Intracellular ROS Generation Mediates Maleimide-induced Cytotoxicity in Leukemia Cells

ISSN: 1875-5992 (Online)
ISSN: 1871-5206 (Print)


Volume 16, 12 Issues, 2016


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Anti-Cancer Agents in Medicinal Chemistry

Formerly: Current Medicinal Chemistry - Anti-Cancer Agents

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  • 27th of 59 in Chemistry, Medicinal

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Editor-in-Chief:
Michelle Prudhomme
Universite Blaise Pascal - C.N.R.S
Aubiere Cedex
France


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Intracellular ROS Generation Mediates Maleimide-induced Cytotoxicity in Leukemia Cells



Anti-Cancer Agents in Medicinal Chemistry, 15(9): 1164-1173.

Author(s): Daiane Rosolen, Vania F. Noldin, Evelyn Winter, Fabiola B. Filippin-Monteiro, Fatima Campos-Buzzi, Valdir Cechinel-Filho and Tania B Creczynski-Pasa.

Affiliation: Departamento de Ciencias Farmaceuticas, Centro de Ciencias da Saude, Universidade Federal de Santa Catarina, 88040-900, CP 476 Florianopolis, SC, Brazil.

Abstract

Maleimides consist of an important class of compounds easily synthesized with multiple functional group modification that provides expressive pharmacological properties including, antitumoral activity, mediated mainly by oxidative stress. For this reason, the present study was designed to evaluate the cytotoxicity and the role of reactive oxygen species (ROS) in maleimide-induced cell death. Cell viability assays were performed to determine the cell death type in leukemia cell line induced by the compounds. The oxidative stress in maleimidetreated cells was characterized by antioxidant enzymes activities, intracellular ROS generation, and lipid peroxidation. In addition, we evaluated mitochondrial membrane potential and ATP level. Maleimide derivatives exhibited cytotoxic effects in leukemia cells with significantly increased ROS generation. However, cell viability was partly restored by catalase-treated cells. Caspases activities and caspase-independent key genes related to apoptosis were not altered by maleimides, suggesting necrosis as the main cell death process. Maleimide-induced necrosis was associated with oxidative stress, as an imbalance between ROS levels and glutathione reductase (GR) activity. This damage was also demonstrated by loss of mitochondrial membrane potential (MMP) and ATP depletion in cells treated with maleimide derivatives. These findings strongly confirmed that maleimide derivatives promoted cell death in leukemia cells triggered by oxidative stress, indicating that these compounds might be promising antitumor agents or lead molecules.




Keywords:

Cytotocixity, leukemia, maleimides, mitochondrial membrane potential, necrosis, ROS generation.



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Article Details

Volume: 15
Issue Number: 9
First Page: 1164
Last Page: 1173
Page Count: 10
DOI: 10.2174/1871520615666150629102158
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