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Anticancer Res ; 40(1): 67-73, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892553


BACKGROUND/AIM: Aberrant expression of the SEI1 oncogene has been prevalently found in a variety of human cancers, including oral squamous cell carcinoma (OSCC). Recent studies have shown that cisplatin up-regulates the expression of SEI1 in breast and bladder cancer cells, thus inhibiting apoptosis and cell death in these cells. In the present study, we investigated the impact of cisplatin on the expression of SEI1 in OSCC cells. MATERIALS AND METHODS: Four OSCC cell lines, CAL27, SCC4, SCC15, and SCC22A were treated with cisplatin and 5-fluorouracil, and changes in SEI1 expression in these cells were evaluated using quantitative Reverse Transcription-Polymerase Chain Reaction (qRT-PCR) analyses. RESULTS: Cisplatin significantly induced SEI1 expression in the tested OSCC cells. Contrarily, cisplatin treatment did not affect the expression of gankyrin and BMI1, two oncogenes frequently overexpressed in a coordinate manner with SEI1 in OSCC. Additionally, 5-fluorouracil did not bring about any detectable changes in SEI1 expression in these cells. CONCLUSION: Cisplatin-induced up-regulation of SEI1 expression in OSCC is specific, and such induction could underlie the development of resistance to cisplatin in OSCC.

Carcinoma de Células Escamosas/genética , Cisplatino/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Bucais/genética , Oncogenes , Fatores de Transcrição/genética , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Fluoruracila/farmacologia , Humanos
Anticancer Res ; 40(1): 133-141, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892561


BACKGROUND/AIM: Aberrant expression of the BMI1 oncogene has been prevalently found in a variety of human cancers, including cervical cancer. Recent studies have shown that PTC209, a specific BMI1 inhibitor, exhibits high potency in inhibiting the growth of colon, breast, oral cancer cells and cancer-initiating cells, indicative of its chemotherapeutic potential. In the current study, we evaluated the inhibitory abilities of PTC209 in cervical cancer cells. MATERIALS AND METHODS: Three cervical cell lines, C33A, HeLa, and SiHa were treated with PTC209. The impacts of PTC209 on BMI1 were investigated using quantitative reverse-transcription PCR assay (qRT-PCR) and western blotting; changes in cell viability, cell cycle distribution, and apoptosis were assessed using cell viability testing, colony formation assay and flow cytometry analyses, respectively. RESULTS: PTC209 exhibited considerably high short-term and long-term cytotoxicities in all tested cervical cancer cell lines regardless of their HPV infection status, TP53 and pRb statuses. PTC209 significantly downregulated the expression of BMI1 in cervical cancer cell lines, and such downregulation led to G0/G1 arrest (p<0.05). Moreover, PTC209 drove more cells into apoptosis (p<0.05). CONCLUSION: PTC209 (BMI1-targeting agents, in general) represents a novel chemotherapeutic agent with potential in cervical cancer therapy.

Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Complexo Repressor Polycomb 1/antagonistas & inibidores , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Complexo Repressor Polycomb 1/genética , Complexo Repressor Polycomb 1/metabolismo , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia
Mol Pharm ; 11(3): 828-35, 2014 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-24433027


Multiple sclerosis (MS) is an autoimmune, demyelinating disease of the central nervous system that can cause loss of motor function and is thought to result, in part, from chronic inflammation due to an antigen-specific T cell immune response. Current treatments suppress the immune system without antigen specificity, increasing the risks of cancer, chronic infection, and other long-term side effects. In this study, we show treatment of experimental autoimmune encephalomyelitis (EAE), a model of MS, by coencapsulating the immunodominant peptide of myelin oligodendrocyte glycoprotein (MOG) with dexamethasone (DXM) into acetalated dextran (Ac-DEX) microparticles (DXM/MOG/MPs) and administering the microparticles subcutaneously. The clinical score of the mice was reduced from 3.4 to 1.6 after 3 injections 3 days apart with the coencapsulated microparticulate formulation (MOG 17.6 µg and DXM 8 µg). This change in clinical score was significantly greater than observed with phosphate-buffered saline (PBS), empty MPs, free DXM and MOG, DXM/MPs, and MOG/MPs. Additionally, treatment with DXM/MOG/MPs significantly inhibited disease-associated cytokine (e.g., IL-17, GM-CSF) expression in splenocytes isolated in treated mice. Here we show a promising approach for the therapeutic treatment of MS using a polymer-based microparticle delivery platform.

Dexametasona/administração & dosagem , Dextranos/química , Sistemas de Liberação de Medicamentos , Encefalomielite Autoimune Experimental/terapia , Glicoproteína Mielina-Oligodendrócito/imunologia , Fragmentos de Peptídeos/administração & dosagem , Polímeros/química , Animais , Proliferação de Células/efeitos dos fármacos , Terapia Combinada , Citocinas/metabolismo , Dexametasona/farmacocinética , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Feminino , Citometria de Fluxo , Camundongos , Camundongos Endogâmicos C57BL , Glicoproteína Mielina-Oligodendrócito/metabolismo , Óxido Nítrico/metabolismo , Fragmentos de Peptídeos/imunologia , Distribuição Tecidual
PLoS One ; 8(8): e72354, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23951313


OBJECTIVE: Mitochondrial transcription factor A (TFAM) is normally bound to and remains associated with mitochondrial DNA (mtDNA) when released from damaged cells. We hypothesized that TFAM, bound to mtDNA (or equivalent CpG-enriched DNA), amplifies TNFα release from TLR9-expressing plasmacytoid dendritic cells (pDCs) by engaging RAGE. MATERIALS AND METHODS: Murine Flt3 ligand-expanded splenocytes obtained from C57BL/6 mice were treated with recombinant human TFAM, alone or in combination with CpG-enriched DNA with subsequent TNFα release measured by ELISA. The role of RAGE was determined by pre-treatment with soluble RAGE or heparin or by employing matching RAGE (-/-) splenocytes. TLR9 signaling was evaluated using a specific TLR9-blocking oligonucleotide and by inhibiting endosomal processing, PI3K and NF-κB. Additional studies examined whether heparin sulfate moieties or endothelin converting enzyme-1 (ECE-1)-dependent recycling of endosomal receptors were required for TFAM and CpG DNA recognition. MAIN RESULTS: TFAM augmented splenocyte TNFα release in response to CpGA DNA, which was strongly dependent upon pDCs and regulated by RAGE and TLR9 receptors. Putative TLR9 signaling pathways, including endosomal acidification and signaling through PI3K and NF-κB, were essential for splenocyte TNFα release in response to TFAM+CpGA DNA. Interestingly, TNFα release depended upon endothelin converting enzyme (ECE)-1, which cleaves and presumably activates TLR9 within endosomes. Recognition of the TFAM-CpGA DNA complex was dependent upon heparin sulfate moieties, and recombinant TFAM Box 1 and Box 2 proteins were equivalent in terms of augmenting TNFα release. CONCLUSIONS: TFAM promoted TNFα release in a splenocyte culture model representing complex cell-cell interactions in vivo with pDCs playing a critical role. To our knowledge, this study is the first to incriminate ECE-1-dependent endosomal cleavage of TLR9 as a critical step in the signaling pathway leading to TNFα release. These findings, and others reported herein, significantly advance our understanding of sterile immune responses triggered by mitochondrial danger signals.

Proteínas de Ligação a DNA/metabolismo , Células Dendríticas/metabolismo , Proteínas Mitocondriais/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Receptor Toll-Like 9/metabolismo , Fatores de Transcrição/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Linhagem Celular , Ilhas de CpG , DNA Mitocondrial/imunologia , DNA Mitocondrial/metabolismo , Células Dendríticas/imunologia , Proteína HMGB1/metabolismo , Proteína HMGB2/metabolismo , Humanos , Masculino , Camundongos , Modelos Biológicos , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Ligação Proteica , Transdução de Sinais , Baço/citologia , Baço/metabolismo
Mol Pharm ; 10(8): 2849-57, 2013 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-23768126


To enhance the immune activity of vaccine adjuvants polyinosinic:polycytidylic acid (poly I:C) and CpG acetalated dextran (Ac-DEX) microparticles can be used. Ac-DEX is a biodegradable and water-insoluble polymer that degrades significantly faster at pH 5.0 (phagosomal pH) than at pH 7.4 and has tunable degradation rates that can range from hours to months. This is an ideal characteristic for delivery of an antigen and adjuvant within the lysosomal compartment of a phagocytic cell. We evaluated poly I:C and CpG encapsulated in Ac-DEX microparticles using RAW macrophages as a model antigen-presenting cell. These cells were cultured with poly I:C or CpG in their free form, encapsulated in a fast degrading Ac-DEX, in slow degrading Ac-DEX, or in the Food and Drug Administration-approved polymer poly(lactic-co-glycolic acid) (PLGA). Ac-DEX had higher encapsulation efficiencies for both poly I:C and CpG than PLGA. Furthermore, poly I:C or CpG encapsulated in Ac-DEX also showed, in general, a significantly stronger immunostimulatory response than PLGA and unencapsulated CpG or poly I:C, which was indicated by a higher rate of nitric oxide release and increased levels of cytokines such as TNF-α, IL-6, IL-10, and IFN-γ. Overall, we have illustrated a method for enhancing the delivery of these vaccine adjuvants to further enhance the development of Ac-DEX vaccine formulations.

Fosfatos de Dinucleosídeos/metabolismo , Poli I-C/metabolismo , Receptores Toll-Like/agonistas , Animais , Linhagem Celular , Dextranos/química , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Microscopia de Força Atômica