Cytostatic in vitro Effects of DTCM-Glutarimide on Bladder Carcinoma Cells

Abstract

Bladder cancer is a common malignancy worldwide. Despite the increased use of cisplatin-based combination therapy, the outcomes for patients with advanced disease remain poor. Recently, altered activation of the PI3K/ Akt/mTOR pathway has been associated with reduced patient survival and advanced stage of bladder cancer, making its upstream or downstream components attractive targets for therapeutic intervention. In the present study, we showed that treatment with DTCM-glutaramide, a piperidine that targets PDK1, results in reduced proliferation, diminished cell migration and G1 arrest in 5637 and T24 bladder carcinoma cells. Conversely, no apoptosis, necrosis or autophagy were detected after treatment, suggesting that reduced cell numbers in vitro are a result of diminished proliferation rather than cell death. Furthermore previous exposure to 10 µg/ml DTCMglutarimide sensitized both cell lines to ionizing radiation. Although more studies are needed to corroborate our findings, our results indicate that PDK1 may be useful as a therapeutic target to prevent progression and abnormal tissue dissemination of urothelial carcinomas.

New insights into the regulation of Cystathionine beta synthase (CBS), an enzyme involved in intellectual deficiency in Down syndrome

“…Among the other compounds identified, eight of them are known to inhibit pro-survival pathways ( Table 1 and Supplementary Table 4 ). Among these compounds, 9-methylstreptimidone, an inhibitor of NF-κB ( Wang et al, 2006 ; Ishikawa et al, 2009 ) and possibly of the Akt/GSK3β pathway ( Brassesco et al, 2012 ; Koide et al, 2015 ), showed a strong capacity to rescue yeast growth on a medium without methionine ( Supplementary Table 4 ). Similarly, 8α-hydroxy verrucarin A and chrysomycin A, both inhibitors of NF-κB and of the Akt/GSK3β pathway ( Deeb et al, 2016 ; Liu et al, 2016 ), also counteracted the growth defect phenotype induced by Cys4p overexpression ( Supplementary Table 4 ).…”

CISD2 promotes the proliferation of glioma cells via suppressing beclin-1-mediated autophagy and is targeted by microRNA-449a

“…The role of autophagy in cancer differs depending on the situation ( 18 ). Studies have shown that the inhibition of autophagy promotes cancer initiation, however, others have shown that it can also suppress the growth of certain malignancies, including breast cancer and hepatocellular carcinoma ( 19 – 22 ). Therefore, it is necessary to investigate the involvement of autophagy in the function of CISD2 in glioma.…”

Avaliação comparativa dos efeitos antitumorais dos inibidores de NF-κB DHMEQ, DTCM-g e SEMBL em sarcoma de Ewing

“…Partindo deste ponto, testou-se a inibição de NF-κB in vitro na linhagem celular BRASSESCO, Maria S. et al, 2012;CANDIDO et al, 2020;SIDTHIPONG et al, 2017).…”

“…A sua capacidade de inibir o NF-κB se dá pela indução da clivagem da subunidade Rel-B na Asp205 (KUBOKI et al, 2015). Da mesma forma que o DHMEQ, este composto não apresenta citotoxicidade para células normais, mas possui efeitos antimetastáticos, pró-apoptóticos, antiproliferativos, incluindo a indução de parada do clico celular, redução na capacidade clonogênica, além de efeito sinérgico com outros quimioterápicos e radiação em células tumorais cultivadas in vitro (BRASSESCO, Maria S. et al, 2012;BRASSESCO, María Sol et al, 2013;KUBOKI et al, 2015;ROBERTO et al, 2018). Estes efeitos foram desencadeados pela regulação negativa de genes como PDPN, MMP2, TIMP1 e TIMP2, como mostrado por BRASSESCO, María Sol et al (2013).…”