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1.
Int J Biol Sci ; 20(11): 4407-4423, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39247817

RESUMO

Various cancer treatment approaches that inhibit the activity of the programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) axis, a key player in tumor immune evasion, have been developed. We show that the immunomodulatory small tellurium complexes AS101 (ammonium trichloro(dioxoethylene-o,o')tellurate) and SAS (octa-O-bis(R,R)-tartarate ditellurane) suppress PD-L1 expression in a variety of human and mouse malignant cells via the modulation of α4ß1 very late antigen-4 (VLA-4) integrin activity. Consequently, the expression of pAkt and its downstream effector pNFκB are inhibited. Additionally, SAS promotes the death of mouse malignant cells by activated syngeneic splenocytes or CD8+ T cells, preventing the development of chemoresistance in malignant cells. Moreover, AS101 and SAS may increase, at least in part, chemosensitivity through inhibition of the VLA-4/IL-10/PD-L1 pathway. Additionally, AS101 or SAS treatment of B16/F10 melanoma-bearing mice decreased tumor cell PD-L1 expression, leading to increased CD8+ T-cell infiltration into the tumors and tumor shrinkage. Combination treatment with an αPD-1 antibody and either tellurium compound significantly increased the antitumor efficacy of immunotherapy. Overall, VLA-4 integrin signaling is critical for tumor immune evasion and is a potential target for cancer treatment. Finally, AS101 or SAS, biologically active tellurium compounds, can effectively enhance the therapeutic efficacy of αPD-1-based cancer immunotherapy.


Assuntos
Antígeno B7-H1 , Integrina alfa4beta1 , Telúrio , Animais , Camundongos , Humanos , Telúrio/farmacologia , Antígeno B7-H1/metabolismo , Linhagem Celular Tumoral , Integrina alfa4beta1/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Camundongos Endogâmicos C57BL , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/efeitos dos fármacos , Etilenos
2.
Front Immunol ; 8: 240, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28326083

RESUMO

Crescentic glomerulonephritis (CGN) is the most aggressive form of GN and, if untreated, patients can progress to end-stage renal failure within weeks of presentation. The α4ß1 integrin very late antigen-4 (VLA-4) is an adhesion molecule of fundamental importance to the recruitment of leukocytes in inflammation. We addressed the role of VLA-4 in mediating progressive renal injury in a rat model of CGN using a small tellurium compound. AS101 [ammonium trichloro(dioxoethylene-o,o')tellurate]. This compound has been previously shown to uniquely inhibit VLA-4 activity by redox inactivation of adjacent thiols in the exofacial domain of VLA-4. The study shows that administration of AS101 either before or after glomerular basement membrane anti-serum injection ameliorates crescent formation or preserves renal function. This was associated with profound inhibition of critical inflammatory mediators, accompanied by decreased glomerular infiltration of macrophages. Mechanistic studies demonstrated vla-4 inactivation on glomerular macrophages both in vitro and in vivo as well as inhibition of caspase-1 activity. Importantly, this cysteine protease activity modification was dependent on VLA-4 inactivation and was associated with the anti-inflammatory activity of AS101. We propose that inactivation of macrophage VLA-4 by AS101 in vivo results in a decrease of inflammatory cytokines and chemokines produced in the glomeruli of diseased rats, resulting in decreased further macrophage recruitment and decreased extracellular matrix expansion. Thus, AS101, which is currently in clinical trials for other indications, might be beneficial for treatment of CGN.

3.
Chembiochem ; 17(10): 918-27, 2016 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-26991356

RESUMO

Organic Te(IV) compounds (organotelluranes) differing in their labile ligands exhibited anti-integrin activities in vitro and anti-metastatic properties in vivo. They underwent ligand substitution with l-cysteine, as a thiol model compound. Unlike inorganic Te(IV) compounds, the organotelluranes did not form a stable complex with cysteine, but rather immediately oxidized it. The organotelluranes inhibited integrin functions, such as adhesion, migration, and metalloproteinase secretion mediation in B16F10 murine melanoma cells. In comparison, a reduced derivative with no labile ligand inhibited adhesion of B16F10 cells to a significantly lower extent, thus pointing to the importance of the labile ligands of the Te(IV) atom. One of the organotelluranes inhibited circulating cancer cells in vivo, possibly by integrin inhibition. Our results extend the current knowledge on the reactivity and mechanism of organotelluranes with different labile ligands and highlight their clinical potential.


Assuntos
Integrinas/metabolismo , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Telúrio/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Modelos Animais de Doenças , Integrina alfa4beta1/antagonistas & inibidores , Integrina alfa4beta1/metabolismo , Integrinas/antagonistas & inibidores , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Espectroscopia de Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Compostos Organometálicos/uso terapêutico , Ligação Proteica/efeitos dos fármacos , Transplante Homólogo
4.
Mol Cancer Res ; 13(3): 411-22, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25351768

RESUMO

UNLABELLED: Cancer cell resistance to chemotherapy is a major concern in clinical oncology, resulting in increased tumor growth and decreased patient survival. Manipulation of apoptosis has emerged as a new therapeutic strategy to eliminate cancer cells. The focus of this study resides within a novel approach to target survivin, an integrator of both cell death and mitosis. This protein plays a pivotal role in the resistance of tumors to chemotherapy, especially to paclitaxel. The data herein demonstrate an indirect repression of survivin in both B- and T-cell lymphoma and human NHL by the nontoxic tellurium compound, AS101 [ammonium trichloro(dioxoethylene-o,o')tellurate], via inhibition of tumor autocrine IL10-STAT3-Survivin signaling. As a result of survivin abrogation, sensitization of lymphomas to paclitaxel or to Abraxane, the new albumin-stabilized nanoparticle formulation of paclitaxel, occurs both in vitro and in vivo. Importantly, inhibition of lymphoma cell IL10 secretion is mediated by inactivation of the VLA-4 integrin, recently shown to be an important target of AS101. This activity is followed by inhibition of the PI3K-AKT axis that mediates IL10 suppression. Because a wide variety of lymphomas and other tumor types express VLA-4 and secrete IL10 in an autocrine manner, inhibition of survivin with a small nontoxic agent has vast clinical significance in modulating chemosensitivity in many tumor types. IMPLICATIONS: Combination therapy with AS101 and paclitaxel has novel therapeutic potential targeting deregulated active pathways in lymphoma, overcoming endogenous resistance to apoptosis.


Assuntos
Antineoplásicos/administração & dosagem , Etilenos/administração & dosagem , Linfoma de Células B/tratamento farmacológico , Linfoma de Células T/tratamento farmacológico , Paclitaxel/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Etilenos/farmacologia , Humanos , Proteínas Inibidoras de Apoptose/metabolismo , Integrina alfa4beta1/metabolismo , Interleucina-10/metabolismo , Linfoma de Células B/metabolismo , Linfoma de Células T/metabolismo , Camundongos , Transplante de Neoplasias , Paclitaxel/farmacologia , Proteínas Repressoras/metabolismo , Survivina
5.
PLoS One ; 9(12): e114287, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25474550

RESUMO

Diabetic nephropathy (DN) is characterized by proliferation of mesangial cells, mesangial expansion, hypertrophy and extracellular matrix accumulation. Previous data have cross-linked PKB (AKT) to TGFß induced matrix modulation. The non-toxic compound AS101 has been previously shown to favorably affect renal pathology in various animal models and inhibits AKT activity in leukemic cells. Here, we studied the pharmacological properties of AS101 against the progression of rat DN and high glucose-induced mesangial dysfunction. In-vivo administration of AS101 to Streptozotocin injected rats didn't decreased blood glucose levels but ameliorated kidney hypotrophy, proteinuria and albuminuria and downregulated cortical kidney phosphorylation of AKT, GSK3ß and SMAD3. AS101 treatment of primary rat glomerular mesangial cells treated with high glucose significantly reduced their elevated proliferative ability, as assessed by XTT assay and cell cycle analysis. This reduction was associated with decreased levels of p-AKT, increased levels of PTEN and decreased p-GSK3ß and p-FoxO3a expression. Pharmacological inhibition of PI3K, mTORC1 and SMAD3 decreased HG-induced collagen accumulation, while inhibition of GSK3ß did not affect its elevated levels. AS101 also prevented HG-induced cell growth correlated to mTOR and (rp)S6 de-phosphorylation. Thus, pharmacological inhibition of the AKT downstream pathway by AS101 has clinical potential in alleviating the progression of diabetic nephropathy.


Assuntos
Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/tratamento farmacológico , Proteína Oncogênica v-akt/biossíntese , Transdução de Sinais/efeitos dos fármacos , Animais , Glicemia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/genética , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Etilenos/administração & dosagem , Expressão Gênica/efeitos dos fármacos , Células Mesangiais/efeitos dos fármacos , Células Mesangiais/patologia , Proteína Oncogênica v-akt/genética , PTEN Fosfo-Hidrolase/biossíntese , Fosfatidilinositol 3-Quinases/biossíntese , Fosfatidilinositol 3-Quinases/genética , Fosforilação , Ratos , Proteína Smad3/biossíntese , Proteína Smad3/genética , Fator de Crescimento Transformador beta/biossíntese
6.
Cancer Res ; 74(11): 3092-103, 2014 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-24699624

RESUMO

Interaction between the integrin VLA-4 on acute myelogenous leukemia (AML) cells with stromal fibronectin is a decisive factor in chemotherapeutic resistance. In this study, we provide a rationale for a drug repositioning strategy to blunt integrin activation in AML cells and restore their sensitivity to chemotherapy. Specifically, we demonstrate that the nontoxic tellurium compound AS101, currently being evaluated in clinical trials, can abrogate the acquired resistance of AML. Mechanistic investigations revealed that AS101 caused redox inactivation of adjacent thiols in the exofacial domain of VLA-4 after its ligation to stromal fibronectin. This effect triggered cytoskeletal conformational changes that decreased PI3K/Akt/Bcl2 signaling, an obligatory step in chemosensitization by AS101. In a mouse xenograft of AML derived from patient leukemic cells with high VLA-4 expression and activity, we demonstrated that AS101 abrogated drug resistance and prolonged survival in mice receiving chemotherapy. Decreased integrin activity was confirmed on AML cells in vivo. The chemosensitizing activity of AS101 persisted in hosts with defective adaptive and innate immunity, consistent with evidence that integrin deactivation was not mediated by heightening immune attack. Our findings provide a mechanistic rationale to reposition the experimental clinical agent, AS101, to degrade VLA-4-mediated chemoresistance and improve clinical responses in patients with AML.


Assuntos
Etilenos/farmacologia , Integrina alfa4beta1/metabolismo , Leucemia Mieloide/tratamento farmacológico , Oxirredução/efeitos dos fármacos , Compostos de Sulfidrila/metabolismo , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Fibronectinas/metabolismo , Células HL-60 , Humanos , Integrina alfa4beta1/antagonistas & inibidores , Leucemia Mieloide/metabolismo , Masculino , Camundongos , Camundongos SCID , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células U937 , Proteína de Morte Celular Associada a bcl/metabolismo
7.
J Biol Chem ; 289(24): 17215-27, 2014 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-24764299

RESUMO

Inflammatory bowel diseases (IBDs) are a group of idiopathic, chronic immune-mediated diseases characterized by an aberrant immune response, including imbalances of inflammatory cytokine production and activated innate and adaptive immunity. Selective blockade of leukocyte migration into the gut is a promising strategy for the treatment of IBD. This study explored the effect of the immunomodulating tellurium compound ammonium trichloro (dioxoethylene-o,o') tellurate (AS101) on dextran sodium sulfate (DSS)-induced murine colitis. Both oral and intraperitoneal administration of AS101 significantly reduced clinical manifestations of IBD. Colonic inflammatory cytokine levels (IL-17 and IL-1ß) were significantly down-regulated by AS101 treatment, whereas IFN-γ was not affected. Neutrophil and α4ß7(+) macrophage migration into the tissue was inhibited by AS101 treatment. Adhesion of mesenteric lymph node cells to mucosal addressin cell adhesion molecule (MAdCAM-1), the ligand for α4ß7 integrin, was blocked by AS101 treatment both in vitro and in vivo. DSS-induced destruction of colonic epithelial barrier/integrity was prevented by AS101, via up-regulation of colonic glial-derived neurotrophic factor, which was found previously to regulate the intestinal epithelial barrier through activation of the PI3K/AKT pathway. Indeed, the up-regulation of glial-derived neurotrophic factor by AS101 was associated with increased levels of colonic pAKT and BCL-2 and decreased levels of BAX. Furthermore, AS101 treatment reduced colonic permeability to Evans blue and decreased colonic TUNEL(+) cells. Our data revealed multifunctional activities of AS101 in the DSS-induced colitis model via anti-inflammatory and anti-apoptotic properties. We suggest that treatment with the small, nontoxic molecule AS101 may be an effective early therapeutic approach for controlling human IBD.


Assuntos
Colite/tratamento farmacológico , Etilenos/uso terapêutico , Fatores Imunológicos/uso terapêutico , Administração Oral , Animais , Apoptose , Moléculas de Adesão Celular/metabolismo , Colite/induzido quimicamente , Colite/metabolismo , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Sulfato de Dextrana/toxicidade , Etilenos/administração & dosagem , Etilenos/farmacologia , Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/farmacologia , Injeções Intraperitoneais , Interferon gama/genética , Interferon gama/metabolismo , Interleucina-17/genética , Interleucina-17/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Mucoproteínas , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
8.
Cancer Res ; 64(5): 1843-52, 2004 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-14996748

RESUMO

Cancer cells of different solid and hematopoietic tumors express growth factors in respective stages of tumor progression, which by autocrine and paracrine effects enable them to grow autonomously. Here we show that the murine B16 melanoma cell line and two human primary cultures of stomach adenocarcinoma and glioblastoma multiforme (GBM) constitutively secrete interleukin (IL)-10 in an autocrine/paracrine manner. This cytokine is essential for tumor cell proliferation because its neutralization decreases clonogenicity of malignant cells, whereas addition of recombinant IL-10 increases cell proliferation. The immunomodulator ammonium trichloro(dioxoethylene-o,o')tellurate (AS101) decreased cell proliferation by inhibiting IL-10. This activity was abrogated by exogenous addition of recombinant IL-10. IL-10 inhibition by AS101 results in dephosphorylation of Stat3, followed by reduced expression of Bcl-2. Moreover, these activities of AS101 are associated with sensitization of tumor cells to chemotherapeutic drugs, resulting in their increased apoptosis. More importantly, AS101 sensitizes the human aggressive GBM tumor to paclitaxel both in vitro and in vivo by virtue of IL-10 inhibition. AS101 sensitizes GBM cells to paclitaxel at concentrations that do not affect tumor cells. This sensitization can also be obtained by transfection of GBM cells with IL-10 antisense oligonucleotides. Sensitization of GBM tumors to paclitaxel (Taxol) in vivo was obtained by either AS101 or by implantation of antisense IL-10-transfected cells. The results indicate that the IL-10 autocrine/paracrine loop plays an important role in the resistance of certain tumors to chemotherapeutic drugs. Therefore, anti-IL-10 treatment modalities with compounds such as AS101, combined with chemotherapy, may be effective in the treatment of certain malignancies.


Assuntos
Antineoplásicos/farmacologia , Etilenos/farmacologia , Interleucina-10/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Animais , Proteínas de Ligação a DNA/metabolismo , Humanos , Masculino , Melanoma Experimental/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Oligonucleotídeos Antissenso/farmacologia , Paclitaxel/farmacologia , Fosforilação , Fator de Transcrição STAT3 , Transativadores/metabolismo
9.
FASEB J ; 18(2): 400-2, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-14656992

RESUMO

The synthetic immunomodulator AS101[ammonium trichloro(dioxoethylene-o,o')tellurate] was previously found to protect cancer patients from chemotherapy-induced bone marrow toxicity and alopecia. Here we show that AS101 induces hair growth in nude and normal mice. AS101 possesses the dual ability to both induce anagen and retard spontaneous catagen in the C57BL/6 mouse model. Anagen induced by AS101 is mediated by keratinocyte growth factor (KGF), as it is abrogated both in nude mice co-treated with AS101 plus neutralizing anti KGF antibodies and in AS101-treated transgenic mice expressing a dominant-negative KGF receptor transgene in basal keratinocytes. AS101 up-regulates KGF expression by activating the ras signaling pathway in cultured fibroblasts. AS101-induced delayed catagen is associated with inhibition of terminal differentiation marker expression both in nude and C57BL/6 mice epidermal follicular keratinocytes and in cultures of primary mouse follicular keratinocytes induced to differentiate. This activity is associated with relatively sustained elevation of p21waf. Delayed expression of terminal differentiation markers was not induced by AS101 in follicular keratinocytes from p21waf knockout mice. Because similar results were obtained with cultures of primary human keratinocytes and fibroblasts, preliminary case report studies revealed substantial hair growth when AS101 was topically applied on three adolescents who had remained alopeciac 1-2 years after chemotherapy. The results emphasize the unique mode of action of AS101 and highlight its potential clinical use for treating certain types of alopecia.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Etilenos/farmacologia , Fatores de Crescimento de Fibroblastos/metabolismo , Cabelo/efeitos dos fármacos , Queratinócitos/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Proteínas ras/metabolismo , Adjuvantes Imunológicos/farmacologia , Alopecia/tratamento farmacológico , Animais , Fator 7 de Crescimento de Fibroblastos , Fatores de Crescimento de Fibroblastos/genética , Fibroblastos , Cabelo/crescimento & desenvolvimento , Queratinócitos/citologia , Queratinócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Camundongos Transgênicos , Telúrio/farmacologia
10.
Am J Physiol Cell Physiol ; 284(6): C1593-603, 2003 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12734112

RESUMO

One of the most common side effects of treatment with cyclosporin A (CsA) is hypertrichosis. This study shows that calcineurin activity is associated with hair keratinocyte differentiation in vivo, affecting nuclear factor of activated T cells (NFAT1) activity in these cells. Treatment of nude or C57BL/6 depilated normal mice with CsA inhibited the expression of keratinocyte terminal differentiation markers associated with catagen, along with the inhibition of calcineurin and NFAT1 nuclear translocation. This was associated with induction of hair growth in nude mice and retardation of spontaneous catagen induction in depilated normal mice. Furthermore, calcineurin inhibition blocked the expression of p21(waf/cip1) and p27(kip1), which are usually induced with differentiation. This was also associated with an increase in interleukin-1alpha expression (nude mice), a decrease in transforming growth factor-beta (nude and normal mice), and no change in keratinocyte growth factor expression in the skin. Retardation of catagen in CsA-treated mice was accompanied by significant alterations in apoptosis-related gene product expression in hair follicle keratinocytes. The ratio of the anti-apoptotic Bcl-2 to proapoptotic Bax expression increased, and expression of p53 and interleukin-1beta converting enzyme activity decreased. These data provide the first evidence that calcineurin is functionally active in follicular keratinocytes and that inhibition of the calcineurin-NFAT1 pathway in these cells in vivo by CsA enhances hair growth.


Assuntos
Calcineurina/metabolismo , Ciclosporina/farmacologia , Proteínas de Ligação a DNA/metabolismo , Cabelo/crescimento & desenvolvimento , Imunossupressores/farmacologia , Queratinócitos/efeitos dos fármacos , Proteínas Nucleares , Fatores de Transcrição/metabolismo , Animais , Proteínas de Ciclo Celular/metabolismo , Inibidor de Quinase Dependente de Ciclina p21 , Inibidor de Quinase Dependente de Ciclina p27 , Ciclinas/metabolismo , Folículo Piloso/citologia , Folículo Piloso/metabolismo , Humanos , Hipertricose/metabolismo , Queratinócitos/citologia , Queratinócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Fatores de Transcrição NFATC , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Pele/anatomia & histologia , Pele/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Proteína X Associada a bcl-2
11.
J Am Soc Nephrol ; 14(3): 620-30, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12595497

RESUMO

Mesangial cell (MC) proliferation is essential for the pathogenesis and progression of various glomerular diseases. This study shows that glial cell line-derived neurotrophic factor (GDNF) and IL-10 are mesangial autocrine growth factors that play a pivotal role in rat MC proliferation in vitro. Downstream targets of GDNF signaling and their role in MC hyperplasia are identified. The phosphatidylinositol 3-kinase (PI3K) pathway and its downstream target NF-kappaB were found to mediate GDNF-induced MC mitogenesis. This pathway also mediates GDNF-induced decrease in the cyclin-dependent kinase inhibitor p27(kip1) expression, resulting in the increased formation of cyclin D1/cdk4 and cyclin E/cdk2 complexes, followed by hyperphosphorylation of retinoblastoma, a key event for G1 to S phase progression. IL-10 appears to be a more potent MC growth factor that negatively regulates GDNF expression. Indeed, its inhibition by the nontoxic tellurium anti-IL-10 compound, ammonium trichloro(dioxoethylene-o,o') tellurate (AS101), extensively decreased MC clonogenicity despite GDNF upregulation. Identification of the mesangial GDNF and IL-10 pathways as critical mediators of mesangial cell proliferation may provide another target for therapeutic intervention in certain glomerular diseases. In vivo animal studies using AS101, currently undergoing phase II clinical trials on cancer patients, are warranted to determine its potential in the management of glomerular diseases associated with mesangial cell proliferation.


Assuntos
Adjuvantes Imunológicos/farmacologia , Etilenos/farmacologia , Mesângio Glomerular/metabolismo , Interleucina-10/genética , Fatores de Crescimento Neural/genética , Animais , Comunicação Autócrina/efeitos dos fármacos , Comunicação Autócrina/imunologia , Proteínas de Ciclo Celular/metabolismo , Divisão Celular/efeitos dos fármacos , Células Cultivadas , Inibidor de Quinase Dependente de Ciclina p21 , Inibidor de Quinase Dependente de Ciclina p27 , Ciclinas/metabolismo , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/imunologia , Fator Neurotrófico Derivado de Linhagem de Célula Glial , Mesângio Glomerular/citologia , Mesângio Glomerular/imunologia , Interleucina-10/metabolismo , Masculino , NF-kappa B/metabolismo , Fatores de Crescimento Neural/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Proteínas Supressoras de Tumor/metabolismo , Proteínas ras/metabolismo
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