Mitochondria as a pharmacological target: Magnum overview

Olszewska, Anna; Szewczyk, Adam

doi:10.1002/iub.1147

Cited by 64 publications

(40 citation statements)

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“…Here, we propose that epoxy-␣-lapachone is able to act in any metabolic pathway by compromising the ⌬ m of intracellular (primarily mitochondrial) organelles, as revealed by reductions in TMRE staining. The collapse of the mitochondrial transmembrane potential is related to the opening of mitochondrial permeability pores, leading to the release of cytochrome c into the cytosol, which then leads to other events in the apoptotic cascade (39).…”

Section: Discussionmentioning

confidence: 99%

Epoxy-α-Lapachone Has In Vitro and In Vivo Anti-Leishmania (Leishmania) amazonensis Effects and Inhibits Serine Proteinase Activity in This Parasite

Souza-Silva

Bourguignon

Pereira

et al. 2015

Antimicrob Agents Chemother

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Leishmania (Leishmania) amazonensis is a protozoan that causes infections with a broad spectrum of clinical manifestations. The currently available chemotherapeutic treatments present many problems, such as several adverse side effects and the development of resistant strains. Natural compounds have been investigated as potential antileishmanial agents, and the effects of epoxy-␣-lapachone on L. (L.) amazonensis were analyzed in the present study. This compound was able to cause measurable effects on promastigote and amastigote forms of the parasite, affecting plasma membrane organization and leading to death after 3 h of exposure. This compound also had an effect in experimentally infected BALB/c mice, causing reductions in paw lesions 6 weeks after treatment with 0.44 mM epoxy-␣-lapachone (mean lesion area, 24.9 ؎ 2.0 mm 2 ), compared to untreated animals (mean lesion area, 30.8 ؎ 2.6 mm 2 ) or animals treated with Glucantime (mean lesion area, 28.3 ؎ 1.5 mm 2 ). In addition, the effects of this compound on the serine proteinase activities of the parasite were evaluated. Serine proteinase-enriched fractions were extracted from both promastigotes and amastigotes and were shown to act on specific serine proteinase substrates and to be sensitive to classic serine proteinase inhibitors (phenylmethylsulfonyl fluoride, aprotinin, and antipain). These fractions were also affected by epoxy-␣-lapachone. Furthermore, in silico simulations indicated that epoxy-␣-lapachone can bind to oligopeptidase B (OPB) of L. (L.) amazonensis, a serine proteinase, in a manner similar to that of antipain, interacting with an S1 binding site. This evidence suggests that OPB may be a potential target for epoxy-␣-lapachone and, as such, may be related to the compound's effects on the parasite.

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Section: Discussionmentioning

confidence: 99%

Epoxy-α-Lapachone Has In Vitro and In Vivo Anti-Leishmania (Leishmania) amazonensis Effects and Inhibits Serine Proteinase Activity in This Parasite

Souza-Silva

Bourguignon

Pereira

et al. 2015

Antimicrob Agents Chemother

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“…Mitochondrial therapies, particularly those involving mitochondria-targeted antioxidants, have been considered to be effective in treating cancer7, 35. In this study, a TPP carrier was used to target HCAs to mitochondria.…”

Section: Discussionmentioning

confidence: 99%

Synthesis of hydroxycinnamic acid derivatives as mitochondria-targeted antioxidants and cytotoxic agents

Wang

et al. 2017

Acta Pharmaceutica Sinica B

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In order to develop agents with superior chemopreventive and chemotherapeutic properties against hepatocellular carcinomas, mitochondria-targeted hydroxycinnamic acids (MitoHCAs) were synthesized by conjugation with a triphenylphosphonium cation. These synthetic compounds were evaluated for their antioxidant activities in hepatic mitochondria, including against OH∙− and ROO∙− induced lipid peroxidation. H2O2 production was decreased significantly by increasing glutathione peroxidase and catalase activities. In addition, cell proliferation data from three cell lines (HepG2, L02 and WI38) indicated that the MitoHCAs were selective for cancer cells. Interestingly, the MitoHCAs both with or without Ca2+ triggered mitochondrial dysfunction by inducing mitochondrial swelling, collapsing the mitochondrial membrane potential and causing cytochrome c release. In particular, an inhibitor of the mitochondrial permeability transition pore (mPTP), cyclosporin A, attenuated mitochondrial damage and cell apoptosis, indicating that mPTP may be involved in the antiproliferative activity of MitoHCAs. Further studies focused on structural optimization of these compounds are onging.

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“…The only noncoding region of mtDNA is a small regulatory region (∼5% of the genome) with critical elements for transcription (promoters for both strands) and replication (origin of replication). Because mtDNA is essential for mitochondria (Chinnery and Hudson, 2013), its targeting with drugs offers potential for new therapeutics, as well as molecular tools to study mtDNA homeostasis and their effects on mitochondria (Rowe et al, 2001;Neuzil et al, 2013;Olszewska and Szewczyk, 2013).…”

Section: Introductionmentioning

confidence: 99%