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Estudo mostra promessa na prevenção de doenças cardíacas em sobreviventes de câncer

Um novo estudo realizado por pesquisadores da Washington State University sugere que uma proteína chamada CDK2 desempenha um papel crítico nos danos cardíacos causados ​​pela doxorrubicina, um medicamento quimioterápico comumente usado.

WSU assistant professor Zhaokang Cheng and postdoctoral fellow Peng Xia, l-r, examine bacterial cultures used to grow genes of interest to their research, such as the CDK2 gene. The genes are then isolated and introduced into cardiac muscle cells to study their function.

Using a rodent model, the researchers showed that doxorubicin increases CDK2 activity in cardiac muscle cells, resulting in cell death. O que mais, they demonstrated that suppressing CDK2 levels alleviated damage to cardiac muscle cells following treatment with doxorubicin.

Published in the Journal of Biological Chemistry, their finding could be used as the basis for future development of treatment strategies and drugs to reduce heart disease risk in cancer survivors, especially those treated in childhood.

doenças cardíacas após o tratamento do câncer

As recentes melhorias no diagnóstico e tratamento do câncer têm aumentado as chances de sobrevivência de pacientes com câncer. Nos E.U.A., um estimado 16 million people — or 5 percent of the population — are cancer survivors. Depois de recorrência do cancro, doença cardíaca é a causa número um de morte nesse grupo. toxicidade cardíaca associada com o uso de doxorrubicina e drogas quimioterápicas relacionados é pensado para ser responsável pelo aumento do risco de doença cardíaca desenvolvimento dos sobreviventes de câncer.

“Doxorubicin is very effective at controlling tumor growth, but when used in large cumulative doses it causes damage to cardiac muscle cells that may, ao longo do tempo, lead to heart disease,” said study author Zhaokang Cheng, assistant professor in the WSU College of Pharmacy and Pharmaceutical Sciences.

To better understand how this works at the molecular level, Cheng and his research team looked at cyclin-dependent kinase 2 (CDK2), a protein that is part of a family of more than 20 CDKs that have been implicated in cancer growth.

CDKs are essential proteins in the multiplication and division of different cell types, especially during development. As tumors grow, cancer cells show increased levels of CDK activity, whereas cardiac muscle cells — which do not regenerate in adults — show low levels of CDK.

CDK levels in cancer vs. heart muscle cells

As part of their study, the research team exposed a group of mice to doxorubicin and observed its effects on cardiac muscle cells and levels of CDK2 in those cells, as compared to control mice. Os ratos que receberam a doxorrubicina mostraram um aumento da morte de células do músculo cardíaco e a actividade de CDK2 elevada em células do músculo cardíaco, que veio como uma surpresa.

“Sabe-se que a quimioterapia diminui a actividade da CDK em células cancerosas e que esta está envolvida na paragem do crescimento tumoral,”Cheng disse. “Curiosamente, Apesar, quando olhamos para os níveis de CDK no coração, aumento da actividade de CDK quimioterapia, que era o oposto do que os cientistas pensavam “.

Em outras palavras, while doxorubicin causes cancer cells to Parecrescendo, it appears to make cardiac muscle cells start crescendo. Since doxorubicin kills cancer cells by causing DNA damage, Cheng suggests that damaged DNA in multiplying cardiac muscle cells eventually causes those cells to stop replicating and die, weakening the heart. He said that could also explain why children — whose hearts are still growing — are more sensitive to heart toxicity from chemotherapy treatment.

CDK inhibitor to reduce heart toxicity

Próximo, os pesquisadores analisaram para ver se inibir CDK2 poderia parar o crescimento das células cardíacas e proteger o coração contra os danos induzidos pela doxorrubicina. They treated a group of mice with both doxorubicin and roscovitine — an immunosuppressive substance that selectively inhibits CDK2 — and found that heart function in those mice was preserved. Os mesmos resultados também foram confirmados em células do coração de ratos.

The study shows early promise that CDK inhibitor drugs could be used to stave off heart toxicity in patients being treated with doxorubicin.

CDK inhibitors are a newer class of anticancer drugs. Only three such drugs — palbociclib, ribociclib and abemaciclib — are currently FDA-approved for the treatment of different types of breast cancers, while another dozen or so are being tested in clinical trials.

“Our findings suggest that combining doxorubicin with a CDK inhibitor could be a viable strategy for protecting patients’ hearts while they are being treated for cancer,”Cheng disse. “It could provide a much stronger anticancer effect with less toxicity to the heart.”

Continued research

The WSU research team plans to do further research to identify the molecular pathways involved in doxorubicin-induced activation of CDK2 and its subsequent harmful effect on cardiac muscle cells. Their ultimate goal is to determine whether a currently available CDK inhibitor could be used or whether they could develop a new, better CDK inhibitor designed specifically to be used as a heart-protective drug during chemotherapy.

Funding for their published study came from a five‑year grant from the National Heart, Lung and Blood Institute — a component of the National Institutes of Health — along with internal funding provided by the WSU College of Pharmacy and Pharmaceutical Sciences.


Fonte: news.wsu.edu, by Judith Van Dongen

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