Pharmacologic effects on mitochondrial function

Cohen, Bruce H.

doi:10.1002/ddrr.106

Cited by 43 publications

(45 citation statements)

References 101 publications

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“…Once imported in mammalian cells, a putative target of PA–CAM conjugates would be the mitochondrion, due to its highly negative membrane potential. As previously detected, destabilization of mitochondrial membranes and/or inhibition of mitochondrial protein synthesis may promote release of organelle's components and/or ROS generation, leading to apoptosis (26) or autophagy (65,66). In fact, CAM itself is a well-documented example of a drug that inhibits both bacterial and mitochondrial translation (20).…”

Section: Discussionmentioning

confidence: 82%

Conjugation with polyamines enhances the antibacterial and anticancer activity of chloramphenicol

et al. 2014

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Chloramphenicol (CAM) is a broad-spectrum antibiotic, limited to occasional only use in developed countries because of its potential toxicity. To explore the influence of polyamines on the uptake and activity of CAM into cells, a series of polyamine–CAM conjugates were synthesized. Both polyamine architecture and the position of CAM-scaffold substitution were crucial in augmenting the antibacterial and anticancer potency of the synthesized conjugates. Compounds 4 and 5, prepared by replacement of dichloro-acetyl group of CAM with succinic acid attached to N4 and N1 positions of N8,N8-dibenzylspermidine, respectively, exhibited higher activity than CAM in inhibiting the puromycin reaction in a bacterial cell-free system. Kinetic and footprinting analysis revealed that whereas the CAM-scaffold preserved its role in competing with the binding of aminoacyl-tRNA 3′-terminus to ribosomal A-site, the polyamine-tail could interfere with the rotatory motion of aminoacyl-tRNA 3′-terminus toward the P-site. Compared to CAM, compounds 4 and 5 exhibited comparable or improved antibacterial activity, particularly against CAM-resistant strains. Compound 4 also possessed enhanced toxicity against human cancer cells, and lower toxicity against healthy human cells. Thus, the designed conjugates proved to be suitable tools in investigating the ribosomal catalytic center plasticity and some of them exhibited greater efficacy than CAM itself.

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Section: Discussionmentioning

confidence: 82%

Conjugation with polyamines enhances the antibacterial and anticancer activity of chloramphenicol

et al. 2014

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“…This opened up investigations into alternate mechanisms of mt toxicity. Other proposed targets of NRTI toxicity include ATP synthesis, mt biogenesis, depleted native nucleotide pools, transcription of mtDNA, mt membrane integrity and transport and protein synthesis [Setzer et al, 2008;Cohen, 2010].…”

mentioning

confidence: 99%

Mitochondrial and Oxidative Stress Response in HepG2 Cells Following Acute and Prolonged Exposure to Antiretroviral Drugs

Nagiah

Phulukdaree

Chuturgoon

2015

J of Cellular Biochemistry

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Chronic HIV treatment with antiretroviral drugs has been associated with adverse health outcomes. Mitochondrial toxicity exhibited by nucleoside reverse transcriptase inhibitors (NRTIs) is pinpointed as a molecular mechanism of toxicity. This study evaluated the effect of NRTIs: Zidovudine (AZT, 7.1 μM), Stavudine (d4T, 4 μM) and Tenofovir (TFV, 1.2 μM), on mitochondrial (mt) stress response, mtDNA integrity and oxidative stress response in human hepatoma cells at 24 and 120 h. Markers for mt function, mt biogenesis, oxidative stress parameters, and antioxidant response were evaluated by spectrophotometry, luminometry, flow cytometry, qPCR and western blots. We found that AZT and d4T reduced mtDNA integrity (120 h, AZT: 76.1%; d4T:36.1%, P < 0.05) and remained unchanged with TFV. All three NRTIs, however, reduced ATP levels (AZT: 38%; d4T: 56.4%; TFV: 27.4%, P = 0.01) and mt membrane potential at 120 h (P < 0.005). Oxidative damage and reactive oxygen species (ROS) were increased by TFV and AZT at 24 h, and by d4T at 120 h (P < 0.05). Antioxidant response molecules and mt biogenesis markers were elevated by all NRTIs, with TFV causing the most significant increase (P < 0.05). Data from this study suggest that AZT, d4T and TFV alter mt function. TFV, however, achieves this independently of mtDNA depletion. Furthermore, AZT exerts toxicity soon after exposure as noted from changes at 24 h and d4T exerts greater toxicity over prolonged exposure (120 h).

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“…[23][24][25] Histopathologically, such exposures are associated with long-term disruption of mitochondrial morphogenesis that is reflected by enlarged and deranged mitochondria with highly fragmented cristae and limiting inner membranes. 26 Each of these drug classes has been shown to disrupt mitochondrial oxidative phosphorylation in vitro 5,7 and thus has the potential of interfering with the synchronous timing for the stimulation of mitochondrial bioenergetics to meet the increased energy demands associated with synaptogenesis during this critical period of neurodevelopment. [15][16][17]27 Although mitochondria are distributed through the neuron, they tend to aggregate in compartments of greatest energetic demands, such as the growth cone of the developing neuron and at synaptic termini, [28][29][30] further accentuating the importance of mitochondrial disease in synaptogenesis of the developing brain.…”

Section: Mitochondrial Toxicity and The Developing Brainmentioning

confidence: 99%

Drug-Induced Mitochondrial Neuropathy in Children

Wallace

2014

J Child Neurol

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Mitochondrial disease arises from genetic or nongenetic events that interfere either directly or indirectly with the bioenergetic function of the mitochondrion and manifest clinically in some form of metabolic disorder. In primary mitochondrial disease, the critical molecular target is one or more of the individual subunits of the respiratory complexes or their assembly and incorporation into the inner mitochondrial membrane, whereas with secondary mitochondrial disease the bioenergetic deficits are secondary to effects on targets other than the electron transport chain and oxidative phosphorylation. Primary genetic events include mutations to or altered expression of proteins targeted to the mitochondrial compartment, whether they are encoded by the nuclear or mitochondrial genome. In this review, we emphasize the occurrence of nongenetic mitochondrial disease resulting from therapeutic drug administration, review the broad scope of drugs implicated in affecting specific primary mitochondrial targets, and describe evidence demonstrating critical windows of risk for the developing neonate to drug-induced mitochondrial disease and neuropathy.

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Pharmacologic effects on mitochondrial function

Cited by 43 publications

References 101 publications

Conjugation with polyamines enhances the antibacterial and anticancer activity of chloramphenicol

Conjugation with polyamines enhances the antibacterial and anticancer activity of chloramphenicol

Mitochondrial and Oxidative Stress Response in HepG2 Cells Following Acute and Prolonged Exposure to Antiretroviral Drugs

Drug-Induced Mitochondrial Neuropathy in Children

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