of cleaved PARP, FACS analysis, and Hoechst staining, we found that the c-Jun N-terminal kinase (Jnk) inhibitor SP600125 (SP) sensitized the antimitotic drug-resistant KBV20C cancer cell line. The sensitization mechanism was independent of p-glycoprotein (P-gp) inhibition. Interestingly, SP-induced sensitization was greater in resistant KBV20C cancer cells than in KB parent cells. The mechanism of SP-induced sensitization involved G2 arrest. KBV20C cells treated with SP and antimitotic drugs were more sensitized than cells treated with SP alone. This suggests that SP can restore sensitization for antimitotic drugs in resistant cancer cells. Our findings may contribute to the development of SP-based combination therapies for patients receiving anti-cancer agents that target microtubules.


Assuntos
Antracenos/farmacologia , Antimitóticos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos
15.
Biochem Biophys Res Commun ; 441(3): 655-60, 2013 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-24284282

RESUMO

The purpose of this study was to identify conditions that will increase the sensitivity of resistant cancer cells to anti-mitotic drugs. Currently, atovaquine (ATO), chloroquine (CHL), primaquine (PRI), mefloquine (MEF), artesunate (ART), and doxycycline (DOY) are the most commonly used anti-malarial drugs. Herein, we tested whether anti-malarial drugs can sensitize drug-resistant KBV20C cancer cells. None of the six tested anti-malarial drugs was found to better sensitize the drug-resistant cells compared to the sensitive KB cells. With an exception of DOY, all other anti-malarial drugs tested could sensitize both KB and KBV20C cells to a similar extent, suggesting that anti-malarial drugs could be used for sensitive as well as resistant cancer cells. Furthermore, we examined the effects of anti-malarial drugs in combination with an antimitotic drug, vinblastine (VIN) on the sensitisation of resistant KBV20C cells. Using viability assay, microscopic observation, assessment of cleaved PARP, and Hoechst staining, we identified that two anti-malarial drugs, PRI and MEF, highly sensitized KBV20C-resistant cells to VIN treatment. Moreover, PRI- or MEF-induced sensitisation was not observed in VIN-treated sensitive KB parent cells, suggesting that the observed effect is specific to resistant cancer cells. We demonstrated that the PRI and MEF sensitisation mechanism mainly depends on the inhibition of p-glycoprotein (P-gp). Our findings may contribute to the development of anti-malarial drug-based combination therapies for patients resistant to anti-mitotic drugs.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Antimaláricos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Mefloquina/farmacologia , Primaquina/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Artemisininas/farmacologia , Artesunato , Linhagem Celular Tumoral , Cloroquina/farmacologia , Doxiciclina/farmacologia , Humanos , Verapamil/farmacologia , Vimblastina/farmacologia
16.
Int J Mol Sci ; 14(9): 17304-18, 2013 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-23975168

RESUMO

The present study identified a novel salinomycin (Sal)-sensitization mechanism in cancer cells. We analyzed the signal proteins Akt, Jnk, p38, Jak, and Erk1/2 in cancer cell lines that had arrested growth following low amounts of Sal treatment. We also tested the signal molecules PI3K, PDK1, GSK3ß, p70S6K, mTOR, and PTEN to analyze the PI3K/Akt/mTOR pathway. The results showed that Sal sensitization positively correlates with large reductions in p70S6K activation. Interestingly, Akt was the only signal protein to be significantly activated by Sal treatment. The Akt activation appeared to require the PI3K pathway as its activation was abolished by the PI3K inhibitors LY294002 and wortmannin. The Akt activation by Sal was conserved in the other cell lines analyzed, which originated from other organs. Both Akt activation and C-PARP production were proportionally increased with increased doses of Sal. In addition, the increased levels of pAkt were not reduced over the time course of the experiment. Co-treatment with Akt inhibitors sensitized the Sal-treated cancer cells. The results thereby suggest that Akt activation is increased in cells that survive Sal treatment and resist the cytotoxic effect of Sal. Taken together; these results indicate that Akt activation may promote the resistance of cancer cells to Sal.


Assuntos
Proteínas Proto-Oncogênicas c-akt/metabolismo , Piranos/farmacologia , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Androstadienos/farmacologia , Western Blotting , Linhagem Celular Tumoral , Cromonas/farmacologia , Citometria de Fluxo , Humanos , Morfolinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Wortmanina
17.
Int J Mol Sci ; 13(10): 13169-82, 2012 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-23202945

RESUMO

The present study identified a novel salinomycin (Sal) sensitization mechanism in cancer. We tested whether Sal reduced proliferation in a high-density population by counting attached cell numbers after Sal treatment. Sal reduced proliferation in high-density cell populations. Longer exposure to Sal further reduced proliferation. Sal concentrations of 0.1 and 5 μM had similar sensitization effects, suggesting that Sal toxicity was minimal with longer exposure to a high-density cell population. The results suggest that Sal can be applied at a relatively low concentration for a longer time to overcome drug-resistant solid tumors. The 0.5 μM Sal treatment resulted in fewer attached cells than that of the 5 μM Sal treatment with a longer exposure. The lower Sal concentration mainly increased the number of easily detachable cells on the surface. In particular, 0.5 μM Sal increased cellular detachment of newly produced daughter cells. The easily-detachable cells were undergoing apoptosis. It seems that the 0.5 μM Sal treatment also increased cellular toxicity. These novel findings may contribute to the development of Sal-based therapy for patients with drug-resistant cancer or a high-density solid tumor.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Piranos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Células MCF-7 , Fatores de Tempo
18.
Eur J Pharmacol ; 697(1-3): 24-31, 2012 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-23085270

RESUMO

In this study, we synthesized a novel carbazole derivative, MHY407, as a sensitizer of cancer cells to increase DNA damage. We then evaluated the anticancer effects of MHY407 and identified the molecular mechanism for the sensitization of breast cancer cell lines. MHY407 significantly increased DNA damage as determined by DNA breakage, levels of damage-responsive proteins, and DNA foci. In addition, MHY407 increased p21 and decreased cyclin D1 protein levels. MHY407 also involved increased cell cycle arrest at the S phase. Furthermore, in doxorubicin and etoposide-treated breast cancer cells, co-treatment with MHY407 reduced cell viability and increased apoptosis. Co-treatment of MHY407 with doxorubicin or etoposide increased DNA damage-related proteins and foci formation, suggesting that increased DNA damage by MHY407 plays an important role in the sensitization. In addition, MHY407 also sensitized the cancer cells to DNA damaging radiation treatment. These results may contribute to the development of MHY407-based treatments for cancer patients receiving DNA-damage therapy.


Assuntos
Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carbazóis/farmacologia , Dano ao DNA , Doxorrubicina/farmacologia , Compostos de Epóxi/farmacologia , Etoposídeo/farmacologia , Neoplasias/patologia , Radiossensibilizantes/farmacologia , Apoptose/efeitos dos fármacos , Carbazóis/síntese química , Sobrevivência Celular/efeitos dos fármacos , Ciclina D1/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Relação Dose-Resposta a Droga , Relação Dose-Resposta à Radiação , Compostos de Epóxi/síntese química , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Células MCF-7 , Neoplasias/genética , Neoplasias/metabolismo , Radiossensibilizantes/síntese química , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos , Fatores de Tempo
19.
Biochem Biophys Res Commun ; 418(1): 98-103, 2012 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-22244892

RESUMO

Here, we investigated whether Sal could sensitize cancer cells to antimitotic drugs. We demonstrated that Sal sensitized paclitaxcel (PAC)-, docetaxcel (DOC)-, vinblastin (VIN)-, or colchicine (COL)-treated cancer cell lines, suggesting that Sal has the ability to sensitize the cells to any form of microtubule-targeting drugs. Sensitization to the antimitotic drugs could be achieved with very low concentrations of Sal, suggesting that there is a possibility to minimize Sal toxicity associated with human cancer patient treatments. Sensitization by Sal increased apoptosis, which was observed by C-PARP production. Sal sensitized the cancer cells to antimitotic drugs by preventing G2 arrest, suggesting that Sal contributes to the induction of mitotic catastrophe. Sal generally reduced cyclin D1 levels in PAC-, DOC-, and VIN-treated cells. In addition, Sal treatment increased pH2AX levels and reduced p21 levels in antimitotic drugs-treated cells. These observations suggest that the mechanisms underlying Sal sensitization to DNA-damaging compounds, radiation, and microtubule-targeting drugs are similar. Our data demonstrated that Sal sensitizes cancer cells to antimitotic drugs by increasing apoptosis through the prevention of G2 arrest via conserved Sal-sensitization mechanisms. These results may contribute to the development of Sal-based chemotherapy for cancer patients treated with antimitotic drugs.


Assuntos
Antimitóticos/farmacologia , Apoptose/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Piranos/farmacologia , Linhagem Celular Tumoral , Colchicina/farmacologia , Ciclina D1/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Dano ao DNA , Docetaxel , Humanos , Paclitaxel/farmacologia , Taxoides/farmacologia , Vimblastina/farmacologia
20.
Invest New Drugs ; 30(4): 1311-8, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21573958

RESUMO

Salinomycin (Sal) is potentially useful for the treatment of cancer. The present study examined a novel mechanism of Sal sensitization in cancer cells. Sal sensitized radiation-treated cancer cells by inducing G2 arrest and causing DNA damage. Sal treatment also reduced p21 levels in radiation-treated cells. Considering that Sal sensitizes doxorubicin (DOX)- or etoposide (ETO)-treated cancer cells by causing DNA damage and reducing p21 expression, the results from our study suggest that the mechanism underlying Sal sensitization is conserved in both chemo- and radiation-treated cells. We also tested the ability of Sal to inhibit p-glycoprotein (P-gp), which plays a role in the efflux of anti-cancer drugs to reduce cellular damage. In particular, we compared Sal to verapamil (Ver), a well-known P-gp inhibitor. Sal inhibits P-gp with a different substrate distinct from that of Ver. In addition, Sal sensitized Ver-resistant cells, indicating that this compound is more effective for sensitizing than Ver. Taken together, the results from our study may contribute to the development of Sal-based therapy for cancer patients treated with P-gp-inhibiting drugs or radiation therapy.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Dano ao DNA , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Piranos/farmacologia , Piranos/uso terapêutico , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Linhagem Celular Tumoral , Terapia Combinada , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias/patologia , Especificidade por Substrato/efeitos dos fármacos , Verapamil/farmacologia , Verapamil/uso terapêutico
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