PMID- 26349827
OWN - NLM
STAT- MEDLINE
DCOM- 20160831
LR  - 20181113
IS  - 1098-6596 (Electronic)
IS  - 0066-4804 (Print)
IS  - 0066-4804 (Linking)
VI  - 59
IP  - 12
DP  - 2015 Dec
TI  - Cyclopalladated Compound 7a Induces Apoptosis- and Autophagy-Like Mechanisms in 
      Paracoccidioides and Is a Candidate for Paracoccidioidomycosis Treatment.
PG  - 7214-23
LID - 10.1128/AAC.00512-15 [doi]
AB  - 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 mug/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 LysoTracker 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.
CI  - Copyright (c) 2015, American Society for Microbiology. All Rights Reserved.
FAU - Arruda, Denise C
AU  - Arruda DC
AD  - Departamento de Microbiologia, Imunologia e Parasitologia, Escola Paulista de 
      Medicina-Universidade Federal de Sao Paulo, EPM-UNIFESP, Sao Paulo, SP, Brazil 
      Nucleo Integrado de Biotecnologia, Universidade de Mogi das Cruzes, UMC, Mogi das 
      Cruzes, SP, Brazil.
FAU - Matsuo, Alisson L
AU  - Matsuo AL
AD  - Departamento de Microbiologia, Imunologia e Parasitologia, Escola Paulista de 
      Medicina-Universidade Federal de Sao Paulo, EPM-UNIFESP, Sao Paulo, SP, Brazil.
FAU - Silva, Luiz S
AU  - Silva LS
AD  - Departamento de Microbiologia, Imunologia e Parasitologia, Escola Paulista de 
      Medicina-Universidade Federal de Sao Paulo, EPM-UNIFESP, Sao Paulo, SP, Brazil.
FAU - Real, Fernando
AU  - Real F
AD  - Departamento de Microbiologia, Imunologia e Parasitologia, Escola Paulista de 
      Medicina-Universidade Federal de Sao Paulo, EPM-UNIFESP, Sao Paulo, SP, Brazil.
FAU - Leitao, Natanael P Jr
AU  - Leitao NP Jr
AD  - Departamento de Microbiologia, Imunologia e Parasitologia, Escola Paulista de 
      Medicina-Universidade Federal de Sao Paulo, EPM-UNIFESP, Sao Paulo, SP, Brazil.
FAU - Pires, Jhon H S
AU  - Pires JH
AD  - Departamento de Microbiologia, Imunologia e Parasitologia, Escola Paulista de 
      Medicina-Universidade Federal de Sao Paulo, EPM-UNIFESP, Sao Paulo, SP, Brazil.
FAU - Caires, Antonio Carlos F
AU  - Caires AC
AD  - Centro Interdisciplinar de Investigacao Bioquimica, Universidade de Mogi das 
      Cruzes, UMC, Mogi das Cruzes, SP, Brazil.
FAU - Garcia, Daniel M
AU  - Garcia DM
AD  - Centro Interdisciplinar de Investigacao Bioquimica, Universidade de Mogi das 
      Cruzes, UMC, Mogi das Cruzes, SP, Brazil.
FAU - Cunha, Fernanda F M
AU  - Cunha FF
AD  - Nucleo Integrado de Biotecnologia, Universidade de Mogi das Cruzes, UMC, Mogi das 
      Cruzes, SP, Brazil.
FAU - Puccia, Rosana
AU  - Puccia R
AD  - Departamento de Microbiologia, Imunologia e Parasitologia, Escola Paulista de 
      Medicina-Universidade Federal de Sao Paulo, EPM-UNIFESP, Sao Paulo, SP, Brazil 
      ropuccia@gmail.com.
FAU - Longo, Larissa V G
AU  - Longo LV
AD  - Departamento de Microbiologia, Imunologia e Parasitologia, Escola Paulista de 
      Medicina-Universidade Federal de Sao Paulo, EPM-UNIFESP, Sao Paulo, SP, Brazil.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150908
PL  - United States
TA  - Antimicrob Agents Chemother
JT  - Antimicrobial agents and chemotherapy
JID - 0315061
RN  - 0 (Antifungal Agents)
RN  - 0 (Chromatin)
RN  - 0 (Fungal Proteins)
RN  - 0 (Organometallic Compounds)
RN  - 11062-77-4 (Superoxides)
RN  - 5TWQ1V240M (Palladium)
RN  - EC 3.4.22.- (Caspases)
RN  - I9N81SC5HD (monodansylcadaverine)
RN  - L90BEN6OLL (Cadaverine)
SB  - IM
MH  - Animals
MH  - Antifungal Agents/chemical synthesis/*pharmacology
MH  - Apoptosis/drug effects
MH  - Autophagy/drug effects
MH  - Cadaverine/analogs & derivatives/biosynthesis
MH  - Candida albicans/drug effects/growth & development
MH  - Caspases/genetics/metabolism
MH  - Chromatin/drug effects/pathology/ultrastructure
MH  - Cryptococcus neoformans/drug effects/growth & development
MH  - DNA Fragmentation/drug effects
MH  - Dose-Response Relationship, Drug
MH  - Fungal Proteins/genetics/metabolism
MH  - Gene Expression
MH  - Lung/drug effects/microbiology/pathology
MH  - Male
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Organometallic Compounds/chemical synthesis/*pharmacology
MH  - Palladium/chemistry/*pharmacology
MH  - Paracoccidioides/*drug effects/genetics/growth & development/ultrastructure
MH  - Paracoccidioidomycosis/*drug therapy/microbiology/pathology
MH  - Superoxides/metabolism
MH  - Vacuoles/drug effects/pathology/ultrastructure
PMC - PMC4649154
EDAT- 2015/09/10 06:00
MHDA- 2016/09/01 06:00
PMCR- 2016/06/01
CRDT- 2015/09/10 06:00
PHST- 2015/03/03 00:00 [received]
PHST- 2015/08/26 00:00 [accepted]
PHST- 2015/09/10 06:00 [entrez]
PHST- 2015/09/10 06:00 [pubmed]
PHST- 2016/09/01 06:00 [medline]
PHST- 2016/06/01 00:00 [pmc-release]
AID - AAC.00512-15 [pii]
AID - 00512-15 [pii]
AID - 10.1128/AAC.00512-15 [doi]
PST - ppublish
SO  - Antimicrob Agents Chemother. 2015 Dec;59(12):7214-23. doi: 10.1128/AAC.00512-15. 
      Epub 2015 Sep 8.