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1.
Can J Physiol Pharmacol ; 100(7): 612-620, 2022 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-35852219

RESUMO

Aberrant upregulation of mitochondrial biogenesis is observed in breast cancer and holds potential therapeutic option. In our work, we showed that inhibition of mitochondrial function by anisomycin is effective against triple-negative breast cancer (TNBC). Anisomycin inhibits growth and induces caspase-dependent apoptosis in a panel of TNBC cell lines. Of note, anisomycin at a tolerable dose remarkably suppresses growth of TNBC in mice. In addition, anisomycin effectively targets breast cancer angiogenesis through inhibiting capillary network formation, migration, proliferation, and survival. Mechanistic studies show that although anisomycin activates p38 and JNK, their activations are not required for anisomycin's action. In contrast, anisomycin inhibits mitochondrial respiration, and decreases mitochondrial membrane potential and adenosine triphosphate (ATP) level. The inhibitory effect of anisomycin is significantly reversed in mitochondria respiration-deficient ρ0 cells. As a consequence, anisomycin activates AMPK and inhibits mammalian target-of-rapamycin signaling pathways. Our work demonstrated that anisomycin is a useful addition to the treatment armamentarium for TNBC.


Assuntos
Anisomicina , Mitocôndrias , Neoplasias de Mama Triplo Negativas , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Anisomicina/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Camundongos , Mitocôndrias/patologia , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia
2.
Dermatol Ther ; 35(8): e15649, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35716099

RESUMO

Immunosuppressive agents are essential for graft survival in solid-organ transplant recipients (SOTRs), but they have substantial durable side effects, including a higher incidence of aggressive nonmelanoma skin cancers (NMSCs). Hitherto, only one class of immunosuppressants, mammalian target of rapamycin inhibitors (mTORi), may inhibit skin tumor formation, however their durable effectiveness is controversial. To evaluate the sustained effectiveness of mTORi in reducing NMSCs' incidence in SOTRs, a retrospective study was conducted in a specialized dermatology clinic for SOTRs of a tertiary university-affiliated medical center. SOTRs with a history of at least one histologically proven NMSC were followed for 6 years: 3 years after transplantation, before initiation of mTORi, and 3 years under mTORi treatment. The cohort consisted of 44 SOTRs. Treatment with mTORi was initiated on average 6.27 (3.34-6.34) years following transplantation. In the 3 years before mTORi treatment initiation, the mean number of new NMSCs per patient was 2.11 (1-14). This value decreased to 1.2 (0-19) in the 3 years under mTORi treatment (p = 0.0007). Analysis by NMSC type yielded a significant decrease in both SCCs and BCCs. This study found that mTORi are effective for prolonged secondary prevention of NMSCs in SOTRs.


Assuntos
Carcinoma Basocelular , Carcinoma de Células Escamosas , Imunossupressores , Inibidores MTOR , Transplante de Órgãos , Neoplasias Cutâneas , Carcinoma Basocelular/etiologia , Carcinoma Basocelular/patologia , Carcinoma Basocelular/prevenção & controle , Carcinoma de Células Escamosas/etiologia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/prevenção & controle , Humanos , Imunossupressores/efeitos adversos , Inibidores MTOR/uso terapêutico , Transplante de Órgãos/efeitos adversos , Estudos Retrospectivos , Prevenção Secundária , Sirolimo/uso terapêutico , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/prevenção & controle , Serina-Treonina Quinases TOR/antagonistas & inibidores
3.
Metab Brain Dis ; 37(6): 1909-1929, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35687217

RESUMO

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder marked by social and communication deficits as well as repetitive behaviour. Several studies have found that overactivation of the PI3K/AKT/mTOR signalling pathways during brain development plays a significant role in autism pathogenesis. Overexpression of the PI3K/AKT/mTOR signalling pathway causes neurological disorders by increasing cell death, neuroinflammation, and oxidative stress. Chrysophanol, also known as chrysophanic acid, is a naturally occurring chemical obtained from the plant Rheum palmatum. This study aimed to examine the neuroprotective effect of CPH on neurobehavioral, molecular, neurochemical, and gross pathological alterations in ICV-PPA induced experimental model of autism in adult rats. The effects of ICV-PPA on PI3K/AKT/mTOR downregulation in the brain were studied in autism-like rats. Furthermore, we investigated how CPH affected myelin basic protein (MBP) levels in rat brain homogenate and apoptotic biomarkers such as caspase-3, Bax, and Bcl-2 levels in rat brain homogenate and blood plasma samples. Rats were tested for behavioural abnormalities such as neuromuscular dysfunction using an actophotometer, motor coordination using a beam crossing task (BCT), depressive behaviour using a forced swim test (FST), cognitive deficiency, and memory consolidation using a Morris water maze (MWM) task. In PPA-treated rats, prolonged oral CPH administration from day 12 to day 44 of the experimental schedule reduces autistic-like symptoms. Furthermore, in rat brain homogenates, blood plasma, and CSF samples, cellular, molecular, and cell death markers, neuroinflammatory cytokines, neurotransmitter levels, and oxidative stress indicators were investigated. The recent findings imply that CPH also restores abnormal neurochemical levels and may prevent autism-like gross pathological alterations, such as demyelination volume, in the rat brain.


Assuntos
Antraquinonas , Transtorno do Espectro Autista , Transtorno Autístico , Inibidores de Fosfoinositídeo-3 Quinase , Animais , Antraquinonas/farmacologia , Transtorno do Espectro Autista/induzido quimicamente , Transtorno do Espectro Autista/tratamento farmacológico , Transtorno Autístico/induzido quimicamente , Transtorno Autístico/tratamento farmacológico , Modelos Animais de Doenças , Fosfatidilinositol 3-Quinases/metabolismo , Propionatos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo
4.
Front Endocrinol (Lausanne) ; 13: 867822, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35721701

RESUMO

The mammalian target of rapamycin (mTOR) inhibitor everolimus has been shown to display antiproliferative effects on a wide spectrum of tumors. In vitro studies demonstrated that everolimus inhibited pituitary neuroendocrine tumor (PitNET) cell growth in a subset of patients. Sensitivity to everolimus is reduced by an escape mechanism that increases AKT phosphorylation (p-AKT), leading to pro-survival pathway activation. Dopamine receptor type 2 (DRD2) mediates a reduction of p-AKT in a subgroup of non-functioning PitNETs (NF-PitNETs) and in prolactin-secreting tumor cells (MMQ cells) through a ß-arrestin 2-dependent mechanism. The aim of this study was to investigate the efficacy of everolimus combined with DRD2 agonist cabergoline in reducing NF-PitNET primary cells and MMQ cell proliferation and to evaluate AKT phosphorylation and a possible role of ß-arrestin 2. We found that 9 out of 14 NF-PitNETs were resistant to everolimus, but the combined treatment with cabergoline inhibited cell proliferation in 7 out of 9 tumors (-31.4 ± 9.9%, p < 0.001 vs. basal) and reduced cyclin D3 expression. In the everolimus-unresponsive NF-PitNET group, everolimus determined a significant increase of p-AKT/total-AKT ratio (2.1-fold, p < 0.01, vs. basal) that was reverted by cabergoline cotreatment. To investigate the molecular mechanism involved, we used MMQ cells as a model of everolimus escape mechanism. Indeed everolimus did not affect MMQ cell proliferation and increased the p-AKT/total-AKT ratio (+1.53 ± 0.24-fold, p < 0.001 vs. basal), whereas cabergoline significantly reduced cell proliferation (-22.8 ± 6.8%, p < 0.001 vs. basal) and p-AKT. The combined treatment of everolimus and cabergoline induced a reduction of both cell proliferation (-34.8 ± 18%, p < 0.001 vs. basal and p < 0.05 vs. cabergoline alone) and p-AKT/total-AKT ratio (-34.5 ± 14%, p < 0.001 vs. basal and p < 0.05 vs. cabergoline alone). To test ß-arrestin 2 involvement, silencing experiments were performed in MMQ cells. Our data showed that the lack of ß-arrestin 2 prevented the everolimus and cabergoline cotreatment inhibitory effects on both p-AKT and cell proliferation. In conclusion, this study revealed that cabergoline might overcome the everolimus escape mechanism in NF-PitNETs and tumoral lactotrophs by inhibiting upstream AKT activation. The co-administration of cabergoline might improve mTOR inhibitor antitumoral activity, paving the way for a potential combined therapy in ß-arrestin 2-expressing NF-PitNETs or other PitNETs resistant to conventional treatments.


Assuntos
Cabergolina , Everolimo , Tumores Neuroendócrinos , Neoplasias Hipofisárias , Receptores de Dopamina D2 , Serina-Treonina Quinases TOR , Cabergolina/farmacologia , Interações Medicamentosas , Everolimo/farmacologia , Humanos , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/patologia , Neoplasias Hipofisárias/tratamento farmacológico , Neoplasias Hipofisárias/metabolismo , Neoplasias Hipofisárias/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , beta-Arrestina 2/metabolismo
5.
J Nanobiotechnology ; 20(1): 187, 2022 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-35413842

RESUMO

BACKGROUND: Non-redundant properties such as hypoxia and acidosis promote tumor metabolic adaptation and limit anti-cancer therapies. The key to the adaptation of tumor cells to hypoxia is the transcriptional and stable expression of hypoxia-inducible factor-1 alpha (HIF-1α). The phosphorylation-activated tumorigenic signal PI3K/AKT/mTOR advances the production of downstream HIF-1α to adapt to tumor hypoxia. Studies have elucidated that acid favors inhibition of mTOR signal. Nonetheless, carbonic anhydrase IX (CAIX), overexpressed on membranes of hypoxia tumor cells with pH-regulatory effects, attenuates intracellular acidity, which is unfavorable for mTOR inhibition. Herein, a drug delivery nanoplatform equipped with dual PI3K/mTOR inhibitor Dactolisib (NVP-BEZ235, BEZ235) and CAIX inhibitor 4-(2-aminoethyl) benzene sulfonamide (ABS) was designed to mitigate hypoxic adaptation and improve breast cancer treatment. RESULTS: ABS and PEG-NH2 were successfully modified on the surface of hollow polydopamine (HPDA), while BEZ235 and Chlorin e6 (Ce6) were effectively loaded with the interior of HPDA to form HPDA-ABS/PEG-BEZ235/Ce6 (H-APBC) nanoparticles. The release of BEZ235 from H-APBC in acid microenvironment could mitigate PI3K/mTOR signal and resist HIF-1α-dependent tumor hypoxia adaptation. More importantly, ABS modified on the surface of H-APBC could augment intracellular acids and enhances the mTOR inhibition. The nanoplatform combined with phototherapy inhibited orthotopic breast cancer growth while reducing spontaneous lung metastasis, angiogenesis, based on altering the microenvironment adapted to hypoxia and extracellular acidosis. CONCLUSION: Taken together, compared with free BEZ235 and ABS, the nanoplatform exhibited remarkable anti-tumor efficiency, reduced hypoxia adaptation, mitigated off-tumor toxicity of BEZ235 and solved the limited bioavailability of BEZ235 caused by weak solubility.


Assuntos
Neoplasias da Mama , Anidrase Carbônica IX , Nanopartículas , Fototerapia , Quinolinas , Serina-Treonina Quinases TOR , Acidose , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Anidrase Carbônica IX/antagonistas & inibidores , Hipóxia Celular , Linhagem Celular Tumoral , Proliferação de Células , Sistemas de Liberação de Medicamentos , Humanos , Imidazóis , Terapia de Alvo Molecular , Nanopartículas/administração & dosagem , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Quinolinas/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Hipóxia Tumoral
7.
Curr Oncol Rep ; 24(7): 819-824, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35305210

RESUMO

PURPOSE OF REVIEW: Lung neuroendocrine tumors (NETs)-typical carcinoids and atypical carcinoids-have unique molecular alterations that are distinct from neuroendocrine carcinomas of the lung and non-small cell lung cancers. Here, we review the role of molecular profiling in the prognosis and treatment of lung NETs. RECENT FINDINGS: There have been no recently identified molecular prognostic factors for lung NETs and none that have been routinely used to guide management of patients with lung NETs. Previous findings suggest that patients with loss of chromosome 11q may have a worse prognosis along with upregulation of anti-apoptotic pathways (e.g., loss of CD44 and OTP protein expression). Lung NETs rarely harbor driver mutations commonly found in non-small cell lung cancer (NSCLC) or TP53/RB1 mutations found universally in small cell lung cancer. Lung NETs also have low tumor mutation burden and low PD-L1 expression. Everolimus, an mTOR inhibitor and the only FDA approved therapy for unresectable lung NETs, is an effective treatment but the presence of a molecular alteration in the PI3K/AKT/mTOR pathway is not known to predict treatment response. The predominant mutations in lung NETs occur in genes regulating chromatin remodeling and histone modification, with potential targeted therapies emerging in clinical trials. Lung NETs have recurring alterations in genes that regulate the epigenome. Future targeted therapy interfering with epigenetic pathways may hold promise.


Assuntos
Antineoplásicos , Tumor Carcinoide , Carcinoma Neuroendócrino , Carcinoma Pulmonar de Células não Pequenas , Everolimo , Neoplasias Pulmonares , Tumores Neuroendócrinos , Antineoplásicos/uso terapêutico , Tumor Carcinoide/tratamento farmacológico , Tumor Carcinoide/genética , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Everolimo/uso terapêutico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Recidiva Local de Neoplasia/metabolismo , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/genética , Fosfatidilinositol 3-Quinases/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores
8.
JCI Insight ; 7(3)2022 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-35132962

RESUMO

Aortic dissection and rupture are triggered by decreased vascular wall strength and/or increased mechanical loads. We investigated the role of mTOR signaling in aortopathy using a well-described model of angiotensin II-induced dissection, aneurysm, or rupture of the suprarenal abdominal aorta in Apoe-deficient mice. Although not widely appreciated, nonlethal hemorrhagic lesions present as pseudoaneurysms without significant dissection in this model. Angiotensin II-induced aortic tears result in free rupture, contained rupture with subadventitial hematoma (forming pseudoaneurysms), dilatation, or healing, while the media invariably thickens regardless of mural tears. Medial thickening results from smooth muscle cell hypertrophy and extracellular matrix accumulation, including matricellular proteins. Angiotensin II activates mTOR signaling in vascular wall cells, and inhibition of mTOR signaling by rapamycin prevents aortic rupture but promotes dissection. Decreased aortic rupture correlates with decreased inflammation and metalloproteinase expression, whereas extensive dissection correlates with induction of matricellular proteins that modulate adhesion of vascular cells. Thus, mTOR activation in vascular wall cells determines whether aortic tears progress to dissection or rupture. Previous mechanistic studies of aortic aneurysm and dissection by angiotensin II in Apoe-deficient mice should be reinterpreted as clinically relevant to pseudoaneurysms, and mTOR inhibition for aortic disease should be explored with caution.


Assuntos
Falso Aneurisma/prevenção & controle , Aneurisma da Aorta Torácica/prevenção & controle , Ruptura Aórtica/prevenção & controle , Regulação da Expressão Gênica , Serina-Treonina Quinases TOR/genética , Falso Aneurisma/genética , Falso Aneurisma/metabolismo , Angiotensina II/toxicidade , Animais , Aneurisma da Aorta Torácica/genética , Aneurisma da Aorta Torácica/patologia , Ruptura Aórtica/genética , Modelos Animais de Doenças , Progressão da Doença , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , RNA/genética , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/biossíntese
9.
Pharmacol Res Perspect ; 10(1): e00930, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35142090

RESUMO

We and others have shown that aberrant activation of the mammalian target of rapamycin (mTOR) signalling is essential for retinoblastoma progression and has potential therapeutic value. TAK-228 is a potent inhibitor of mTOR1 and 2 with preclinical activity in a variety of cancers. In this study, we report that TAK-228 is a dual inhibitor of retinoblastoma and angiogenesis. TAK-228 inhibits growth and induces apoptosis in a panel of retinoblastoma cell lines, with IC50 at ~0.2 µM. Under the same experimental conditions, TAK-228 was less effective in inhibiting growth and survival in normal retinal and fibroblast cells than retinoblastoma cells. In addition, TAK-228 inhibited retinal endothelial cell capillary network formation, migration, growth and survival. We further demonstrate that TAK-228 inhibits retinoblastoma and retinal angiogenesis through inhibiting mTOR signalling. Rescue studies confirm that mTOR is the target of TAK-228 in both retinoblastoma and retinal endothelial cells. Finally, we confirm the inhibitory effects of TAK-228 on tumor and angiogenesis in retinoblastoma xenograft mouse model. Our findings provide a preclinical rationale to explore TAK-228 as a strategy to treat retinoblastoma and highlight the therapeutic value of targeting mTOR in retinoblastoma.


Assuntos
Antineoplásicos/farmacologia , Benzoxazóis/farmacologia , Pirimidinas/farmacologia , Neoplasias da Retina/tratamento farmacológico , Retinoblastoma/tratamento farmacológico , Inibidores da Angiogênese/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Concentração Inibidora 50 , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Neovascularização Patológica/tratamento farmacológico , Neoplasias da Retina/patologia , Retinoblastoma/patologia , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/antagonistas & inibidores , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Life Sci ; 293: 120332, 2022 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-35041835

RESUMO

Lung cancer is the foremost cause of cancer related mortality among men and one of the most fatal cancers among women. Notably, the 5-year survival rate of lung cancer is very low; 5% in developing countries. This low survival rate can be attributed to factors like late stage diagnosis, rapid postoperative recurrences in the patients undergoing treatment and development of chemoresistance against different agents used for treating lung cancer. Therefore, in this study we evaluated the potential of a recently identified protein namely TIPE3 which is known as a transfer protein of lipid second messengers as a lung cancer biomarker. TIPE3 was found to be significantly upregulated in lung cancer tissues indicating its role in the positive regulation of lung cancer. Supporting this finding, knockout of TIPE3 was also found to reduce the proliferation, survival and migration of lung cancer cells and arrested the G2 phase of cell cycle through inactivation of Akt/mTOR, NF-κB, STAT-3 signaling. It is well evinced that tobacco is the major risk factor of lung cancer which affects both males and females. Therefore, this study also evaluated the involvement of TIPE3 in tobacco mediated lung carcinogenesis. Notably, this study shows for the first time that TIPE3 positively regulates tobacco induced proliferation, survival and migration of lung cancer through modulation of Akt/mTOR signaling. Thus, TIPE3 plays critical role in the pathogenesis of lung cancer and hence it can be specifically targeted to develop novel therapeutic strategies.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Neoplasias Pulmonares/metabolismo , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Transcrição STAT3/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Biomarcadores Tumorais/deficiência , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Sobrevivência Celular/fisiologia , Técnicas de Inativação de Genes/métodos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Neoplasias Pulmonares/patologia , NF-kappa B/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Fator de Transcrição STAT3/antagonistas & inibidores , Serina-Treonina Quinases TOR/antagonistas & inibidores
11.
Microbiol Spectr ; 10(1): e0200721, 2022 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-35019705

RESUMO

In the present study, in vitro and in vivo interactions of TOR inhibitor AZD8055 and azoles, including itraconazole, voriconazole, posaconazole and fluconazole, against a variety of pathogenic fungi were investigated. A total of 69 isolates were studied via broth microdilution checkerboard technique, including 23 isolates of Aspergillus spp., 20 isolates of Candida spp., 9 isolates of Cryptococcus neoformans complex, and 17 isolates of Exophiala dermatitidis. The results revealed that AZD8055 individually did not exert any significant antifungal activity. However, synergistic effects between AZD8055 and itraconazole, voriconazole or posaconazole were observed in 23 (33%), 13 (19%) and 57 (83%) isolates, respectively, including azole-resistant A. fumigatus strains and Candida spp., potentiating the efficacy of azoles. The combination effect of AZD8055 and fluconazole was investigated against non-auris Candida spp. and C. neoformans complex. Synergism between AZD8055 and fluconazole was observed in six strains (60%) of Candida spp., resulting in reversion of fluconazole resistance. Synergistic combinations resulted in 4-fold to 256-fold reduction of effective MICs of AZD8055 and azoles. No antagonism was observed. In vivo effects of AZD8055-azole combinations were evaluated by survival assay in Galleria mellonella model infected with A. fumigatus strain AF002, E. dermatitidis strain BMU00038, C. auris strain 383, C. albicans strain R15, and C. neoformans complex strain Z2. AZD8055 acted synergistically with azoles and significantly increased larvae survival (P < 0.05). In summary, the results suggested that AZD8055 combined with azoles may help to enhance the antifungal susceptibilities of azoles against pathogenic fungi and had the potential to overcome azole resistance issues. IMPORTANCE Limited options of antifungals and the emergence of drug resistance in fungal pathogens has been a multifaceted clinical challenge. Combination therapy represents a valuable alternative to antifungal monotherapy. The target of rapamycin (TOR), a conserved serine/threonine kinase from yeast to humans, participates in a signaling pathway that governs cell growth and proliferation in response to nutrient availability, growth factors, and environmental stimuli. AZD8055 is an orally bioavailable, potent, and selective TOR kinase inhibitor that binds to the ATP binding cleft of TOR kinase and inhibits both TORC1 and TORC2. Synergism between AZD8055 and azoles suggested that the concomitant application of AZD8055 and azoles may help to enhance azole therapeutic efficacy and impede azole resistance. TOR inhibitor with fungal specific target is promising to be served as combination regimen with azoles.


Assuntos
Antifúngicos/farmacologia , Azóis/farmacologia , Fungos/efeitos dos fármacos , Morfolinas/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Aspergillus , Candida/efeitos dos fármacos , Candida albicans , Farmacorresistência Fúngica/efeitos dos fármacos , Exophiala/efeitos dos fármacos , Humanos , Itraconazol , Testes de Sensibilidade Microbiana , Sirolimo/farmacologia , Triazóis , Voriconazol
12.
Am J Transplant ; 22(5): 1475-1482, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35038362

RESUMO

Kidney transplant recipients (KTRs) have been considered as patients at higher risk of SARS-CoV-2-related disease severity, thus COVID-19 vaccination was highly recommended. However, possible interferences of different immunosuppression with development of both humoral and T cell-mediated immune response to COVID-19 vaccination have not been determined. Here we evaluated the association between mTOR-inhibitors (mTOR-I) and immune response to mRNA BNT162b2 (Pfizer-BioNTech) vaccine in KTR. To this aim 132 consecutive KTR vaccinated against COVID-19 in the early 2021 were enrolled, and humoral and T cell-mediated immune response were assessed after 4-5 weeks. Patients treated with mTOR-I showed significantly higher anti-SARS-CoV-2 IgG titer (p = .003) and higher percentages of anti-SARS-CoV-2 S1/RBD Ig (p = .024), than those without. Moreover, SARS-CoV-2-specific T cell-derived IFNγ release was significantly increased in patients treated with mTOR-I (p < .001), than in those without. Multivariate analysis confirmed that therapy with mTOR-I gained better humoral (p = .005) and T cell-mediated immune response (p = .005) in KTR. The presence of mTOR-I is associated with a better immune response to COVID-19 vaccine in KTR compared to therapy without mTOR-I, not only by increasing vaccine-induced antibodies but also by stimulating anti-SARS-CoV-2 T cell response. These finding are consistent with a potential beneficial role of mTOR-I as modulators of immune response to COVID-19 vaccine in KTR.


Assuntos
Vacina BNT162 , COVID-19 , Transplante de Rim , Inibidores MTOR , Anticorpos Antivirais , Vacina BNT162/imunologia , COVID-19/prevenção & controle , Humanos , Imunidade Celular , Imunidade Humoral , SARS-CoV-2 , Serina-Treonina Quinases TOR/antagonistas & inibidores , Transplantados
13.
Ann Clin Transl Neurol ; 9(2): 181-192, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35040598

RESUMO

OBJECTIVE: To determine whether sirolimus, a mechanistic target of rapamycin (mTOR) inhibitor, reduces epileptic seizures associated with focal cortical dysplasia (FCD) type II. METHODS: Sixteen patients (aged 6-57 years) with FCD type II received sirolimus at an initial dose of 1 or 2 mg/day based on body weight (FCDS-01). In 15 patients, the dose was adjusted to achieve target trough ranges of 5-15 ng/mL, followed by a 12-week maintenance therapy period. The primary endpoint was a lower focal seizure frequency during the maintenance therapy period. Further, we also conducted a prospective cohort study (RES-FCD) in which 60 patients with FCD type II were included as an external control group. RESULTS: The focal seizure frequency reduced by 25% in all patients during the maintenance therapy period and by a median value of 17%, 28%, and 23% during the 1-4-, 5-8-, and 9-12-week periods. The response rate was 33%. The focal seizure frequency in the external control group reduced by 0.5%. However, the background characteristics of external and sirolimus-treated groups differed. Adverse events were consistent with those of mTOR inhibitors reported previously. The blood KL-6 level was elevated over time. INTERPRETATION: The reduction of focal seizures did not meet the predetermined level of statistical significance. The safety profile of the drug was tolerable. The potential for a reduction of focal seizures over time merit further investigations.


Assuntos
Epilepsia/complicações , Malformações do Desenvolvimento Cortical do Grupo I/complicações , Inibidores de Proteínas Quinases/farmacologia , Convulsões/tratamento farmacológico , Convulsões/etiologia , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Adolescente , Adulto , Criança , Humanos , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Sirolimo/administração & dosagem , Sirolimo/efeitos adversos , Adulto Jovem
14.
ChemMedChem ; 17(1): e202100434, 2022 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-34569159

RESUMO

In order to improve the antitumor potency and therapeutic margins of natural product sophoridine, its novel nitrogen mustard carbamate derivatives were designed and synthesized. In screening their in vitro activity, we found all the tested compounds were more potent against the highly aggressive triple-negative breast cancer cell line MDA-MB-231. Cellular functional assays showed that representative compounds could induce G1-phase arrest and trigger apoptosis, evidenced by the alteration of Bax, Bcl-2, caspase-3 and PARP levels. Furthermore, these compounds significantly enhanced the autophagic flux with increased expression of LC3-II and Beclin-1, as well as decreased level of p62, which may attribute to simultaneously inhibition of the phosphorylation of p70S6K, 4E-BP1 and AKT, the key substrates of the mTOR signaling pathway. In vivo, two compounds revealed potent antitumor activity in mice bearing MDA-MB-231. Altogether, our work describes novel leads to yield more potent chemotherapeutics against triple-negative breast cancers, possibly mesenchymal stem-like subtype.


Assuntos
Alcaloides/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Quinolizinas/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Alcaloides/síntese química , Alcaloides/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Estrutura Molecular , Quinolizinas/síntese química , Quinolizinas/química , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Serina-Treonina Quinases TOR/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
15.
Mol Biol Rep ; 49(1): 451-461, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34731371

RESUMO

BACKGROUND: Sulforaphane (SFN) is a kind of isothiocyanate from cruciferous vegetables with extensive anti-tumor activity. Esophageal squamous cell carcinoma (ESCC) is a popular malignancy in East Asia, East and South Africa, while the more efficient medicines and therapeutic strategies are still lack. This study aims to explore the anti-tumor activity of SFN alone and combined with Akt/mTOR pathway inhibitors as well as the potential molecular mechanism in ESCC. METHODS AND RESULTS: Cell proliferation, migration, cell cycle phase, apoptosis and protein expression were detected with MTT assay, clone formation experiment, wound healing assays, flow cytometry and Western blot, respectively, after ESCC cells ECa109 and EC9706 treated with SFN alone or combined with Akt/mTOR inhibitors. Xenograft models were used to evaluate the efficiency and mechanism of SFN combined with PP242 in vivo. The results showed that SFN significantly inhibited the viability and induced apoptosis of ECa109 and EC9706 cells by increasing expression of Cleaved-caspase 9. SFN combined with PP242, but not MK2206 and RAD001, synergetic inhibited proliferation of ESCC cells. Moreover, compared to SFN alone, combination of SFN and PP242 had stronger inhibiting efficiency on clone formation, cell migratory, cell cycle phase and growth of xenografts, as well as the more powerful apoptosis-inducing effects on ESCC. The mechanism was that PP242 abrogated the promoting effects of SFN on p-p70S6K (Thr389) and p-Akt (Ser473) in ESCC. CONCLUSIONS: Our findings demonstrate that PP242 enhances the anti-tumor activity of SFN by blocking SFN-induced activation of Akt/mTOR pathway in ESCC, which provides a rationale for treating ESCC using SFN combined with Akt/mTOR pathway inhibitors.


Assuntos
Indóis/farmacologia , Isotiocianatos/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Purinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sulfóxidos/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Sinergismo Farmacológico , Neoplasias Esofágicas , Humanos , Imunofenotipagem , Camundongos , Modelos Biológicos , Ensaios Antitumorais Modelo de Xenoenxerto
16.
J Endocrinol ; 252(3): 179-193, 2022 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-34874016

RESUMO

Compelling evidence has described that the incidence of hypertension and left ventricular hypertrophy (LVH) in postmenopausal women is significantly increased worldwide. Our team's previous research identified that androgen was an underlying factor contributing to increased blood pressure and LVH in postmenopausal women. However, little is known about how androgens affect LVH in postmenopausal hypertensive women. The purpose of this study was to evaluate the role of mammalian rapamycin receptor (mTOR) signaling pathway in myocardial hypertrophy in androgen-induced postmenopausal hypertension and whether mTOR inhibitors can protect the myocardium from androgen-induced interference to prevent and treat cardiac hypertrophy. For that, ovariectomized (OVX) spontaneously hypertensive rats (SHR) aged 12 weeks were used to study the effects of testosterone (T 2.85 mg/kg/weekly i.m.) on blood pressure and myocardial tissue. On the basis of antihypertensive therapy (chlorthalidone 8 mg/kg/day ig), the improvement of blood pressure and myocardial hypertrophy in rats treated with different dose gradients of rapamycin (0.8 mg/kg/day vs 1.5 mg/kg/day vs 2 mg/kg/day i.p.) in OVX + estrogen (E 9.6 mg/kg/day, ig) + testosterone group was further evaluated. After testosterone intervention, the OVX female rats exhibited significant increments in the heart weight/tibial length (TL), area of cardiomyocytes and the mRNA expressions of ANP, ß-myosin heavy chain and matrix metalloproteinase 9 accompanied by a significant reduction in the uterine weight/TL and tissue inhibitor of metalloproteinase 1. mTOR, ribosomal protein S6 kinase (S6K1), 4E-binding protein 1 (4EBP1) and eukaryotic translation initiation factor 4E in myocardial tissue of OVX + estrogen + testosterone group were expressed at higher levels than those of the other four groups. On the other hand, rapamycin abolished the effects of testosterone-induced cardiac hypertrophy, decreased the systolic and diastolic blood pressure of SHR, and inhibited the activation of mTOR/S6K1/4EBP1 signaling pathway in a concentration-dependent manner. Collectively, these data suggest that the mTOR/S6K1/4EBP1 pathway is an important therapeutic target for the prevention of LVH in postmenopausal hypertensive female rats with high testosterone levels. Our findings also support the standpoint that the mTOR inhibitor, rapamycin, can eliminate testosterone-induced cardiomyocyte hypertrophy.


Assuntos
Hipertrofia Ventricular Esquerda/prevenção & controle , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Miocárdio/metabolismo , Proteínas Quinases S6 Ribossômicas/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Pressão Sanguínea , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Feminino , Hipertrofia Ventricular Esquerda/etiologia , Ovariectomia , Ratos Endogâmicos SHR , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Testosterona
17.
Biochem Biophys Res Commun ; 589: 1-8, 2022 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-34883284

RESUMO

BNIP3 is found to eliminate cancer cells via causing mitochondrial damage and endoplasmic reticulum stress, but it remains elusive of its role in regulating DNA double strand breaks (DSBs). In this study, we find that silibinin triggers DNA DSBs, ROS accumulation and expressional upregulation of BNIP3 in glioma cells. Mitigation of ROS with antioxidant GSH significantly inhibits silibinin-induced DNA DSBs and glioma cell death. Then, we find knockdown of BNIP3 with SiRNA obviously prevents silibinin-induced DNA DSBs and ROS accumulation. Mechanistically, BNIP3 knockdown not only reverses silibinin-triggered depletion of cysteine and GSH via maintaining xCT level, but also abrogates catalase decrease. Notably, silibinin-induced dephosphorylation of mTOR is also prevented when BNIP3 is knocked down. Given that activated mTOR could promote xCT expression and inhibit autophagic degradation of catalase, our data suggest that BNIP3 contributes to silibinin-induced DNA DSBs via improving intracellular ROS by inhibition of mTOR.


Assuntos
Quebras de DNA de Cadeia Dupla , Glioma/metabolismo , Glioma/patologia , Proteínas de Membrana/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Silibina/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Sistema y+ de Transporte de Aminoácidos/metabolismo , Catalase/metabolismo , Linhagem Celular Tumoral , Cisteína/metabolismo , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Glutationa/metabolismo , Humanos , Espécies Reativas de Oxigênio/metabolismo , Serina-Treonina Quinases TOR/metabolismo
18.
J Invest Dermatol ; 142(2): 382-389, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34536484

RESUMO

Expression-based systematic drug repositioning has been explored to predict novel treatments for a number of skin disorders. In this study, we utilize this approach to identify, to our knowledge, previously unreported therapies for epidermolysis bullosa simplex (EBS). RNA sequencing analysis was performed on skin biopsies of acute blisters (<1 week old) (n = 9) and nonblistered epidermis (n = 11) obtained from 11 patients with EBS. Transcriptomic analysis of blistered epidermis in patients with EBS revealed a set of 1,276 genes dysregulated in EBS blisters. The IL-6, IL-8, and IL-10 pathways were upregulated in the epidermis from EBS. Consistent with this, predicted upstream regulators included TNF-α, IL-1ß, IL-2, IL-6, phosphatidylinositol 3-kinase, and mTOR. The 1,276 gene EBS blister signature was integrated with molecular signatures from cell lines treated with 2,423 drugs using the Connectivity Map CLUE platform. The mTOR inhibitors and phosphatidylinositol 3-kinase inhibitors most opposed the EBS signature. To determine whether mTOR inhibitors could be used clinically in EBS, we conducted an independent pilot study of two patients with EBS treated with topical sirolimus for painful plantar keratoderma due to chronic blistering. Both individuals experienced marked clinical improvement and a notable reduction of keratoderma. In summary, a computational drug repositioning analysis successfully identified, to our knowledge, previously unreported targets in the treatment of EBS.


Assuntos
Reposicionamento de Medicamentos , Epidermólise Bolhosa Simples/tratamento farmacológico , Sirolimo/uso terapêutico , Administração Cutânea , Adolescente , Adulto , Biópsia , Criança , Pré-Escolar , Biologia Computacional , Epiderme/efeitos dos fármacos , Epiderme/metabolismo , Epiderme/patologia , Epidermólise Bolhosa Simples/genética , Epidermólise Bolhosa Simples/patologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Queratinócitos/patologia , Masculino , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/uso terapêutico , Projetos Piloto , RNA-Seq , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Resultado do Tratamento , Adulto Jovem
19.
Anticancer Agents Med Chem ; 22(3): 596-602, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-33797387

RESUMO

BACKGROUND: Papillary Thyroid Carcinoma (PTC) represents the most common thyroid cancer. Until recently, treatment options for PTC patients are limited. Nilotinib is the second-generation tyrosine kinase inhibitor, and has been widely used in the treatment of Chronic Myeloid Leukemia (CML). OBJECTIVES: We aimed to explore whether nilotinib is effective for the suppression PTC cancer progression and the underlying mechanisms. METHODS: In this study, the three human PTC cell lines (KTC-1, BCPAP, and TPC1) were used to verify the effects of nilotinib on cell growth. The half maximal inhibitory concentration (IC50) was calculated according to the growth curve post nilotinib treatment at different concentrations. Cell counting kit-8 and colony formation analysis were used to monitor cell growth after nilotinib treatment. Cell apoptosis and autophagy related proteins and phosphorylation of PI3K/Akt/mTOR were detected by Western blotting analysis. RESULTS: Nilotinib treatment could effectively inhibit PTC cell growth, which was accompanied by an increase in apoptosis and induction of autophagy. Mechanistically, nilotinib treatment repressed the phosphorylation of the PI3K/Akt/mTOR pathway. CONCLUSION: Collectively, our results demonstrated that nilotinib may display anti-tumor effect against PTC via inhibiting PI3K/Akt/mTOR pathway and inducing apoptosis and autophagy.


Assuntos
Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Câncer Papilífero da Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirimidinas/química , Relação Estrutura-Atividade , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Câncer Papilífero da Tireoide/metabolismo , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia , Células Tumorais Cultivadas
20.
Life Sci ; 288: 120150, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34793770

RESUMO

AIMS: Tacrolimus-a widely used immunosuppressant to prevent allograft rejection after organ transplantation-is nephrotoxic, increasing the risk of kidney injury accompanied by kidney fibrosis. The mammalian target of rapamycin (mTOR) inhibitor, everolimus, is an immunosuppressant used together with tacrolimus. Although mTOR signaling inhibition has been demonstrated to exhibit antifibrotic effects, the efficacy of everolimus against tacrolimus-induced kidney fibrosis has not been explored. Therefore, we evaluated the protective effects of everolimus against tacrolimus-induced kidney fibrosis. MAIN METHODS: To assess antifibrotic effect of everolimus against tacrolimus-induced kidney fibrosis, male Wistar rats were subcutaneously administered vehicle or tacrolimus (5 mg/kg per day) and/or everolimus (0.2 mg/kg per day) for 2 weeks after bilateral renal ischemia for 45 min. The antifibrotic effect of everolimus was also assessed using rat kidney fibroblast cell line (NRK-49F). KEY FINDINGS: Tacrolimus administration increased predominant profibrotic cytokine transforming growth factor-ß (TGF-ß) and fibroblast activation marker α-smooth muscle actin (α-SMA) expression and promoted the infiltration of macrophages in the kidney cortex, resulting in renal interstitial fibrosis in rats. Tacrolimus increased serum creatinine, blood urea nitrogen, kidney injury molecule-1 (KIM-1), and kidney injuries, such as tubular dilation, vacuolization, and glomerular atrophy. Everolimus administration attenuated tacrolimus-induced kidney fibrosis and the associated abnormalities. Everolimus strongly suppressed TGF-ß-induced kidney fibroblast activation and extracellular matrix protein expression by the mTOR signaling inhibition. SIGNIFICANCE: We demonstrated that everolimus attenuates tacrolimus-induced renal interstitial fibrosis in rats. Owing to its protective effect against tacrolimus-induced kidney fibrosis, everolimus may be useful when used concomitantly with tacrolimus.


Assuntos
Everolimo/farmacologia , Fibrose/tratamento farmacológico , Nefropatias/tratamento farmacológico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Tacrolimo/toxicidade , Fator de Crescimento Transformador beta/metabolismo , Animais , Fibrose/induzido quimicamente , Fibrose/metabolismo , Fibrose/patologia , Imunossupressores/farmacologia , Nefropatias/induzido quimicamente , Nefropatias/metabolismo , Nefropatias/patologia , Masculino , Ratos , Ratos Wistar , Fator de Crescimento Transformador beta/genética
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