Apoptotic Events Induced by Maleimides on Human Acute Leukemia Cell Lines

Abstract

Cyclic imides are known for their antitumor activity, especially the naphthalimide derivatives, such as Mitonafide and Amonafide. Recently, we have demonstrated the cytotoxic effect of a series of naphthalimide derivatives against B16F10 melanoma cells. On the basis of this fact, we have developed a study starting from the synthesis of different cyclic imides and the evaluation of their cytotoxic properties on human acute leukemia cells (K562 and Jurkat). Initially, a screening test was conducted to select the compound with the best cytotoxic effect, using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. After this selection, structural modifications were performed in the most active compound to obtain five more derivatives. All compounds presented a good cytotoxic effect. The results of cell cycle analysis, fluorescence microscopy, and Annexin V-FITC assay confirmed that the cells observed in the sub-G0/G1 phase were undergoing apoptosis. From this set of results, cyclic imides 8, 10, and 12 were selected for the evaluation of the mechanisms involved in the apoptotic process. The results demonstrate the involvement of the intrinsic pathway of apoptosis, evidenced by the reduction in mitochondrial potential, an increase in the level of AIF protein expression, a decreased level of expression of anti-apoptotic Bcl-2 protein, and an increased level of expression of pro-apoptotic protein Bax in both K562 and Jurkat cells treated with cyclic imides (8, 10, and 12). Furthermore, cyclic imides 8 and 10 caused an increase in the level of Fas expression in Jurkat cells, indicating the additional involvement of the extrinsic apoptosis pathway. The compounds (8, 10, and 12) also caused a decreased level of expression of anti-apoptotic protein survivin. The biological effects observed with these cyclic imide derivatives in this study suggest promising applications against acute leukemia.

New Thalidomide-Resembling Dicarboximides Target ABC50 Protein and Show Antileukemic and Immunomodulatory Activities

“…It was demonstrated that naphthalimides and maleimides activated the mitochondrial apoptotic pathway by changing the mitochondrial potential, increasing the level of the AIF and pro-apoptotic Bax proteins, and decreasing the level of anti-apoptotic proteins Bcl-2 and survivin [10,24]. On the other hand, maleimides activated the receptor apoptotic pathway by increasing the level of the membrane Fas receptor in Jurkat cells [25]. The profiles of gene expression (Figure 4) were similar to control experiment, where the cells were treated with staurosporine.…”

Cytotoxicity of piano‐stool ruthenium cyclopentadienyl complexes bearing different imidato ligands

“…For example, it was shown that maleimides presented a good cytotoxic effect on human acute leukemia cells—K562 and Jurkat. [ 37 ] The results of cell cycle analysis, fluorescence microscopy, and Annexin V‐FITC assay confirmed that the cells were undergoing apoptosis after incubation with these compounds. The apoptosis induced by maleimides involved the intrinsic pathway, which was evidenced by the increased level of expression of pro‐apoptotic proteins Bax and AIF and the decreased level of expression of anti‐apoptotic protein Bcl‐2, and the extrinsic pathway only for Jurkat cells, evidenced by the increased level of expression of Fas.…”

“…Some of these maleimides also caused a decrease in the level of expression of anti‐apoptotic protein survivin. [ 37 ] Moreover, the cytotoxic effect of 9‐ING‐41, a maleimide‐based ATP‐competitive small molecule glycogen synthase kinase‐3β (GSK‐3β) inhibitor, is well known. [ 15,16 ] Treatment with 9‐ING‐41 has shown antitumor effects in different human cancers, like neuroblastoma, B‐cell lymphoma, glioblastoma, ovarian, pancreatic, renal, and breast cancer.…”

Antibacterial Mechanism of N-PMI and the Characteristics of PMMA-co-N-PMI Copolymer

“…The research results of Natalia S. et al [24] showed that N-substituted maleimides affected biosynthesis of chitin and β (1,3) glucan, components of the fungal cell wall. Furthermore, Karina [25] believed that N-PMI could trigger the apoptosis of erythrocyte, tumor cells, etc. and showed obviously the characteristic behaviors of apoptosis via ow cytometry, uorescene microscopy and Annexin V-FITC assay.…”