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1.
Anticancer Res ; 39(12): 6743-6750, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31810939

RESUMO

BACKGROUND: Glioblastoma (GBM) is the most aggressive type of primary malignant brain tumour. The interaction between high-mobility group box 1 (HMGB1) and receptor for advanced glycation end-products (RAGE) is important for tumour cell growth. Previously, we identified an anticancer candidate, papaverine, that inhibited the HMGB1-RAGE interaction. MATERIALS AND METHODS: Our study assessed the anticancer effects of papaverine alone or in combination with temozolomide on U87MG and T98G human GBM cells using clonogenicity assays, as well as in a U87MG xenograft mouse model. The radiosensitizing efficacy of papaverine was measured based on the clonogenicity of T98G cells. RESULTS: Papaverine significantly inhibited the clonogenicity of U87MG and T98G cells. Compared with single treatment, the combination of papaverine and temozolomide more highly suppressed the clonogenicity of T98G cells and delayed tumour growth in the U87MG xenograft mouse model. Furthermore, papaverine increased the radiosensitivity of T98G cells. CONCLUSION: Papaverine is a potential anticancer drug in GBM treatment.


Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Papaverina/uso terapêutico , Temozolomida/uso terapêutico , Animais , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/radioterapia , Linhagem Celular Tumoral , Glioblastoma/metabolismo , Glioblastoma/patologia , Glioblastoma/radioterapia , Proteína HMGB1/antagonistas & inibidores , Proteína HMGB1/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Tolerância a Radiação/efeitos dos fármacos , Receptor para Produtos Finais de Glicação Avançada/antagonistas & inibidores , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Anticancer Res ; 39(11): 6087-6095, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704836

RESUMO

BACKGROUND: RAS GTPase-activating protein-binding protein (G3BP1) is an RNA-binding protein that is essential for assembling stress granules. Many functions related to the survival and progression of cancer have been reported. The current study aimed to investigate the role of G3BP1 in radio-sensitisation of cancer cells. MATERIALS AND METHODS: Radiation sensitivity and chemosensitivity were analysed in A549 and H460 cells transfected with G3BP1 siRNAs, and N-acetyl-L-cysteine (NAC) was used to elucidate the involvement of reactive oxygen species (ROS). RESULTS: G3BP1 depletion sensitised lung cancer cell lines to radiation, and the effect was related to ROS. G3BP1 depletion impaired the intracellular ROS scavenging system and NAC abolished the radiation-sensitive phenotypes caused by G3BP1 depletion. CONCLUSION: The study suggested G3BP1 as a promising target for radio- and chemosensitisation of lung cancer.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/radioterapia , Dano ao DNA/efeitos da radiação , DNA Helicases/antagonistas & inibidores , Neoplasias Pulmonares/radioterapia , Estresse Oxidativo/efeitos da radiação , Proteínas de Ligação a Poli-ADP-Ribose/antagonistas & inibidores , RNA Helicases/antagonistas & inibidores , Proteínas com Motivo de Reconhecimento de RNA/antagonistas & inibidores , Tolerância a Radiação/efeitos dos fármacos , Antibióticos Antineoplásicos/farmacologia , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Proliferação de Células , DNA Helicases/genética , DNA Helicases/metabolismo , Doxorrubicina/farmacologia , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Estresse Oxidativo/efeitos dos fármacos , Proteínas de Ligação a Poli-ADP-Ribose/genética , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , RNA Helicases/genética , RNA Helicases/metabolismo , Proteínas com Motivo de Reconhecimento de RNA/genética , Proteínas com Motivo de Reconhecimento de RNA/metabolismo , RNA Interferente Pequeno/genética , Espécies Reativas de Oxigênio/metabolismo , Células Tumorais Cultivadas
3.
Int J Radiat Oncol Biol Phys ; 105(4): 861-874, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31419512

RESUMO

PURPOSE: Telomerase is reactivated in non-small cell lung cancer (NSCLC), and it increases cell resistance to irradiation through protecting damaged telomeres and enhancing DNA damage repair. We investigated the radiosensitizing effect of BIBR1532, a highly selective telomerase inhibitor, and its corresponding mechanism in NSCLC. METHODS AND MATERIALS: Cell proliferation, telomerase activity, and telomere dysfunction-induced foci were measured with CCK-8 assay, real-time fluorescent quantitative polymerase chain reaction, and immunofluorescence. The effect of BIBR1532 on the response of NSCLC cells to radiation was analyzed using clonogenic survival and xenograft tumor assays. Cell death and cell senescence induced by BIBR1532 or ionizing radiation (IR), or both, were detected with western blotting, flow cytometry, and senescence-association ß-galactosidase staining assay. RESULTS: We observed dose-dependent direct cytotoxicity of BIBR1532 at relatively high concentrations in NSCLC cells. Low concentrations of BIBR1532 did not appear toxic to NSCLC cells; however, they substantially increased the therapeutic efficacy of IR in vitro by enhancing IR-induced apoptosis, senescence, and mitotic catastrophe. Moreover, in a mouse xenograft model, BIBR1532 treatment synergized with IR at nontoxic dose levels promoted the antitumor efficacy of IR without toxicity to hematologic and internal organs. Mechanistically, lower concentrations of BIBR1532 effectively inhibited telomerase activity and increased IR-induced telomere dysfunction, resulting in disruption of chromosomal stability and inhibition of the ATM/CHK1 (ataxia-telangiectasia-mutated/Checkpoint kinase 1) pathway, which impaired DNA damage repair. CONCLUSIONS: Our findings demonstrate that disturbances in telomerase function by nontoxic dose levels of BIBR1532 effectively enhance the radiosensitivity of NSCLC cells. This finding provides a rationale for the clinical assessment of BIBR1532 as a radiosensitizer.


Assuntos
Aminobenzoatos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Neoplasias Pulmonares/radioterapia , Naftalenos/farmacologia , Tolerância a Radiação/efeitos dos fármacos , Radiossensibilizantes/farmacologia , Telomerase/antagonistas & inibidores , Aminobenzoatos/administração & dosagem , Animais , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Morte Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacologia , Reativadores Enzimáticos/farmacologia , Feminino , Humanos , Neoplasias Pulmonares/enzimologia , Camundongos , Camundongos Nus , Naftalenos/administração & dosagem , Fosforilação/efeitos dos fármacos , Sincalida , Telomerase/metabolismo , Telômero/efeitos dos fármacos , Homeostase do Telômero/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
4.
BMC Cancer ; 19(1): 829, 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31438892

RESUMO

BACKGROUND: Carbon ion (12C) radiotherapy is becoming very promising to kill highly metastatic cancer cells keeping adjacent normal cells least affected. Our previous study shows that combined PARP-1 inhibition with 12C ion reduces MMP-2,-9 synergistically in HeLa cells but detailed mechanism are not clear. To understand this mechanism and the rationale of using PARP-1 inhibitor with 12C ion radiotherapy for better outcome in controlling metastasis, we investigated metastatic potential in two non-small cell lung cancer (NSCLC) A549 and H1299 (p53-deficient) cells exposed with 12C ion in presence and absence of PARP-1 inhibition using siRNA or olaparib. METHODS: We monitored cell proliferation, in-vitro cell migration, wound healing, expression and activity of MMP-2, - 9 in A549 and p53-deficient H1299 cell lines exposed with 12C ion with and without PARP-1 inhibitor olaparib/DPQ. Expression and phosphorylation of NF-kB, EGFR, Akt, p38, ERK was also observed in A549 and H1299 cells exposed with 12C ion with and without PARP-1 inhibition using siRNA or olaparib. We also checked expression of few marker genes involved in epithelial-mesenchymal transition (EMT) pathways like N-cadherin, vimentin, anillin, claudin-1, - 2 in both NSCLC. To determine the generalized effect of 12C ion and olaparib in inhibition of cell's metastatic potential, wound healing and activity of MMP-2, - 9 was also studied in HeLa and MCF7 cell lines after 12C ion exposure and in combination with PARP-1 inhibitor olaparib. RESULTS: Our experiments show that 12C ion and PARP-1 inhibition separately reduces cell proliferation, cell migration, wound healing, phosphorylation of EGFR, Akt, p38, ERK resulting inactivation of NF-kB. Combined treatment abolishes NF-kB expression and hence synergistically reduces MMP-2, - 9 expressions. Each single treatment reduces N-cadherin, vimentin, anillin but increases claudin-1, - 2 leading to suppression of EMT process. However, combined treatment synergistically alters these proteins to suppress EMT pathways significantly. CONCLUSION: The activation pathways of transcription of MMP-2,-9 via NF-kB and key marker proteins in EMT pathways are targeted by both 12C ion and olaparib/siRNA. Hence, 12C ion radiotherapy could potentially be combined with olaparib as chemotherapeutic agent for better control of cancer metastasis.


Assuntos
Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Transição Epitelial-Mesenquimal , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Tolerância a Radiação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , Linhagem Celular Tumoral , Movimento Celular , Sobrevivência Celular/genética , Receptores ErbB/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Radiação Ionizante , Cicatrização , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
5.
Anticancer Res ; 39(8): 4479-4483, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366548

RESUMO

BACKGROUND/AIM: The stereo-configuration (R-, S-configuration) of chiral-2-nitroimidazole derivatives alters their radiosensitizing activity. This study aimed at examining the molecular features of these enantiomers by molecular simulation techniques. MATERIALS AND METHODS: A series of 2-nitroimidazole-based radiosensitizer TX-2036 molecules were synthesized, and their profiles were examined using molecular structural analysis such as conformation analysis, molecular orbital analysis, and electrostatic potential analysis. RESULTS: R-configured TXs (TX-2043, -2030, -2036) had a weaker radiosensitizing activity than S-configured TXs (TX-2044, -2031, -2037), and R-compounds had a small minus electrostatic potential (ESP) field in the cyclopentene-1,3-dione region. S-configured TX-2046 had weaker radiosensitizing activity than R-configured TX-2045, and TX-2046 had a small minus ESP field as well as R-configured TX-2043, -2030, - 2036. CONCLUSION: The cyclopentene-1,3-dione involved in the small minus ESP field affected the radiosensitizing activity of the TX-2036 series of molecules.


Assuntos
Desenho de Drogas , Nitroimidazóis/química , Tolerância a Radiação/efeitos dos fármacos , Radiossensibilizantes/química , Hipóxia Celular/efeitos dos fármacos , Ciclopentanos/síntese química , Ciclopentanos/química , Humanos , Nitroimidazóis/síntese química , Radiossensibilizantes/síntese química , Eletricidade Estática , Estereoisomerismo , Relação Estrutura-Atividade
6.
Eur J Pharmacol ; 859: 172548, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31323224

RESUMO

Due to the radiosensitivity of the airway epithelium, radiation-induced sinusitis or bronchitis is not uncommon, and makes mitigation of resulting inflammatory airway diseases a principal goal of many investigations. This study examined whether Ovatodiolide (Ova) sensitizes the human metastatic nasopharyngeal cancer (NPC) cell line, NPC-BM2, to irradiation using viability, clonogenicity and Western blot assays. Concurrently, we used varying concentrations of histamine and/or Ova to determine the anti-inflammatory potential of Ovatodiolide on normal bronchus epithelial BEAS-2B cells, as well as on the subcellular distribution of Aquaporin 5 (AQP5) and expression levels of p-CREB, AQP5, p38 MAPK, NF-κB, PI3K, Akt and ERK proteins. We demonstrated that Ova in synergism with irradiation inhibited NPC-BM2 cell viability and suppressed their clonogenicity. Immunofluorescence analysis revealed low-dose (≤ 2.5 µM) Ova reversed histamine-induced suppression of AQP5 expression, and abrogated histamine-enhanced NF-κB nuclear translocation, indicating Ova modulates the p38 MAPK/NF-κB signaling pathway and elicits p-CREB/AQP5-mediated antihistamine effects. Similarly, Ova deregulates the PI3K/Akt/ERK signaling in BEAS-2B cells, suggesting its cytoprotective potential. In conclusion, this study highlights the radio-sensitizing anticancer efficacy of Ova in human metastatic NPC cells, as well as its putative cytoprotective role in normal bronchial cells, for airway surface liquid maintenance and homeostasis during or after radiotherapy.


Assuntos
Aquaporina 5/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Diterpenos/farmacologia , Células Epiteliais/efeitos dos fármacos , Carcinoma Nasofaríngeo/patologia , Tolerância a Radiação/efeitos dos fármacos , Brônquios/citologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , NF-kappa B/metabolismo , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/radioterapia , Metástase Neoplásica , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
7.
Int J Mol Sci ; 20(14)2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31315221

RESUMO

Many reports have shown that grains play an important role in our daily lives and can provide energy and nutrients to protect us from various diseases, and they are considered to be indispensable parts of our lives. It has been reported that some constituents in grains could exert functional effects against HIV infections and multiple cancers. Zymolytic grain can produce some new useful molecules and thus support the cell nutrients in the human body. In this study, the effects of zymolytic grain extract (ZGE) supernatants on the changes of nematode indicators were investigated, including lifespan, self-brood size, and body length in environmental conditions (temperature, ultraviolet radiation or 5-fluoro-2'-deoxyuridine (FUDR) stimuli). We found that, compared to the control group, the ZGE supernatant-feeding group could prolong the lifespan of nematodes under normal conditions. More importantly, ZGE supernatants could improve the ability of nematodes to resist stress. When the concentration of FUDR was 400 or 50 µM, the ZGE supernatant-feeding group could prolong lifespan by an average of 38.4% compared to the control group, and the eggs of the ZGE supernatant-feeding group could hatch and develop into adults. These results indicated that ZGE could protect C. elegans from external stress and thus prolong their lifespan and improve the physiological state of nematodes. Therefore, ZGE supernatant has potential to be used as a nutritional product in antioxidant and anti-aging research.


Assuntos
Grão Comestível/química , Longevidade/efeitos dos fármacos , Tolerância a Radiação/efeitos dos fármacos , Estresse Fisiológico/efeitos dos fármacos , Animais , Caenorhabditis elegans , Extratos Vegetais/farmacologia , Raios Ultravioleta
8.
Int J Med Sci ; 16(4): 519-528, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31171903

RESUMO

Oesophageal adenocarcinoma (OAC) is an exemplar model of obesity-associated cancer. Response to neoadjuvant chemoradiotherapy (NA CRT) is a clinical challenge. We examined if visceral adipose tissue and obesity status alter radiosensitivity in OAC. The radioresistant (OE33R) and radioresponsive (OE33P) OAC isogenic model was cultured with adipose tissue conditioned media from three patient cohorts: non-cancer patients, surgery only OAC patients and NA CRT OAC patients. Cell survival was characterised by clonogenic assay, metabolomic profiling by nuclear magnetic resonance spectroscopy and adipokine receptor gene expression by qPCR. A retrospective in vivo study compared tumour response to NA CRT in normal weight (n=53) versus overweight/obese patients (n=148). Adipose conditioned media (ACM) from all patient cohorts significantly increased radiosensitivity in radioresistant OE33R cells. ACM from the NA CRT OAC cohort increased radiosensitivity in OE33P cells. Metabolomic profiling demonstrated separation of the non-cancer and surgery only OAC cohorts and between the non-cancer and NA CRT OAC cohorts. Gene expression profiling of OE33P versus OE33R cells demonstrated differential expression of the adiponectin receptor-1 (AR1), adiponectin receptor-2 (AR2), leptin receptor (LepR) and neuropilin receptor-1 (NRP1) genes. In vivo overweight/obese OAC patients achieved an enhanced tumour response following NA CRT compared to normal weight patients. This study demonstrates that visceral adipose tissue modulates the cellular response to radiation in OAC.


Assuntos
Adenocarcinoma/radioterapia , Neoplasias Esofágicas/radioterapia , Gordura Intra-Abdominal/efeitos dos fármacos , Obesidade Abdominal/radioterapia , Tolerância a Radiação/efeitos dos fármacos , Adenocarcinoma/genética , Adenocarcinoma/patologia , Índice de Massa Corporal , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Humanos , Gordura Intra-Abdominal/patologia , Masculino , Metabolômica , Obesidade Abdominal/genética , Obesidade Abdominal/patologia , Receptores de Adiponectina/genética , Receptores para Leptina/efeitos da radiação
9.
Oncol Rep ; 42(2): 561-570, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173270

RESUMO

Gastric cancer (GC) is a severe public health problem worldwide, particularly in China. Radiotherapy is the main locoregional treatment for various types of unresectable tumor, including GC. However, many patients fail to respond to radiotherapy due to the intrinsic radioresistance of cancer cells. This study was designed to investigate the effects and potential mechanism of radiosensitization associated with DNA­dependent protein kinase catalytic subunit (DNA­PKcs) inhibitor in human GC cell lines in vitro. Among the six GC cell lines (SGC7901, HGC­27, MKN45, MKN74, BGC823 and MGC803) that were exposed to increasing doses of IR (0, 2, 4, 6 and 8 Gy), the mean lethal dose and quasi­threshold dose measurements indicated that BGC823 and MGC803 were relatively insensitive to ionizing radiation (IR). IR induced significant elevation of γ H2A histone family member X (γH2AX) in MKN45 cells compared with BGC823 cells. DNA­PKcs and phospho­DNA­PKcs protein levels were increased in BGC823 and MGC803 cells compared with other GC cell lines (SGC7901, HGC­27, MKN45 and MKN74). DNA­PKcs inhibition led to increased sensitivity of BGC823 and MGC803 cells to IR. NU7441 increased γH2AX expression in the nuclei of BGC823 cells following IR. Combination of DNA­PKcs and CK2 inhibition further increased the sensitivity of GC cells to IR. The combination of NU7441 and CX4945 increased γH2AX expression in the nucleus of BGC823 cells following IR compared with treatment with NU7441 alone. Taken together, the findings suggest that DNA­PKcs inhibitor increased the sensitivity of radioresistant BGC823 and MGC803 cells to radiotherapy through the cleaved­caspase3/γH2AX signaling pathway, thus presenting a potential treatment method for GC.


Assuntos
Cromonas/farmacologia , Proteína Quinase Ativada por DNA/antagonistas & inibidores , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Morfolinas/farmacologia , Tolerância a Radiação/efeitos dos fármacos , Neoplasias Gástricas/radioterapia , Apoptose , Proliferação de Células , Humanos , Radiação Ionizante , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Células Tumorais Cultivadas
10.
Molecules ; 24(9)2019 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-31060229

RESUMO

Background: KDM5 enzymes are H3K4 specific histone demethylases involved in transcriptional regulation and DNA repair. These proteins are overexpressed in different kinds of cancer, including breast, prostate and bladder carcinomas, with positive effects on cancer proliferation and chemoresistance. For these reasons, these enzymes are potential therapeutic targets. Methods: In the present study, we analyzed the effects of three different inhibitors of KDM5 enzymes in MCF-7 breast cancer cells over-expressing one of them, namely KDM5B/JARID1B. In particular we tested H3K4 demethylation (western blot); radio-sensitivity (cytoxicity and clonogenic assays) and damage accumulation (COMET assay and kinetics of H2AX phosphorylation). Results: we show that all three compounds with completely different chemical structures can selectively inhibit KDM5 enzymes and are capable of increasing sensitivity of breast cancer cells to ionizing radiation and radiation-induced damage. Conclusions: These findings confirm the involvement of H3K4 specific demethylases in the response to DNA damage, show a requirement of the catalytic function and suggest new strategies for the therapeutic use of their inhibitors.


Assuntos
Neoplasias da Mama/enzimologia , Histona Desmetilases/antagonistas & inibidores , Histona Desmetilases com o Domínio Jumonji/genética , Proteínas Nucleares/genética , Radiossensibilizantes/farmacologia , Proteínas Repressoras/genética , Bibliotecas de Moléculas Pequenas/farmacologia , Neoplasias da Mama/genética , Neoplasias da Mama/terapia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Histonas/metabolismo , Humanos , Histona Desmetilases com o Domínio Jumonji/metabolismo , Células MCF-7 , Modelos Moleculares , Estrutura Molecular , Proteínas Nucleares/metabolismo , Tolerância a Radiação/efeitos dos fármacos , Radiossensibilizantes/química , Proteínas Repressoras/metabolismo , Bibliotecas de Moléculas Pequenas/química , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/efeitos da radiação
11.
Crit Rev Oncol Hematol ; 138: 214-222, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31092378

RESUMO

The Ataxia Telangiectasia Mutated (ATM)-mediated DNA damage response (DDR) is a major mechanism of resistance of glioblastoma (GB) - initiating cells (GICs) to radiotherapy. The closely related Ataxia Telangiectasia and Rad3-related protein (ATR) is also involved in tumor resistance to radio- and chemotherapy. It has been shown that pharmacological inhibition of ATM protein may overcome the DDR-mediated resistance in GICs and significantly radiosensitize GIC-driven GB. Albeit not essential for life as shown by the decade-long lifespan of AT patients, the ATM protein may be involved in a number of important functions other than the response to DNA damage. We discuss our current knowledge about the toxicity of pharmacologic inhibition of ATM and ATR proteins.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Radiossensibilizantes/farmacologia , Adulto , Animais , Dano ao DNA/efeitos dos fármacos , Humanos , Células-Tronco Neoplásicas/efeitos dos fármacos , Tolerância a Radiação/efeitos dos fármacos
12.
Front Biosci (Landmark Ed) ; 24: 1190-1202, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31136975

RESUMO

Radiation therapy is a major treatment in hepatocellular carcinoma (HCC). Yet, this treatment is ineffective in HCC due to lack of radiosensitivity. For this reason, we examined whether berberine (BBR) might modify the radioresistance of HCC cells. BBR enhances the radiation-induced oxidative stress and apoptosis in Huh7 and HepG2 cells while it protectes HHL-5 cells from radiation damage. To test the importance of Nrf2, a master transcription factor in oxidative damage, the effect of BBR is studied in irradiated Nrf2-deficient cells. BBR fails to induce the radiosensitivity in Nrf2-deficient cells suggesting that Nrf2 is required for the effect of BBR. BBR suppresses the expression of Nrf2 signaling-related proteins (Nrf2, HO-1 and NQO-1) in Huh7 and HepG2 cells, demonstrating that BBR strengthens radiosensitivity via suppressing Nrf2 signaling pathway in HCC cells. Furthermore, experiment using xenografts in nude mice indicated that BBR enhances the growth inhibitory effect of radiation in a Nrf2-dependent manner in vivo. In conclusion, these results suggest that BBR is a promising potential sensitizer for the radiotherapy of HCC.


Assuntos
Berberina/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Fator 2 Relacionado a NF-E2/metabolismo , Tolerância a Radiação/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Apoptose/efeitos da radiação , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/radioterapia , Linhagem Celular , Linhagem Celular Tumoral , Células Hep G2 , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/radioterapia , Camundongos Endogâmicos BALB C , Camundongos Nus , Fator 2 Relacionado a NF-E2/genética , Interferência de RNA , Tolerância a Radiação/genética , Tolerância a Radiação/efeitos da radiação , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/efeitos da radiação
13.
BMC Cancer ; 19(1): 299, 2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30943918

RESUMO

BACKGROUND: Most tumor cells show aberrantly activated Akt which leads to increased cell survival and resistance to cancer radiotherapy. Therefore, targeting Akt can be a promising strategy for radiosensitization. Here, we explore the impact of the Akt inhibitor MK-2206 alone and in combination with the dual PI3K and mTOR inhibitor PI-103 on the radiation sensitivity of glioblastoma cells. In addition, we examine migration of drug-treated cells. METHODS: Using single-cell tracking and wound healing migration tests, colony-forming assay, Western blotting, flow cytometry and electrorotation we examined the effects of MK-2206 and PI-103 and/or irradiation on the migration, radiation sensitivity, expression of several marker proteins, DNA damage, cell cycle progression and the plasma membrane properties in two glioblastoma (DK-MG and SNB19) cell lines, previously shown to differ markedly in their migratory behavior and response to PI3K/mTOR inhibition. RESULTS: We found that MK-2206 strongly reduces the migration of DK-MG but only moderately reduces the migration of SNB19 cells. Surprisingly, MK-2206 did not cause radiosensitization, but even increased colony-forming ability after irradiation. Moreover, MK-2206 did not enhance the radiosensitizing effect of PI-103. The results appear to contradict the strong depletion of p-Akt in MK-2206-treated cells. Possible reasons for the radioresistance of MK-2206-treated cells could be unaltered or in case of SNB19 cells even increased levels of p-mTOR and p-S6, as compared to the reduced expression of these proteins in PI-103-treated samples. We also found that MK-2206 did not enhance IR-induced DNA damage, neither did it cause cell cycle distortion, nor apoptosis nor excessive autophagy. CONCLUSIONS: Our study provides proof that MK-2206 can effectively inhibit the expression of Akt in two glioblastoma cell lines. However, due to an aberrant activation of mTOR in response to Akt inhibition in PTEN mutated cells, the therapeutic window needs to be carefully defined, or a combination of Akt and mTOR inhibitors should be considered.


Assuntos
Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Compostos Heterocíclicos com 3 Anéis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Radiossensibilizantes/farmacologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/efeitos da radiação , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/efeitos da radiação , Dano ao DNA , Furanos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Glioblastoma/genética , Glioblastoma/terapia , Humanos , Mutação , PTEN Fosfo-Hidrolase/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Piridinas/farmacologia , Pirimidinas/farmacologia , Tolerância a Radiação/efeitos dos fármacos , Análise de Célula Única , Serina-Treonina Quinases TOR/metabolismo
14.
Biomed Pharmacother ; 112: 108656, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30970507

RESUMO

Radiotherapy is an adjuvant treatment of surgery in prostate cancer, while radioresistance has been the challenge of treatment. It has been reported that α-Solanine exhibits anti-cancer activity and enhances the chemo- and radio-sensitivity in several human cancers, whereas the role of α-Solanine on radiosensitivity to PCa remains to be uncovered yet. We found α-Solanine decreased cell viability in human PCa cells rather than normal prostate epithelial cells in vitro. Functional experiments showed that cell viability and colonies formation were declined & apoptosis rate and DNA double strand breaks (DSBs) marker γ-H2AX expressions were elevated by α-Solanine in PCa cells treated with X-ray irradiation, compared with X-ray irradiation treatment only. GAS5 was down-regulated & miR-18a was up-regulated in PCa cells, which was reversed in the presence of α-Solanine. Effects of ectopic GAS5 on inhibiting cell viability and survival & promoting apoptosis and DNA damage were reversed by miR-18a overexpression in PCa cells. Moreover, GAS5 regulated miR-18a expression by target binding during α-Solanine treatment. Collectively, α-Solanine suppresses cell proliferation and promotes radiosensitivity through up-regulating GAS5/miR-18a pathway in PCa. Our results provide a novel mechanism of α-Solanine treatment in human prostate cancer and help to develop a new approach to sensitizing radioresistant prostate cancer cells by targeting GAS5/miR-18a.


Assuntos
Proliferação de Células/genética , MicroRNAs/genética , Neoplasias da Próstata/genética , RNA Longo não Codificante/genética , Tolerância a Radiação/genética , Radiossensibilizantes/farmacologia , Solanina/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Apoptose/efeitos da radiação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Sobrevivência Celular/efeitos da radiação , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Humanos , Masculino , Neoplasias da Próstata/patologia , Tolerância a Radiação/efeitos dos fármacos , Tolerância a Radiação/efeitos da radiação , Raios X
15.
PLoS One ; 14(4): e0214670, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30933998

RESUMO

Radiation therapy is often combined with androgen deprivation therapy in the treatment of aggressive localized prostate cancer. However, castration-resistant disease may not respond to testosterone deprivation approaches. Enzalutamide is a second-generation anti-androgen with high affinity and activity that is used for the treatment of metastatic disease. Although radiosensitization mechanisms are known to be mediated through androgen receptor activity, this project aims to uncover the detailed DNA damage repair factors influenced by enzalutamide using multiple models of androgen-sensitive (LNCaP) and castration-resistant human prostate cancer (22Rv1 and DU145). Enzalutamide is able to radiosensitize both androgen-dependent and androgen-independent human prostate cancer models in cell culture and xenografts in mice, as well as a treatment-resistant patient-derived xenograft. The enzalutamide-mediated mechanism of radiosensitization includes delay of DNA repair through temporal prolongation of the repair factor complexes and halting the cell cycle, which results in decreased colony survival. Altogether, these findings support the use of enzalutamide concurrently with radiotherapy to enhance the treatment efficacy for prostate cancer.


Assuntos
Reparo do DNA/efeitos dos fármacos , Feniltioidantoína/análogos & derivados , Neoplasias da Próstata , Tolerância a Radiação , Radiossensibilizantes/farmacologia , Idoso , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/genética , Reparo do DNA/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos da radiação , Humanos , Masculino , Camundongos , Camundongos Nus , Camundongos Transgênicos , Feniltioidantoína/farmacologia , Feniltioidantoína/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Neoplasias da Próstata/radioterapia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/radioterapia , Tolerância a Radiação/efeitos dos fármacos , Tolerância a Radiação/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Ensaios Antitumorais Modelo de Xenoenxerto
16.
J Cancer Res Ther ; 15(Supplement): S144-S152, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30900637

RESUMO

Purpose: Breast and cervical cancers are the two most common cancers among women worldwide. Morphine is a potent analgesic for cancer pain, and radiation therapy is a conventional treatment for cancer. Unfortunately, the combined adjuvant cellular effects of morphine and ionizing radiation in cancer cells are largely unknown. Materials and Methods: In this study, we examined the effects of morphine and single radiation dose of 2 Gy on viability and survival fraction of human breast cancer cell line MDA-MB 231 and human cervical cancer cell line HeLa, by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and colony formation assays. We were also interested in evaluating these effects in human umbilical vein endothelial cells as well. Results: We found that morphine did not have a dose- and time-dependent manner in endothelial, breast, and cervical cancer cells in vitro. It seems that pretreatment of breast and cervical cancer cells with morphine at some doses before irradiation reduces the cytotoxic effect of radiation. We also observed that endothelial cells were less sensitive than breast and cervical cancer cells to radiation or morphine + radiation. Based on the results of endothelial cells, morphine or radiation might not have a selective effect on the viability and clonogenic survival of different cell lines. Conclusions: Our data may suggest that morphine and radiotherapy could not be administered together to breast and cervical cancer patients if additional and in vivo studies confirm our results.


Assuntos
Neoplasias da Mama/radioterapia , Dor do Câncer/tratamento farmacológico , Morfina/farmacologia , Tolerância a Radiação/efeitos dos fármacos , Neoplasias do Colo do Útero/radioterapia , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Neoplasias da Mama/complicações , Dor do Câncer/etiologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Relação Dose-Resposta a Droga , Relação Dose-Resposta à Radiação , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Morfina/uso terapêutico , Neoplasias do Colo do Útero/complicações
17.
Nutrients ; 11(3)2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30875792

RESUMO

Resistance to both chemotherapy and radiation therapy is frequent in triple-negative breast cancer (TNBC) patients. We established treatment-resistant TNBC MDA-MB-231/IR cells by irradiating the parental MDA-MB-231 cells 25 times with 2 Gy irradiation and investigated the molecular mechanisms of acquired resistance. The resistant MDA-MB-231/IR cells were enhanced in migration, invasion, and stem cell-like characteristics. Pathway analysis by the Database for Annotation, Visualization and Integrated Discovery revealed that the NF-κB pathway, TNF signaling pathway, and Toll-like receptor pathway were enriched in MDA-MB-231/IR cells. Among 77 differentially expressed genes revealed by transcriptome analysis, 12 genes involved in drug and radiation resistance, including interferon-induced protein with tetratricopeptide repeats 2 (IFIT2), were identified. We found that baicalein effectively reversed the expression of IFIT2, which is reported to be associated with metastasis, recurrence, and poor prognosis in TNBC patients. Baicalein sensitized radio- and chemoresistant cells and induced apoptosis, while suppressing stem cell-like characteristics, such as mammosphere formation, side population, expression of Oct3/4 and ABCG2, and CD44highCD24low population in MDA-MB-231/IR cells. These findings improve our understanding of the genes implicated in radio- and chemoresistance in breast cancer, and indicate that baicalein can serve as a sensitizer that overcomes treatment resistance.


Assuntos
Antineoplásicos/farmacologia , Flavanonas/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas/análise , Proteínas/genética , Proteínas/metabolismo , Tolerância a Radiação/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas
18.
Cancer Cell ; 35(3): 504-518.e7, 2019 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-30827889

RESUMO

Ionizing radiation (IR) and chemotherapy are standard-of-care treatments for glioblastoma (GBM) patients and both result in DNA damage, however, the clinical efficacy is limited due to therapeutic resistance. We identified a mechanism of such resistance mediated by phosphorylation of PTEN on tyrosine 240 (pY240-PTEN) by FGFR2. pY240-PTEN is rapidly elevated and bound to chromatin through interaction with Ki-67 in response to IR treatment and facilitates the recruitment of RAD51 to promote DNA repair. Blocking Y240 phosphorylation confers radiation sensitivity to tumors and extends survival in GBM preclinical models. Y240F-Pten knockin mice showed radiation sensitivity. These results suggest that FGFR-mediated pY240-PTEN is a key mechanism of radiation resistance and is an actionable target for improving radiotherapy efficacy.


Assuntos
Neoplasias Encefálicas/terapia , Núcleo Celular/metabolismo , Glioma/terapia , PTEN Fosfo-Hidrolase/metabolismo , Pirimidinas/administração & dosagem , Tolerância a Radiação/efeitos dos fármacos , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Animais , Neoplasias Encefálicas/metabolismo , Reparo do DNA/efeitos dos fármacos , Feminino , Glioma/metabolismo , Humanos , Masculino , Camundongos , Fosforilação/efeitos dos fármacos , Pirimidinas/farmacologia , Rad51 Recombinase/metabolismo , Tirosina/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Radiat Res ; 191(4): 335-341, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30730283

RESUMO

To elucidate the potential influence of stimulating bone marrow before cell-cycle-dependent irradiation, we sought to determine overall survival in mice receiving total-body irradiation (TBI) when administered granulocyte stimulating factor (G-CSF) at different time points. Gender differences were also studied. C57/BL/6J mice, aged 9-14 weeks, received 8 Gy TBI in a perspex cage using a linear accelerator. In each of five different experiments, three groups were studied: 1. one control group receiving TBI only; 2. one group treated with filgrastim [500 lg/kg subcutaneously/intraperitoneally (s.c./i.p.)] the day before TBI, followed by daily filgrastim injections postirradiation (1-5 days); and 3. one group treated with daily filgrastim injections only post-TBI (1-5 days). Each experimental group included male and female mice. Survival of the mice was monitored daily, and mice were euthanized when their condition deteriorated. A total of 293 mice were monitored for at least 37 days post-TBI. Control mice that received 8 Gy TBI showed a significant gender difference, with a median survival of 22 days in females and 17 days in males. Addition of G-CSF, irrespective of pre- or postirradiation, significantly improved survival, but in males the improvement was significantly better when G-CSF was not given before TBI. Improved survival in females was independent of the order of administration of GCSF. Multiple filgrastim injections were more effective than a single injection, and s.c. administration was not better than i.p. In conclusion, these findings indicate that male mice are more sensitive to TBI than females. Filgrastim improved survival in both genders irrespective of whether given pre- or postirradiation, but in males the improvement was significantly less if an injection was given before irradiation. These results suggest that, to prevent toxicity most effectively, GCSF should not be given before cytotoxic therapy. While a completely different experimental model was used here, these results may also be extrapolated to indicate that endocrine cell-cycle suppression therapy should not be given before or during cytotoxic therapy of hormone-dependent tumors (e.g., breast and prostate cancer), thus a reduction in the efficacy of cell-cycle-dependent therapy can be prevented.


Assuntos
Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/farmacologia , Tolerância a Radiação/efeitos dos fármacos , Caracteres Sexuais , Animais , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Análise de Sobrevida , Irradiação Corporal Total/efeitos adversos
20.
Acta Pharmacol Sin ; 40(8): 1085-1094, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30796356

RESUMO

Resistance to radiotherapy causes non-small cell lung cancer (NSCLC) treatment failure associated with local recurrence and metastasis. Thus, understanding the radiosensitization of NSCLC cells is crucial for developing new treatments and improving prognostics. mTORC1 has been shown to regulate tumor cell radiosensitivity, but the underlying mechanisms are unclear. Moreover, mTORC1 also regulates epithelial-mesenchymal transition (EMT) that is important to metastasis and recurrence. In this study we explored whether mTORC1 regulated NSCLC cell radiosensitivity by altering EMT. We performed immunohistichemical analysis using tumor, adjacent and normal tissues from 50 NSCLC patients, which confirmed significantly elevated mTOR protein expression in NSCLC tissue. Then we used NCI-H460 and NCI-H661 cell lines to examine the effects of the mTORC1 inhibitor RAD001 (everolimus) on in vitro radiosensitivity, protein expression and dose-survival curves. RAD001 (10 nmol/L) significantly inhibited the mTORC1 pathway in both the cell lines. Pretreatment with RAD001 (0.1 nmol/L) enhanced the radiosensitivity in NCI-H661 cells with wild-type PIK3CA and KRAS but not in NCI-H460 cells with mutant PIK3CA and KRAS; the sensitivity enhancement ratios in the two NSCLC cell lines were 1.40 and 1.03, respectively. Furthermore, pretreatment with RAD001 (0.1 nmol/L) significantly decreased the migration and invasion with altered expression of several EMT-associated proteins (significantly increased E-cadherin and decreased vimentin expression) in irradiated NCI-H661 cells. Publicly available expression data confirmed that irradiation affected mTOR and EMT-associated genes at the transcript level in NSCLC cells. These results suggest that mTORC1 inhibition enhances the in vitro radiosensitivity of NSCLC cells with wild-type PIK3CA and KRAS by affecting EMT. Our preclinical data may provide a potential new strategy for NSCLC treatment.


Assuntos
Transição Epitelial-Mesenquimal/efeitos dos fármacos , Everolimo/farmacologia , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Tolerância a Radiação/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Linhagem Celular Tumoral , Classe I de Fosfatidilinositol 3-Quinases/genética , Histonas/metabolismo , Humanos , Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/radioterapia , Proteínas Proto-Oncogênicas p21(ras)/genética , Transdução de Sinais/efeitos dos fármacos
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