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Cyclopalladated Compound 7a Induces Apoptosis- and Autophagy-Like Mechanisms in Paracoccidioides and Is a Candidate for Paracoccidioidomycosis Treatment

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Arruda, Denise C. [1, 2] ; Matsuo, Alisson L. [1] ; Silva, Luiz S. [1] ; Real, Fernando [1] ; Leitao, Jr., Natanael P. [1] ; Pires, Jhon H. S. [1] ; Caires, Antonio Carlos F. [3] ; Garcia, Daniel M. [3] ; Cunha, Fernanda F. M. [2] ; Puccia, Rosana [1] ; Longo, Larissa V. G. [1]
Número total de Autores: 11
Afiliação do(s) autor(es):
[1] Univ Fed Sao Paulo, EPM UNIFESP, Escola Paulista Med, Dept Microbiol Imunol & Parasitol, Sao Paulo - Brazil
[2] Univ Mogi das Cruzes, Nucleo Integrado Biotecnol, Mogi Das Cruzes, SP - Brazil
[3] Univ Mogi das Cruzes, Ctr Interdisciplinar Invest Bioquim, Mogi Das Cruzes, SP - Brazil
Número total de Afiliações: 3
Tipo de documento: Artigo Científico
Fonte: Antimicrobial Agents and Chemotherapy; v. 59, n. 12, p. 7214-7223, DEC 2015.
Citações Web of Science: 4
Assunto(s):Apoptose   Paracoccidioidomicose   Paracoccidioides   Saccharomyces cerevisiae

Paracoccidioidomycosis (PCM), caused by Paracoccidioides species, is the main cause of death due to systemic mycoses in Brazil and other Latin American countries. Therapeutic options for PCM and other systemic mycoses are limited and time-consuming, and there are high rates of noncompliance, relapses, toxic side effects, and sequelae. Previous work has shown that the cyclopalladated 7a compound is effective in treating several kinds of cancer and parasitic Chagas disease without significant toxicity in animals. Here we show that cyclopalladated 7a inhibited the in vitro growth of Paracoccidioides lutzii Pb01 and P. brasiliensis isolates Pb18 (highly virulent), Pb2, Pb3, and Pb4 (less virulent) in a dose-response manner. Pb18 was the most resistant. Opportunistic Candida albicans and Cryptococcus neoformans were also sensitive. BALB/c mice showed significantly lighter lung fungal burdens when treated twice a day for 20 days with a low cyclopalladated 7a dose of 30 mu g/ml/day for 30 days after intratracheal infection with Pb18. Electron microscopy images suggested that apoptosis-and autophagy-like mechanisms are involved in the fungal killing mechanism of cyclopalladated 7a. Pb18 yeast cells incubated with the 7a compound showed remarkable chromatin condensation, DNA degradation, superoxide anion production, and increased metacaspase activity suggestive of apoptosis. Autophagy-related killing mechanisms were suggested by increased autophagic vacuole numbers and acidification, as indicated by an increase in Lyso Tracker and monodansylcadaverine (MDC) staining in cyclopalladated 7a-treated Pb18 yeast cells. Considering that cyclopalladated 7a is highly tolerated in vivo and affects yeast fungal growth through general apoptosis- and autophagy-like mechanisms, it is a novel promising drug for the treatment of PCM and other mycoses. (AU)

Processo FAPESP: 08/51256-7 - Peptídeos e derivados baseados na estrutura de CDRs de imunoglobulinas: atividade anti-tumoral de mAbc C7 H2 e MAb hua L1 anti-melanoma (b16f-10-nex2 e melanoma humano) e anti-leucemia (HL-60) in vitro e in vivo e possíveis mecanismos de ação
Beneficiário:Denise Costa Arruda
Linha de fomento: Bolsas no Brasil - Pós-Doutorado