Synthesis, molecular docking, and biological activity of thioether derived from juglone in preclinical models of chronic myeloid leukemia

Portilho, Adrhyann Jullyanne de Sousa; Gomes, Carinne B. S. M. R.; Moreira, Caroline S.; Forezi, Luana da S. M.; Cordeiro, Pâmella; Nascimento, Vanessa; Daniel, Julio Paulino; Vasconcellos, Marne Carvalho de; Moraes, Maria Elisabete Amaral de; Moreira-Nunes, Caroline Aquino; Ferreira, Vı́tor F.; Montenegro, Raquel Carvalho; Rocha, David R. da

doi:10.1016/j.comtox.2021.100197

Cited by 1 publication

(6 citation statements)

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“…Our previous study showed that CNN1 is more potent to resistance cell lines FEPS (IC50 0.60 µM) and K-562-Lucena-1 (IC50 0.90 µM) when compared to a parental sensitive cell line K-562 (IC50 1.12 µM) [ 28 ]. Moreover, it was observed that CNN1 is less toxic to normal human cells such as fibroblasts (IC50 15.34 µM) when compared to leukemia cell lines.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, CNN1 showed a possible preferential genotoxic effect against K-562 and FEPS cells and did not cause significant DNA damage in peripheral blood mononuclear cells (PBMC). Data from previous work by our group showed that CNN1 reduced TOP1 expression levels in both leukemia cell lines [ 28 ]. Thus, this evidence suggests that suppression of TOP1 expression can be correlated with a genomic damage induced by CNN1 [ 53 ].…”

Section: Discussionmentioning

confidence: 99%

“…Stock solution of CNN1 (1mM) was dissolved in DMSO (0.02%) from Sigma ® , and Imatinib Mesylate (IM) (1mM) were used as a positive controls. In other studies conducted by our group, CNN1 demonstrated cytotoxic activity against K-562, K-562-Lucena1 and FEPS cells after 72 h. The concentration of CNN1 (0.1 µM) used in tests was based in CI50 determined before [ 28 ].…”

Section: Methodsmentioning

confidence: 99%

“…In the case of K-562-Lucena-1 and FEPS, the medium was maintained with vincristine sulfate at a final concentration of 60 nM and daunorubicin at a concentration of 466 nM, respectively. The following experiments were performed only in K-562 and FEPS cell lines based in previous study [ 28 ].…”

Section: Methodsmentioning

confidence: 99%

“…Although a great number of naphthoquinones have been studied in medicinal chemistry, as they possess several pharmacologic properties, these compounds have drawn attention especially for their antitumor activity [ 24 ]. In addition, the naphthoquinones are potent inhibitors of topoisomerase, DNA repair enzymes, and can also induce DNA damage [ 25 , 26 , 27 , 28 ].…”

Section: Introductionmentioning

confidence: 99%

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1,4-Naphthoquinone (CNN1) Induces Apoptosis through DNA Damage and Promotes Upregulation of H2AFX in Leukemia Multidrug Resistant Cell Line

Portilho

Silva

Bezerra

et al. 2022

IJMS

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The multidrug resistance (MDR) phenotype is one of the major obstacles in the treatment of chronic myeloid leukemia (CML) in advantage stages such as blast crisis. In this scenario, more patients develop resistance mechanisms during the course of the disease, making tyrosine kinase inhibitors (TKIs) target therapies ineffective. Therefore, the aim of the study was to examine the pharmacological role of CNN1, a para-naphthoquinone, in a leukemia multidrug resistant cell line. First, the in vitro cytotoxic activity of Imatinib Mesylate (IM) in K-562 and FEPS cell lines was evaluated. Subsequently, membrane integrity and mitochondrial membrane potential assays were performed to assess the cytotoxic effects of CNN1 in K-562 and FEPS cell lines, followed by cell cycle, alkaline comet assay and annexin V-Alexa Fluor® 488/propidium iodide assays (Annexin/PI) using flow cytometry. RT-qPCR was used to evaluate the H2AFX gene expression. The results demonstrate that CNN1 was able to induce apoptosis, cell membrane rupture and mitochondrial membrane depolarization in leukemia cell lines. In addition, CNN1 also induced genotoxic effects and caused DNA fragmentation, cell cycle arrest at the G2/M phase in leukemia cells. No genotoxicity was observed on peripheral blood mononuclear cells (PBMC). Additionally, CNN1 increased mRNA levels of H2AFX. Therefore, CNN1 presented anticancer properties against leukemia multidrug resistant cell line being a potential anticancer agent for the treatment of resistant CML.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%