ZIM, a Norbornene Derived from 4-Aminoantipyrine, Induces DNA Damage and Cell Death but in Association Reduces the Effect of Commercial Chemotherapeutics
Year: 2022
Type: article
Abstract: Cancer incidence is increasing, and the drugs are not very selective. These drugs cause adverse effects, and the cells become resistant. Therefore, new drugs are needed. Here, we evaluated the effects of ZIM, a candidate for chemotherapy, and 4-AA alone and in association with commercial chemotherapeutic agents. Subsequently, the results of ZIM and 4-AA were compared. Male Swiss mice were treated with doses of 12, 24, or 48 mg/kg ZIM or 4-AA alone or in association with cisplatin (6 mg/kg), doxorubicin (16 mg/kg), and cyclophosphamide (100 mg/kg). Biometric parameters, DNA damage (comet and micronuclei), cell death, and splenic phagocytosis were evaluated. DNA docking was also performed to confirm the possible interactions of ZIM and 4-AA with DNA. 4-AA has been shown to have low genotoxic potential, increase the frequency of cell death, and activate phagocytosis. ZIM causes genomic and chromosomal damage in addition to causing cell death and activating phagocytosis. In association with chemotherapeutical agents, both 4-AA and ZIM have a chemopreventive effect and, therefore, reduce the frequency of DNA damage, cell death, and splenic phagocytosis. The association of 4-AA and ZIM with commercial chemotherapeutic agents increased the frequency of lymphocytes compared to chemotherapeutic agents alone. Molecular docking demonstrated that ZIM has more affinity for DNA than 4-AA and its precursors ( 1 and 2 ). This was confirmed by the lower interaction energy of the complex (−119.83 kcal/mol). ZIM can break the DNA molecule and, therefore, its chemotherapeutic effect can be related to DNA damage. It is considered that ZIM has chemotherapeutic potential. However, it should not be used in combination with cisplatin, doxorubicin, and cyclophosphamide as it reduces the effects of these drugs.
Source: Chemical Research in Toxicology
Authors: Rodrigo Juliano Oliveira, Ingridhy Ostaciana Maia Freitas da Silveira, Silvia C. das Neves, Barbara Mitsuyasu, Allana C. Martins, Claudia Berno, Jiyan Mohammad, Halie Raj, Flavio H. S. de Araujo, Cristiane Regina Hortelan, Luana Machado, Eufrânio N. da Silva Júnior, Marcelo L. B. Vilela, Valter Aragão Nascimento, Adilson Beatriz, Roberto da Silva Gomes
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: green
Funders: North Dakota State University, North Dakota Established Program to Stimulate Competitive Research, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Conselho Nacional de Desenvolvimento Científico e Tecnológico, Fundação de Amparo à Pesquisa do Estado de Minas Gerais, Fundação de Amparo à Pesquisa e Inovação do Estado de Santa Catarina, National Institute of General Medical Sciences
Awards: REDE DE PESQUISA E INOVAÇÃO PARA BIOENGENHARIA DE NANOSSISTEMAS, G5675663293, ATIVAÇÃO DE LIGAÇÃO C-H VIA CATÁLISE COM METAIS DE TRANSIÇÃO VISANDO FUNCIONALIZAÇÃO SELETIVA DE SISTEMAS QUINOIDAIS BIOATIVOS E HETEROCÍCLICOS FLUORESCENTES, G7311875959, G7414360154, G800717484, Center for Diagnostic and Therapeutic Strategies in Pancreatic Cancer, G926193026
OpenAlex ID: W4312091566