Anticancer activities of emetine prodrugs that are proteolytically activated by the prostate specific antigen (PSA) and evaluation of in vivo toxicity of emetine derivatives

Akinboye, Emmanuel S.; Rosen, Marc; Bakare, Oladapo; Denmeade, Samuel R.

doi:10.1016/j.bmc.2017.11.015

Cited by 17 publications

(10 citation statements)

References 19 publications

(35 reference statements)

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“…However, these clinical studies did not lead to the clinical application of emetine as they revealed only marginal efficacy and some adverse side effects, such as cardiac damage. In recent years, derivatives of emetine have been synthesized and reported to offer better efficacy against cancer cells along with less toxicity to normal cells (17,18). Moreover, various studies have demonstrated a potent cytotoxic activity of emetine and its biological targets in a variety of human carcinoma cell lines (19–24).…”

Section: Introductionmentioning

confidence: 99%

Emetine exhibits anticancer activity in breast cancer cells as an antagonist of Wnt/β‑catenin signaling

Sun

et al. 2019

Oncol Rep

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Emetine, an amoebicidal drug, exerts potent anticancer activity against various solid tumors, however, the underlying molecular mechanism remains unclear. In the present study, the effects of emetine were investigated on various proteins involved in the Wnt/β-catenin signaling pathway, which has been linked to various human cancers. It was revealed that emetine blocked Wnt/β-catenin signaling by targeting components of this pathway, including the low-density lipoprotein-receptor-related protein 6 (LRP6) and disheveled (DVL). Moreover, nanomolar concentrations of emetine decreased phosphorylation of these proteins and suppressed the expression of Wnt target genes, including fibronectin, frizzled-7 (Fzd7), c-Myc, Nanog and CD133 in MDA-MB-231 and MDA-MB-468 breast cancer cells. Additionally, emetine treatment induced apoptosis and suppressed the viability, migration, invasion, and sphere formation of breast cancer cells. Collectively the present results indicated that emetine antagonizes Wnt/β-catenin signaling, providing insight into the molecular mechanism underlying the anticancer activity of emetine.

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Section: Introductionmentioning

confidence: 99%

Emetine exhibits anticancer activity in breast cancer cells as an antagonist of Wnt/β‑catenin signaling

Sun

et al. 2019

Oncol Rep

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“…Эметин является основным алкалоидом ипекакуаны, или рвотного корня -травянистого растения семейства Мареновых рода Carapichea. Он ингибирует синтез белка в эукариотических клетках путем необратимого блокирования движения рибосом вдоль цепи мРНК за счет ингибирования переноса пептидил тРНК из акцепторного в донорный сайт рибосомы [11]. В недавних исследованиях было показано, что эметин индуцирует апоптоз за счет повышения экспрессии генов проапоптотических факторов (антагонист-киллер Bcl-2 (BAK1), каспаза 8, каспаза 9, ассоциированный с клеточной гибелью белок DAXX, гранзим B (GZMB)) и снижения экспрессии антиапоптотических генов (Bcl-xL, рецептор эпидермального фактора роста (EGFR), фактор некроза опухоли (TNF)) [12,13].…”

Section: Discussionunclassified

Inhibition of Redd1 Expression for the Reduction of Glucocorticoid-Induced Side Effects

Lylova¹,

Savinkova

Zhidkova³

et al. 2020

Sib. onkol. ž.

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Glucocorticoids (GC ) have been an integral component of the treatment of leukemias and lymphomas for several decades. Specific cytotoxic effect of GC on transformed lymphoblasts mediates their use at the stage of the remission induction as well as consolidation of treatment. However, the main problem of the long-term GC use is the development of atrophic and metabolic side effects as well as GC resistance. The biological effects of GC are realized via activation of the glucocorticoid receptor (GR) by two mechanisms: transrepression (TR) associated with the therapeutic effects of GC , and transactivation (TA ), which mediates the development of metabolic and atrophic complications. It was demonstrated that an increase in the expression of the GC - dependent gene REDD1 associated with GC -induced skin, muscle and bone atrophy of the skin, muscle and bone tissue was realized via the induction of transactivation. Therefore, identification of potential inhibitors of REDD1 expression and study of their biological effects in combination with GC in models of leukemia and lymphoma is of particular interest. In our recent study we have selected a number of drugs from the class of PI 3K/Akt/mTO R modulators using bioinformatic screening. These drugs effectively inhibited REDD1 expression, modulated GR activity and shifted it towards transrepression, and prevented the development of GC -induced side effects in mice. Here we aimed to study the effects of potential inhibitors of REDD1 expression from different pharmacological groups, the compounds Emetine and CGP -60474, on leukemia and lymphoma cells in combination with GC . We demonstrated antitumor effect of the compounds in vitro, a decrease in the expression of TA -associated genes and an increase in TR induction. Further studies of the antitumor effects of REDD1 expression inhibitors (Emetine and CGP -60474 is a promising area of research.

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“…Methods for the synthesis and characterization of the FLASH and D-FLASH probes are presented in the Supporting Information. , …”

Section: Methodsmentioning

confidence: 99%

Chemiluminescent Protease Probe for Rapid, Sensitive, and Inexpensive Detection of Live Mycobacterium tuberculosis

et al. 2021

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Tuberculosis (TB) is a top-ten cause of death worldwide. Successful treatment is often limited by insufficient diagnostic capabilities, especially at the point of care in low-resource settings. The ideal diagnostic must be fast, be cheap, and require minimal clinical resources while providing high sensitivity, selectivity, and the ability to differentiate live from dead bacteria. We describe here the development of a fast, luminescent, and affordable sensor of Hip1 (FLASH) for detecting and monitoring drug susceptibility of Mycobacterium tuberculosis ( Mtb ). FLASH is a selective chemiluminescent substrate for the Mtb protease Hip1 that, when processed, produces visible light that can be measured with a high signal-to-noise ratio using inexpensive sensors. FLASH is sensitive to fmol of recombinant Hip1 enzyme in vitro and can detect as few as thousands of Mtb cells in culture or in human sputum samples within minutes. The probe is highly selective for Mtb compared to other nontuberculous mycobacteria and can distinguish live from dead cells. Importantly, FLASH can be used to measure antibiotic killing of Mtb in culture with greatly accelerated timelines compared to traditional protocols. Overall, FLASH has the potential to enhance both TB diagnostics and drug resistance monitoring in resource-limited settings.

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Anticancer activities of emetine prodrugs that are proteolytically activated by the prostate specific antigen (PSA) and evaluation of in vivo toxicity of emetine derivatives

Cited by 17 publications

References 19 publications

Emetine exhibits anticancer activity in breast cancer cells as an antagonist of Wnt/β‑catenin signaling

Emetine exhibits anticancer activity in breast cancer cells as an antagonist of Wnt/β‑catenin signaling

Inhibition of Redd1 Expression for the Reduction of Glucocorticoid-Induced Side Effects

Chemiluminescent Protease Probe for Rapid, Sensitive, and Inexpensive Detection of Live Mycobacterium tuberculosis

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