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1.
Anticancer Res ; 39(9): 4805-4810, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519582

RESUMO

BACKGROUND/AIM: Ro 90-7501 has been reported as an inhibitor of the amyloid ß42 fibril assembly that is associated with Alzheimer's disease. The present study aimed to elucidate the radiosensitizing effects of Ro 90-7501 and focused on ATM signaling after irradiation. MATERIALS AND METHODS: Clonogenic survival, apoptosis, and cell-cycle assays as well as western blotting were performed in HeLa cells treated with irradiation and Ro 90-7501. Tumor growth delay assay was also performed using BALB/c-nu mice. RESULTS: The combination of irradiation with Ro 90-7501 showed significant radiosensitizing effects in clonogenic survival and tumor growth delay assays. Ro 90-7501 significantly increased apoptosis and impaired cell cycle after irradiation. Western blotting showed that Ro 90-7501 suppressed the phosphorylation of ATM and its downstream proteins, such as H2AX, Chk1, and Chk2, after irradiation. CONCLUSION: Ro 90-7501 inhibits DNA damage response by inhibiting ATM and has significant radiosensitizing effects on cervical cancer cells.


Assuntos
Aminas/farmacologia , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Benzimidazóis/farmacologia , Radiossensibilizantes/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/efeitos da radiação , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Humanos , Camundongos , Modelos Biológicos , Fosforilação/efeitos dos fármacos , Neoplasias do Colo do Útero/metabolismo
2.
Cancer Invest ; 37(9): 489-500, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31496302

RESUMO

Prostate cancer is the most common cancer and leading cause of cancer death for males. Imipramine (IMI), which is a tricyclic antidepressant, has also been shown to has antineoplastic effect. This study was performed to investigate the radiosensitizing effect of IMI on DU145 prostate cancer cell. Cells were divided into 4 groups. Cell index, apoptotic activity, cell cycle arrest, oxidative stress and EAG1 channel currents were determined in all groups. Our findings showed that combined treatment with IMI and radiotherapy (RAD) did not enhance radiosensitivity of DU145 cells but as unexpected finding, treatment of IMI alone was more effective in DU145 cells.


Assuntos
Canais de Potássio Éter-A-Go-Go/metabolismo , Imipramina/farmacologia , Neoplasias da Próstata/metabolismo , Radiossensibilizantes/farmacologia , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/efeitos da radiação , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/efeitos da radiação , Neoplasias da Próstata/terapia , Radioterapia
3.
Pestic Biochem Physiol ; 158: 25-31, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31378357

RESUMO

Sodium pheophorbide a (SPA) is a natural photosensitizer. To explore its antifungal activity and mechanism, we studied its inhibitory effects on spore germination and mycelial growth of Pestalotiopsis neglecta. We used sorbitol, 2-thiobarbituric acid (TBA) and electron microscopy to determine its effects on cell wall integrity, cell membrane lipid peroxidation and mycelial morphology. Finally, the effects of SPA on enzyme activity in mycelia were determined. The results showed that SPA effectively inhibited spore germination and mycelial growth of P. neglecta under light conditions (4000 lx, 24 h). Scanning electron microscopy (SEM) revealed that SPA treatment resulted in a roughened, twisted and knotted mycelial surface and abnormal mycelial growth. SPA influenced cell wall integrity, and the content of MDA, a cell membrane lipid peroxidation product was significantly increased (P < 0.05). SPA also significantly inhibited SOD, POD and PG activity, but enhanced PPO activity (P < 0.05). In conclusion, SPA may have potential to become a biological pesticide.


Assuntos
Antifúngicos/farmacologia , Clorofila/análogos & derivados , Micélio/efeitos dos fármacos , Radiossensibilizantes/farmacologia , Clorofila/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Microscopia Eletrônica de Varredura , Micélio/ultraestrutura
4.
Br J Radiol ; 92(1100): 20190283, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31219711

RESUMO

OBJECTIVE: The incorporation of high atomic number materials such as gold nanoparticles (GNPs) into tumor cells is being tested to enhance the local radiotherapy (RT) dose. It is also known that the radiosensitivity of tumor cells depends on the phase of their cell cycle. Triple combination of GNPs, phase of tumor cell population, and RT for improved outcomes in cancer treatment. METHODS: We used a double-thymidine block method for synchronization of the tumor cell population. GNPs of diameters 17 and 46 nm were used to capture the size dependent effects. A radiation dose of 2 Gy with 6 MV linear accelerator was used to assess the efficacy of this proposed combined treatment. A triple negative breast cancer cell line, MDA-MB-231 was chosen as the model cell line. Monte Carlo (MC) calculations were done to predict the GNP-mediated cell death using the experimental GNP uptake data. RESULTS: There was a 1.5- and 2- fold increase in uptake of 17 and 46 nm GNPs in the synchronized cell population, respectively. A radiation dose of 2 Gy with clinically relevant 6 MV photons resulted in a 62 and 38 % enhancement in cell death in the synchronized cell population with the incorporation of 17 and 46 nm GNPs, respectively. MC data supported the experimental data, but to a lesser extent. CONCLUSION: A triple combination of GNPs, cell cycle synchronization, and RT could pave the way to enhance the local radiation dose while minimizing side effects to the surrounding healthy tissue. ADVANCES IN KNOWLEDGE: This is the first study to show that the combined use of GNPs, phase of tumor cell population, and RT could enhance tumor cell death.


Assuntos
Ouro/farmacologia , Radiossensibilizantes/farmacologia , Neoplasias de Mama Triplo Negativas/radioterapia , Feminino , Humanos , Nanopartículas Metálicas , Dosagem Radioterapêutica , Células Tumorais Cultivadas
6.
J Enzyme Inhib Med Chem ; 34(1): 1030-1040, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31074303

RESUMO

A series of sulphonamide benzoquinazolinones 5-18 was synthesized and evaluated for cytotoxic activity against MDA-MB-231 cell line. The compounds showed IC50 ranging from 0.26 to 161.49 µM. The promising compounds were evaluated for their inhibitory profile against epidermal growth factor (EGFR) and HER2 enzymes. Compound 10 showed more potent activity on both EGFR and HER2 than erlotinib (IC50 3.90 and 5.40 µM versus 6.21 and 9.42 µM). The pro-apoptotic activity of 10 was evaluated against caspase-3, Bax, B-cell lymphoma protein 2 (Bcl-2) expression levels, and cell cycle analysis. Compound 10 increased the level of caspase-3 by 10 folds, Bax level by 9 folds, decreased the level of the Bcl-2 by 0.14 and arrested the cell cycle in the G2/M phase. The radio-sensitizing activity of 10 was measured using a single dose of 8 Gy gamma radiation (IC50 decreased from 0.31 to 0.22 µM). Molecular docking was performed on EGFR and HER2 receptors.


Assuntos
Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinazolinonas/farmacologia , Radiossensibilizantes/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Sulfonamidas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Quinazolinonas/síntese química , Quinazolinonas/química , Radiossensibilizantes/síntese química , Radiossensibilizantes/química , Receptor ErbB-2/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
7.
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
8.
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
9.
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
10.
Radiat Oncol ; 14(1): 64, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30987655

RESUMO

BACKGROUND: Radiotherapy plays an important role in the multimodal treatment of breast cancer. The response of a breast tumour to radiation depends not only on its innate radiosensitivity but also on tumour repopulation by cells that have developed radioresistance. Development of effective cancer treatments will require further molecular dissection of the processes that contribute to resistance. METHODS: Radioresistant cell lines were established by exposing MDA-MB-231, MCF-7 and ZR-751 parental cells to increasing weekly doses of radiation. The development of radioresistance was evaluated through proliferation and colony formation assays. Phenotypic characterisation included migration and invasion assays and immunohistochemistry. Transcriptomic data were also generated for preliminary hypothesis generation involving pathway-focused analyses. RESULTS: Proliferation and colony formation assays confirmed radioresistance. Radioresistant cells exhibited enhanced migration and invasion, with evidence of epithelial-to-mesenchymal-transition. Significantly, acquisition of radioresistance in MCF-7 and ZR-751 cell lines resulted in a loss of expression of both ERα and PgR and an increase in EGFR expression; based on transcriptomic data they changed subtype classification from their parental luminal A to HER2-overexpressing (MCF-7 RR) and normal-like (ZR-751 RR) subtypes, indicating the extent of phenotypic changes and cellular plasticity involved in this process. Radioresistant cell lines derived from ER+ cells also showed a shift from ER to EGFR signalling pathways with increased MAPK and PI3K activity. CONCLUSIONS: This is the first study to date that extensively describes the development and characterisation of three novel radioresistant breast cancer cell lines through both genetic and phenotypic analysis. More changes were identified between parental cells and their radioresistant derivatives in the ER+ (MCF-7 and ZR-751) compared with the ER- cell line (MDA-MB-231) model; however, multiple and likely interrelated mechanisms were identified that may contribute to the development of acquired resistance to radiotherapy.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/patologia , Raios gama , Tolerância a Radiação , Apoptose , Neoplasias da Mama/genética , Neoplasias da Mama/radioterapia , Movimento Celular , Proliferação de Células , Feminino , Perfilação da Expressão Gênica , Humanos , Invasividade Neoplásica , Radiossensibilizantes/farmacologia , Transdução de Sinais , Sulfonamidas/farmacologia , Células Tumorais Cultivadas
11.
Zhongguo Zhong Yao Za Zhi ; 44(3): 553-558, 2019 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-30989922

RESUMO

Modern pharmacological studies have shown that Shengmai San has the effects of enhancing immunity and improving blood circulation, and Curcumae Longae Rhizoma(Jianghuang) has anti-inflammatory, anti-cancer, anti-oxidation and other functions. Shengmai San combined with Jianghuang is a new research direction in the study of anti-tumor of traditional Chinese medicines. The main treatment for nasopharyngeal carcinoma is radiation therapy, but radiation therapy can cause a variety of side effects, and it also changes the composition of the intestinal flora. In this study, the 16 s rDNA sequencing platform was used to perform macro-sequence sequencing of the intestinal flora samples of nude mice bearing the veins of Shengmai Jianghuang San, and then the results of intestinal flora data were analyzed to investigate the effect of Shengmai Jianghuang San on tumors. The results showed that Shengmai Jianghuang San combined with irradiation could enhance the therapeutic effect of tumor treatment. Radiation therapy would reduce the total number and diversity of intestinal flora in nude mice, and also change the structure of the flora. Shengmai Jianghuang San could protect the diversity of colonies, and also partially restore the colony imbalance caused by irradiation. This study provides a research idea for Shengmai Jianghuang San as a sensitizing adjuvant for radiotherapy of nasopharyngeal carcinoma.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Carcinoma Nasofaríngeo/radioterapia , Radiossensibilizantes/farmacologia , Animais , Camundongos , Camundongos Nus , Tolerância a Radiação
12.
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
13.
Anticancer Res ; 39(4): 1859-1867, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30952726

RESUMO

BACKGROUND: Proteins overexpressed in malignant tissues form important targets in the development of targeted therapeutics, and aptamers comprise an important affinity agent for therapy and drug delivery. In this study, aberrantly expressed mucin 1 glycoprotein was investigated as a therapeutic target in a breast cancer model. MATERIALS AND METHODS: In order to determine the feasibility of using an aptamer against mucin 1 (aptA) as carrier of the cytotoxic compound 1,10-phenanthroline to MCF-7 cells, as a potential radiosensitizer, was studied in experiments using circular dichroism and rhodamine labelling by fluorescent microscopy and flow cytometry. RESULTS: 1,10-Phenanthroline can be intercalated within aptA when complexed with Fe(II) ions, with dissociation constant (Kd) of 30 µM. The complex was subsequently capable of binding to and being internalised in MCF-7 breast cancer cells. CONCLUSION: aptA can carry 1,10-phenanthroline to cancer cells specifically and this complex represents a potential target-directed anticancer therapy.


Assuntos
Aptâmeros de Nucleotídeos/metabolismo , Neoplasias da Mama/metabolismo , Portadores de Fármacos , Endocitose , Mucina-1/metabolismo , Fenantrolinas/metabolismo , Radiossensibilizantes/metabolismo , Aptâmeros de Nucleotídeos/química , Aptâmeros de Nucleotídeos/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/radioterapia , Estudos de Viabilidade , Feminino , Compostos Ferrosos/química , Humanos , Células MCF-7 , Mucina-1/genética , Fenantrolinas/química , Fenantrolinas/farmacologia , Radiossensibilizantes/farmacologia
14.
Int J Mol Sci ; 20(6)2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30875879

RESUMO

Nucleosides, especially pyrimidines modified in the C5-position, can act as radiosensitizers via a mechanism that involves their enzymatic triphosphorylation, incorporation into DNA, and a subsequent dissociative electron attachment (DEA) process. In this paper, we report 5-iodo-4-thio-2'-deoxyuridine (ISdU) as a compound that can effectively lead to ionizing radiation (IR)-induced cellular death, which is proven by a clonogenic assay. The test revealed that the survival of cells, pre-treated with 10 or 100 µM solution of ISdU and exposed to 0.5 Gy of IR, was reduced from 78.4% (for non-treated culture) to 67.7% and to 59.8%, respectively. For a somewhat higher dose of 1 Gy, the surviving fraction was reduced from 68.2% to 54.9% and to 40.8% for incubation with 10 or 100 µM ISdU, respectively. The cytometric analysis of histone H2A.X phosphorylation showed that the radiosensitizing effect of ISdU was associated, at least in part, with the formation of double-strand breaks. Moreover, the cytotoxic test against the MCF-7 breast cancer cell line and human dermal fibroblasts (HDFa line) confirmed low cytotoxic activity of ISdU. Based on the results of steady state radiolysis of ISdU with a dose of 140 Gy and quantum chemical calculations explaining the origin of the MS detected radioproducts, the molecular mechanism of sensitization by ISdU was proposed. In conclusion, we found ISdU to be a potential radiosensitizer that could improve anticancer radiotherapy.


Assuntos
Neoplasias da Mama/genética , Quebras de DNA de Cadeia Dupla , Radiossensibilizantes/farmacologia , Tiouridina/análogos & derivados , Neoplasias da Mama/metabolismo , Neoplasias da Mama/terapia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Histonas/metabolismo , Humanos , Células MCF-7 , Fosforilação/efeitos dos fármacos , Fosforilação/efeitos da radiação , Teoria Quântica , Tiouridina/farmacologia , Terapia por Raios X
15.
Biomed Pharmacother ; 113: 108769, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30870718

RESUMO

AIMS: In this study, we examined whether ß-apopicropodophyllin (APP) could act as a radiosensitizer in non-small cell lung cancer (NSCLC) cells. MAIN METHODS: The in vitro radiosensitizing activity of APP was demonstrated with clonogenic assay, immunoblotting, Annexin V-Propidium iodide (PI) assay, BrdU incorporation, detection of mitochondrial ROS/intracellular of H2O2, mitochondrial membrane potential detection, and performing of isolation of mitochondrial and cytosolic fractions. The in vivo radiosensitizing activity of APP was determined in xenografted mice with co-treatment of APP and IR based on measurement of tumor volumes and apoptotic cell death. KEY FINDINGS: The results of a clonogenic assay indicated that a combination of APP and γ-ionizing radiation (IR) inhibits cell growth and increases cell death in NSCLC cells. Several signal transduction pathways were examined for their potential involvement in the apparent radiosensitization effect of APP, as assessed by immunoblotting analyses and mitochondrial potential determination in vitro. Treatment of NCI-H460 cells with 15 nM APP and NCI-H1299 cells with 10 nM APP yielded dose-enhancement ratios of 1.44 and 1.24, respectively. Enhanced ER stress, disrupted mitochondrial membrane potential, and increased reactive oxygen species (ROS) were observed in cells co-treated with APP and IR, and this was followed by the cytosolic release of cytochrome c and consequent activation of caspase-3 and -9. Notably, inhibition of JNK, which prevents caspase activation, blocked the APP/IR-induced activations of ER stress and apoptotic cell death. In NCI-H460 or NCI-H1299 cell-xenografted mice, APP/IR treatment delayed the time it took tumors to reach a threshold size by 22.38 and 16.83 days, respectively, compared with controls, to yield enhancement factors of 1.53 and 1.38, respectively. SIGNIFICANCE: APP has a radiosensitizing function derived from its ability to induce apoptotic cell death via activation of ER stress, disruption of mitochondrial membrane potential, and induction of the caspase pathway.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/radioterapia , Neoplasias Pulmonares/radioterapia , Podofilina/farmacologia , Radiossensibilizantes/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos da radiação , Humanos , Peróxido de Hidrogênio/metabolismo , Neoplasias Pulmonares/patologia , Potencial da Membrana Mitocondrial , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitocôndrias/metabolismo , Podofilina/administração & dosagem , Radiossensibilizantes/administração & dosagem , Espécies Reativas de Oxigênio/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Nanoscale ; 11(15): 7157-7165, 2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30919835

RESUMO

The development of a new multifunctional nanomedicine capable of enhancing radiosensitization by photo-induced hyperthermia for the inhibition of cancer growth and metastasis is highly required for efficient treatment of cancer cells. Compared to the first near-infrared (NIR) window, the second NIR window light could provide a maximum penetration depth as well as minimizing autofluorescence due to its low scattering and energy absorption. Here, we report a new versatile theranostic agent based on ternary Cu3BiSe3 nanoparticles (NPs) modified by poly(vinylpyrollidone) (PVP-Cu3BiSe3). Benefiting from their preferable X-ray attenuation ability and strong NIR absorbance in the second NIR biological window, PVP-Cu3BiSe3 NPs can not only deposit more radiation doses to destroy the cancer cells, but also conduct the optical energy into hyperthermia for thermal eradication of tumor tissues and the improvement of the tumor oxygenation to overcome the hypoxia-associated radio-resistance of tumors. According to both in vitro and in vivo results, exposure to an X-ray plus 1064 nm laser completely kills cancer cells and even inhibits tumor metastasis, displaying no warning signs of a relapse. On the other hand, PVP-Cu3BiSe3 NPs can be used as a multi-model imaging agent for X-ray computer tomography (CT) and photoacoustic tomography (PAT) imaging. These demonstrate the potential of PVP-Cu3BiSe3 NPs in multimodal imaging-guided synergetic radiophotothermal therapy of deep-seated tumors and effective inhibition of their metastasis.


Assuntos
Hipertermia Induzida , Raios Infravermelhos , Nanopartículas Metálicas , Neoplasias Experimentais , Técnicas Fotoacústicas , Fototerapia , Radiossensibilizantes , Tomografia Computadorizada por Raios X , Animais , Células HeLa , Humanos , Masculino , Nanopartículas Metálicas/química , Nanopartículas Metálicas/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Neoplasias Experimentais/terapia , Radiossensibilizantes/química , Radiossensibilizantes/farmacologia
17.
Photodiagnosis Photodyn Ther ; 25: 472-479, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30738223

RESUMO

BACKGROUND: Some materials such as TiO2 display a luminescence property when exposed to X-ray radiation. Therefore, a proper photosensitizer can induce photodynamic effects by absorbing the emitted photons from these materials during radiotherapy. In this way, the problem of limited photo- penetration depth in photodynamic therapy is resolved. In this paper, following the production of a nanopolymer containing TiO2 cores and imprinted for mitoxantron (MIP), the possibility of utilizing its optical and radio properties on two lines of cancer cells were studied. METHODS: Mitoxantron (MX) was selected as the photosensitizer. The emission spectrum of the nanopolymers synthesized with/without MX was recorded during excitation by 6 MV X-rays. Also, the fluorescence signal of hydroxyl radicals produced into terephthalic acid medium by the nanopolymers were recorded during X irradiation. The percentage of cell survival following irradiation by X-rays was determined for various concentrations of drug agents by MTT assay. The synergistic index and IC50 were calculated to compare the findings. RESULTS: The emission spectrum of the nanopolymer reloaded with MX during X-ray irradiation indicated a considerable decline in comparison with the nanopolymer without MX. The level of free radicals produced by nanopolymer was significantly increased during irradiation with X-rays. The highest mean of synergistic indexes was observed in MIP. CONCLUSION: The higher level of hydroxyl free radicals in MIP and lower cell viability in the DFW cell line as well as enhanced treatment efficiency confirm the hypothesis regarding the production of photodynamic effects by synthesized nanopolymer during radiotherapy.


Assuntos
Quimiorradioterapia/métodos , Mitoxantrona/farmacologia , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacologia , Radiossensibilizantes/farmacologia , Titânio/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Fibrossarcoma/tratamento farmacológico , Humanos , Radical Hidroxila/química , Melanoma/tratamento farmacológico , Nanopartículas/química
18.
Anticancer Res ; 39(2): 759-769, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30711955

RESUMO

BACKGROUND/AIM: Strategies to enhance the therapeutic ratio of radiotherapy in glioblastoma are warranted. Our aim was to report a novel DNA methyltransferase inhibitor as a potential radiosensitizing agent in glioblastoma. MATERIALS AND METHODS: Four glioblastoma cell lines and one normal astrocyte cell line were incubated with a newly-synthetized phthalimido-alkanamide derivative, MA17, and its radiosensitizing effects were assessed. We performed a tumor growth delay assay in two glioblastoma lines: U87MG and U138MG. We evaluated DNA methyltransferase (DNMT) inhibition, apoptosis, autophagy, DNA damage repair, and FANCA expression. RESULTS: MA17 radiosensitized all glioblastoma cells (all p<0.05), but it did not affect normal astrocytes (p=0.193). MA17 significantly prolonged the mean tumor doubling time in vivo, in cells treated in addition with radiotherapy, compared to radiotherapy alone (p<0.05). DNMT activity was down-regulated, and apoptosis and autophagy were induced by MA17. Double-stranded DNA break foci were observed for prolonged periods in cells treated with MA17. FANCA expression was also inhibited. CONCLUSION: A novel phthalimido-alkanamide derivative demonstrated significant radiosensitization in glioblastoma cells in vitro and in vivo. Further investigation is needed to translate these results to the clinic.


Assuntos
Alcanos/farmacologia , DNA (Citosina-5-)-Metiltransferase 1/antagonistas & inibidores , Glioblastoma/tratamento farmacológico , Glioblastoma/radioterapia , Ftalimidas/farmacologia , Radiossensibilizantes/farmacologia , Animais , Apoptose , Astrócitos/efeitos dos fármacos , Astrócitos/efeitos da radiação , Autofagia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Reparo do DNA , Proteína do Grupo de Complementação A da Anemia de Fanconi/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , Tolerância a Radiação/efeitos dos fármacos
19.
Anticancer Res ; 39(2): 713-720, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30711949

RESUMO

BACKGROUND: Radiotherapy (RT) combined with a radiosensitizer represents an important treatment for head and neck squamous cell carcinoma (HNSCC). Only few chemotherapy agents are currently approved as radiosensitizers for targeted therapy. In this study, the potent cyclin-dependent kinase 4/6 (CDK4/6) inhibitor LEE011 was tested for potential to act as a radiosensitizer during RT. MATERIALS AND METHODS: RT enhancement by LEE011 was assessed by in vitro clonogenic assay, flow cytometry, and western blot in a variety of HNSCC cell lines. The HNSCC cell line OML1 and its radiation-resistant clone OML1-R were used. RESULTS: LEE011 induced cell-cycle arrest in SCC4/SCC25 cells during the G1/M phase through inhibition of retinoblastoma protein phosphorylation. LEE011 enhanced the effects of radiation in OML1 cells and overcame radiation resistance in OML1-R cells. CONCLUSION: LEE011 is a potential radiosensitizer that can enhance the cytotoxic effects of RT. Clinical trials including LEE011 during RT for HNSCC should be considered.


Assuntos
Aminopiridinas/farmacologia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/radioterapia , Purinas/farmacologia , Radiossensibilizantes/farmacologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Apoptose/efeitos dos fármacos , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Humanos , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/radioterapia , Fosforilação , Proteínas de Ligação a Retinoblastoma/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
20.
EBioMedicine ; 40: 224-230, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30711517

RESUMO

BACKGROUND: Olaratumab (LY3012207/IMC-3G3/Lartruvo™) is a fully human monoclonal antibody specific for platelet-derived growth factor receptor alpha (PDGFRα). Phase Ib/II trial results of olaratumab plus doxorubicin in adult patients with advanced soft tissue sarcoma (STS) supported accelerated FDA approval of this regimen. Radiation therapy (RT) is frequently used for high-risk localized STS. However, olaratumab has not been tested with concurrent RT. Here, we evaluate the chimeric anti-mouse PDGFRα antibody 1E10Fc as a radiosensitizer in a primary mouse model of STS. METHODS: Primary STS were initiated in mice. When tumors reached 70 mm3, mice were allocated into treatment groups: 1) isotype, 2) 1E10Fc, 3) isotype + RT, 4) 1E10Fc + RT. 1E10Fc or isotype was given biweekly. RT (25 Gy delivered in 5 daily 5 Gy fractions) was initiated on Day 0 with first drug treatment. Tumors were measured 3× per week. Upon reaching 900 mm3, tumors and lungs were harvested. A two-way ANOVA was performed to compare tumor growth delay. Primary tumors were stained for CD31 and PDGFRα and lungs were assessed for micrometastases. A Chi-square test was performed to compare the development of micrometastases in the lungs after treatment with 1E10Fc or isotype. FINDINGS: RT significantly delayed time to tumor quintupling compared to no RT (p < 0·0001) [two-way ANOVA], but no difference in tumor growth was seen between mice receiving isotype or 1E10Fc treatment regardless of concurrent RT. Lower microvessel density was observed in the 1E10Fc + RT group. Fewer mice treated with 1E10Fc had micrometastases, but this difference was not statistically significant (p < 0·09). INTERPRETATION: 1E10Fc did not act as a radiosensitizer in this primary STS model. FUNDING: This study was funded by a research agreement from Eli Lilly and Company.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos Imunológicos/farmacologia , Radiossensibilizantes/farmacologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Sarcoma/metabolismo , Animais , Biomarcadores Tumorais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Transgênicos , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Radioterapia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Sarcoma/patologia , Sarcoma/terapia , Transdução de Sinais/efeitos dos fármacos , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
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