RESUMO
Testing a number of N-[omega-(purin-6-yl)aminoalkanoyl] derivatives of 7,8-difluoro-3,4-dihydro-3-methyl-2H-[1,4]benzoxazine in a panel of nine tumor cell lines has shown that the studied compounds exhibit high cytotoxic activity, especially against 4T1 murine mammary carcinoma, COLO201 human colorectal adenocarcinoma, SNU-1 human gastric carcinoma, and HepG2 human hepatocellular carcinoma cells. Synthesis and study of structural analogs of these compounds made it possible to find that the presence of both a difluorobenzoxazine fragment and a purine residue bound via a linker of a certain length is crucial for the manifestation of the cytotoxic activity of this group of compounds. The study of the effect of the most promising compound on the cell cycle of the human tumor cell lines, the most sensitive and least sensitive to cytotoxic action (MDA-MB-231 breast adenocarcinoma and COLO201 colorectal adenocarcinoma, respectively), allows us to conclude that this compound is an inhibitor of DNA biosynthesis. The found group of purine conjugates may be of interest in the design of new antitumor agents.
Assuntos
Antineoplásicos , Neoplasias da Mama , Carcinoma Hepatocelular , Neoplasias Colorretais , Neoplasias Hepáticas , Camundongos , Humanos , Animais , Feminino , Ácidos Carboxílicos , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Purinas , Neoplasias Hepáticas/tratamento farmacológico , Ensaios de Seleção de Medicamentos Antitumorais , Relação Estrutura-AtividadeRESUMO
Numerous studies have shown that antitumor vaccines based on synthetic peptides are safe and can induce both CD8+ and CD4+ tumor-specific T cell responses. However, clinical results are still scarce, and such approach to antitumor treatment has not gained a wide implication, yet. Recently, particular advances have been achieved due to tumor sequencing and the search for immunogenic neoantigens caused by mutations. One of the most important issues for peptide vaccines, along with the choice of optimal adjuvants and vaccination regimens, is the search for effective target antigens. Extensive studies of peptide vaccines, including those on murine models, are required to reveal the effective vaccine constructs. The review presents transplantable murine tumors with the detected peptides that showed antitumor efficacy as a vaccine compound.
RESUMO
Autophagy is an evolutionarily conserved process regulating cellular homeostasis via digestion of dysfunctional proteins and whole cellular organelles by mechanisms, involving their enclosure into double-membrane vacuoles that are subsequently fused to lysosomes. Glioma stem cells utilize autophagy as a main mechanism of cell survival and stress response. Most recently, we and others demonstrated induction of autophagy in gliomas in response to treatment with chemical drugs, such as temozolomide (TMZ) or oncolytic adenoviruses (Ads). As autophagy has been implicated in the mechanism of Ad-mediated cell killing, autophagy deficiency in some glioma tumors could be the reason for their resistance to oncolysis. Despite the observed connection, the exact relationship between autophagy-activating cell signaling and adenoviral infection remains unclear. Here, we report that inhibition of autophagy in target glioma cells induces their resistance to killing by oncolytic agent CRAd-S-5/3. Furthermore, we found that downregulation of autophagy inducer Beclin-1 inhibits replication-competent Ad-induced oncolysis of human glioma by suppressing cell proliferation and inducing premature senescence. To overcome the autophagy-deficient state of such glioma cells and restore their susceptibility to oncolytic Ad infection, we propose treating glioma tumors with an anticancer drug tamoxifen (TAM) as a means to induce apoptosis in Ad-targeted cancer cells via upregulation of BAX/PUMA genes. In agreement with the above hypothesis, our data suggest that TAM improves susceptibility of Beclin-1-deficient glioma cells to CRAd-S-5/3 oncolysis by means of activating autophagy and pro-apoptotic signaling pathways in the target cancer cells.
Assuntos
Adenoviridae/genética , Proteínas Reguladoras de Apoptose/genética , Autofagia/efeitos dos fármacos , Proteína Beclina-1/genética , Glioma/tratamento farmacológico , Proteínas Proto-Oncogênicas/genética , Tamoxifeno/farmacologia , Regulação para Cima/genética , Proteína X Associada a bcl-2/genética , Células A549 , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Autofagia/genética , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Feminino , Glioma/genética , Células HEK293 , Humanos , Camundongos , Terapia Viral Oncolítica/métodos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genéticaRESUMO
Glioblastoma multiforme (GBM) is the most aggressive neoplastic brain tumor in humans with a median survival of less than 2 years. It is therefore critical to understand the mechanism of glioma progression and to identify future targets for intervention. We investigate the mechanisms of cytomegalovirus as an oncomodulatory agent implicated in glioma progression, as well as immunosuppression. This review provides a comprehensive evaluation of recent investigative developments concerning the role of CMV in cellular processes during glioma growth. The manners in which CMV and its viral products interact with regulatory cellular signaling pathways in the host are of primary interest. Here, we examine some of the most significant oncomodulatory effects that CMV can confer in brain tumors, including the inhibition of apoptosis and promoting the growth of glioma stem cells, which are tightly linked to tumor survival and recurrence.
Assuntos
Neoplasias Encefálicas/virologia , Transformação Celular Viral , Infecções por Citomegalovirus/virologia , Citomegalovirus/patogenicidade , Glioma/virologia , Infecções Tumorais por Vírus/virologia , Animais , Apoptose , Neoplasias Encefálicas/epidemiologia , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/patologia , Ciclo Celular , Proliferação de Células , Citomegalovirus/imunologia , Citomegalovirus/metabolismo , Infecções por Citomegalovirus/epidemiologia , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/metabolismo , Progressão da Doença , Glioma/epidemiologia , Glioma/imunologia , Glioma/patologia , Interações Hospedeiro-Patógeno , Humanos , Mediadores da Inflamação/metabolismo , Evasão Tumoral , Infecções Tumorais por Vírus/epidemiologia , Infecções Tumorais por Vírus/imunologia , Infecções Tumorais por Vírus/metabolismoRESUMO
To examine the cytotoxic activity of congeners of 3-amino-isoquinoline, we performed the phenotypic screening using panel of 60 cell lines and found that (N-(6,7-dimethoxy-1-methyl-isoquinolin-3-yl)-4-{[(1-ethyl-4-methyl-1H-pyrazol-3-yl)methyl]amino}benzamide (4d)) exhibited the significant effect against different tumor cell lines while showing the high activity toward human colorectal cancer HCT-116 cells (IC50 = 18 µm) and human breast cancer T-47D cells (GI50 = 1.9 µm). Virtual screening indicated that these compounds target protein kinases and phosphodiesterases (PDE). However, wet screening among panel of protein kinases did not show any significant activity. By contrast, 50 µm of 4c and 4d inhibited the growth of HKe3-mtKRAS spheroids in the 3D floating (3DF) culture suggesting that 4c and 4d target PDE4B which is selectively upregulated by mtKRAS in 3DF culture.