GSK-3 inhibition in vitro and in vivo enhances antitumor effect of sorafenib in renal cell carcinoma (RCC)

Kawazoe, Hisashi; Bilim, Vladimir; Ugolkov, Andrey; Yuuki, Kaori; Naito, Sei; Nagaoka, Akira; Kato, Tomoyuki; Tomita, Yoshihiko

doi:10.1016/j.bbrc.2012.05.147

Cited by 38 publications

(32 citation statements)

References 23 publications

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“…Várias pesquisas mostram a importância da inibição da enzima GSK-3 em distúrbios importantes, incluindo desordens metabólicas, como aterosclerose, diabetes, doença cardíaca, distúrbios neurológicos, como Parkinson, Alzheimer, esclerose lateral amiotrófica, esquizofrenia, transtorno bipolar e distúrbios do humor, câncer, envelhecimento (senescência celular, células-tronco do câncer, controle de pluripotência e diferenciação de células-tronco), distúrbios imunológicos entre outros (GAO et al, 2012;JUHASZOVA et al, 2009;SHIMURA et al, 2011, FU et al, 2011KAWAZOE et al, 2012).…”

Section: Resultsunclassified

Inibidores Da GSK-3: Uma Nova Estratégia Para a Regeneração Dental

Bentos¹,

Pereira

2017

Iniciac cient Cesumar

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RESUMO:A enzima GSK-3 (glicogênio sintase quinase 3) regula múltiplas etapas da bioquímica celular e alterações em sua atividade estão envolvidas em diversas doenças. Desde a década de 1990, a GSK-3 tornouse importante sítio-alvo para o desenvolvimento de novos fármacos e vários inibidores foram avaliados para o tratamento de diversas patologias como diabetes e doença de Alzheimer. O tideglusibe é um inibidor da GSK-3 planejado para o tratamento da doença de Alzheimer. Recentemente, ficou demonstrado que esse fármaco pode induzir a reparação natural da polpa dental por meio da ativação de células estaminais, levando à regeneração do material dentário da área danificada. Esse processo de regeneração natural representa uma inovação entre as técnicas de restauração dentária ao estimular a multiplicação das células da polpa dental e conduzir à vedação de pequenas cavidades. O objetivo desse artigo é apresentar uma revisão do papel da enzima GSK-3, seus inibidores e os efeitos do tideglusibe na regeneração dental.

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Section: Resultsunclassified

Inibidores Da GSK-3: Uma Nova Estratégia Para a Regeneração Dental

Bentos¹,

Pereira

2017

Iniciac cient Cesumar

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“…Preclinical studies of RCC have validated both STAT3 and GSK-3␣/␤ as targetable molecules for the therapeutic inhibition of RCC progression (32)(33)(34)(35). Additionally, aberrant nuclear accumulation of GSK-3␤ has been reported to occur in Ͼ90% of human RCC cases.…”

Section: Resultsmentioning

confidence: 99%

“…Sorafenib and sunitinib effectively prolong progression-free survival (50,51), but resistance to these drugs invariably limits their efficacy, and mechanisms of resistance are poorly defined (52). It was recently reported that sorafenib treatment increased GSK-3␤ activity in RCC cells and that combination therapy with sorafenib plus GSK-3␣/␤ inhibitors synergistically inhibited xenograft tumor growth in a mouse model of RCC (35). Additionally, aberrant nuclear accumulation of GSK-3␤ is reported to occur in Ͼ90% of RCC cases (34), and an immunohistochemistry analysis of renal tumors showed that tyrosine-phosphorylated nuclear STAT3 is present in approximately 60% of ccRCC and pRCC cases (53).…”

Section: Discussionmentioning

confidence: 99%

Signal Integration and Gene Induction by a Functionally Distinct STAT3 Phosphoform

Waitkus

Chandrasekharan

Willard

et al. 2014

Molecular and Cellular Biology

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Aberrant activation of the ubiquitous transcription factor STAT3 is a major driver of solid tumor progression and pathological angiogenesis. STAT3 activity is regulated by numerous posttranslational modifications (PTMs), including Tyr 705 phosphorylation, which is widely used as an indicator of canonical STAT3 function. Here, we report a noncanonical mechanism of STAT3 activation that occurs independently of Tyr 705 phosphorylation. Using quantitative liquid chromatography-tandem mass spectrometry, we have discovered and characterized a novel STAT3 phosphoform that is simultaneously phosphorylated at Thr

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“…Furthermore, GSK-3 activity induced by sorafenib in cancer cells is one of the potential causes for its resistance. 25 Zinc inhibits GSK-3 and could be an effective option as a combination agent with sorafenib. However, more in-depth studies are warranted to ascertain these findings.…”

Section: Discussionmentioning

confidence: 99%

Antiangiogenic activity of zinc and zinc-sorafenib combination using the chick chorioallantoic membrane assay: a descriptive study

Kumar¹,

Meshram²,

Rastogi³

et al. 2017

Int J Basic Clin Pharmacol

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Background: Zinc, a trace element, is known for downregulating several proangiogenic growth factors and cytokines. However, its antiangiogenic activity is not adequately studied. The present study was aimed to evaluate the possible antiangiogenic activity of zinc via the chick chorioallantoic membrane (CAM) assay. Also, the antiangiogenic activity of the combination therapy of zinc with various doses of sorafenib, a tyrosine kinase inhibitor, was evaluated.Methods: A pilot study was initially conducted so as to select suitable doses of zinc and sorafenib. The antiangiogenic activity after combining zinc 2.5 μg/embryo with sorafenib 1, and 2 μg/embryo was also evaluated. The antiangiogenic activity was quantified in terms of total length of blood vessels, number of junctions, number of branching points, and mean length of the blood vessels.Results: Zinc 2.5 μg/embryo showed significant (p <0.05) antiangiogenic activity, as compared to the control group. However, its effect was not comparable to that of sorafenib 2 μg/embryo. The combination of zinc 2.5 μg/embryo with sorafenib 2 μg/embryo did not show an additive/synergistic effect. The combination of zinc 2.5 μg/embryo with sorafenib 1 μg/embryo produced an antiangiogenic activity which was comparable (p >0.05) to that of sorafenib 2 μg/embryo.Conclusions: Zinc caused significant antiangiogenic activity in the CAM assay. The lack of addition/synergism in the zinc-sorafenib combination could have been due to the variability in the dose/ratio selection. Addition of zinc to sorafenib therapy could improve treatment tolerability, reduce cost of therapy, and reduce the emergence of drug resistance. Future mechanistic studies could identify the exact pharmacodynamics of zinc as an angiogenesis inhibitor.

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GSK-3 inhibition in vitro and in vivo enhances antitumor effect of sorafenib in renal cell carcinoma (RCC)

Cited by 38 publications

References 23 publications

Inibidores Da GSK-3: Uma Nova Estratégia Para a Regeneração Dental

Inibidores Da GSK-3: Uma Nova Estratégia Para a Regeneração Dental

Signal Integration and Gene Induction by a Functionally Distinct STAT3 Phosphoform

Antiangiogenic activity of zinc and zinc-sorafenib combination using the chick chorioallantoic membrane assay: a descriptive study

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