The therapeutic potential of mitochondrial toxins

Kawada, Manabu; Amemiya, Masahide; Yoshida, Junjiro; Ohishi, Tomokazu

doi:10.1038/s41429-021-00436-z

Cited by 4 publications

(4 citation statements)

References 76 publications

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“…Several complex I inhibitors have been evaluated clinically and discontinued due to neurotoxicity and adverse side effects (IACS-010759, Tamoxifen, Piericidin A, Phenformin) 70,71 . MitoQ was found to induce mitochondrial damage in mice kidney cortex tissue 72 , although the concentrations used were much higher than typical dosage in cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Oxphos Targeting of Mycn-Amplified Neuroblastoma

Epp,

Egan,

Poon

et al. 2024

Preprint

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Abstract/SummaryHigh risk - neuroblastoma (HR-NB) is a pediatric solid tumor with high lethality. Half of HR-NB are driven by MYCN gene amplification (MNA). These HR-NBs require high dosage chemotherapy and often relapse. Moreover, current therapies can cause severe long-term side effects and new therapies are urgently needed. This study investigates a novel therapeutic approach targeting the metabolic vulnerabilities of MNA NB cells. We discovered that Diphenyleneiodonium chloride (DPI), an inhibitor of flavoprotein enzymes and mitochondrial complex I, synergizes with mitoquinone mesylate (MitoQ), a mitochondria-targeted antioxidant in 2D and 3Din vitromodels of NB. Similarly to DPI, MitoQ affects MNA cells in a MYCN-dependent way, being more toxic when MYCN levels are high. Furthermore, low nanomolar concentrations of MitoQ significantly decrease MYCN protein expression and induce differentiation of MNA cells. The DPI and MitoQ combination further synergizes with vincristine, a chemotherapeutic agent used in NB treatment. Phosphoproteomics and proteomics analysis suggests that the drug combination induces MNA NB cell death by arresting the cell cycle and inhibiting oxidative phosphorylation (OXPHOS) in the mitochondria. Thus, interference with mitochondrial metabolism may represent an effective strategy to enhance the activity of chemotherapeutic drugs in MNA-NB.

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Section: Discussionmentioning

confidence: 99%

Oxphos Targeting of Mycn-Amplified Neuroblastoma

Epp,

Egan,

Poon

et al. 2024

Preprint

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“…Finally, STA is suggested to represent a potent mitochondrial toxin, consistent with its non-selective bioactivity. Such toxins should rather be eliminated from herbicide screening; however, some of them are potential antitumor agents [82,83].…”

Section: Mechanism Of Action Hypothesesmentioning

confidence: 99%

Effects of Phytotoxic Nonenolides, Stagonolide A and Herbarumin I, on Physiological and Biochemical Processes in Leaves and Roots of Sensitive Plants

Tyutereva

Dalinova

Demchenko

et al. 2023

Toxins

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Phytotoxic macrolides attract attention as prototypes of new herbicides. However, their mechanisms of action (MOA) on plants have not yet been elucidated. This study addresses the effects of two ten-membered lactones, stagonolide A (STA) and herbarumin I (HBI) produced by the fungus Stagonospora cirsii, on Cirsium arvense, Arabidopsis thaliana and Allium cepa. Bioassay of STA and HBI on punctured leaf discs of C. arvense and A. thaliana was conducted at a concentration of 2 mg/mL to evaluate phenotypic responses, the content of pigments, electrolyte leakage from leaf discs, the level of reactive oxygen species, Hill reaction rate, and the relative rise in chlorophyll a fluorescence. The toxin treatments resulted in necrotic and bleached leaf lesions in the dark and in the light, respectively. In the light, HBI treatment caused the drop of carotenoids content in leaves on both plants. The electrolyte leakage caused by HBI was light-dependent, in contrast with that caused by STA. Both compounds induced light-independent peroxide generation in leaf cells but did not affect photosynthesis 6 h after treatment. STA (10 µg/mL) caused strong disorders in root cells of A. thaliana leading to the complete dissipation of the mitochondrial membrane potential one hour post treatment, as well as DNA fragmentation and disappearance of acidic vesicles in the division zone after 8 h; the effects of HBI (50 µg/mL) were much milder. Furthermore, STA was found to inhibit mitosis but did not affect the cytoskeleton in cells of root tips of A. cepa and C. arvense, respectively. Finally, STA was supposed to inhibit the intracellular vesicular traffic from the endoplasmic reticulum to the Golgi apparatus, thus interfering with mitosis. HBI is likely to have another main MOA, probably inhibiting the biosynthesis of carotenoids.

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“…Considering the HER2 molecular target, MUB has reached phase I clinical trials for solid tumor treatment. 13 The pharmacological drug effects upon entering the human body are necessary evidence for the regulatory approval process. 14 However, the bioavailability of MUB still needs to be clarified, highlighting the role of intermolecular drug−biomacromolecule interactions under these circumstances.…”

Section: ■ Introductionmentioning

confidence: 99%

“…MUB is known to be efficient in the treatment of acute myeloid leukemia, breast cancer, spinal cord injury, gastric cancer, chronic allergies, and lung cancer, among other diseases. Considering the HER2 molecular target, MUB has reached phase I clinical trials for solid tumor treatment . The pharmacological drug effects upon entering the human body are necessary evidence for the regulatory approval process .…”

Section: Introductionmentioning

confidence: 99%

Molecular Recognition Study toward the Mitochondrial Electron Transport Chain Inhibitor Mubritinib and Human Serum Albumin

2023

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The ability to bind plasma proteins helps in comprehending relevant aspects related to the pharmacological properties of many drugs. Despite the vital role of the drug mubritinib (MUB) in the prophylaxis of various diseases, its interaction with carrier proteins still needs to be clarified. The present work focuses on the interaction between MUB and Human serum albumin (HSA), investigated by employing multispectroscopic, biochemical, and molecular docking approaches. The results reveal that MUB has quenched HSA intrinsic fluorescence (following a static mechanism) by attaching very close (r = 6.76 Å) and with moderate affinity (K b ≈ 104 M–1) to the protein site I (mainly by H-bonds, hydrophobic and Van der Waals forces). On one side, the HSA–MUB interaction has been accompanied by a slight disturbance in the HSA chemical environment (around the Trp residue) and protein secondary structure modifications. On another side, MUB competitively inhibits HSA esterase-like activity, which is very similar to other Tyrosine kinase inhibitors, and evidence that protein functional alterations have been triggered by MUB interaction. In summary, all of the presented observations can shed light on diverse pharmacological factors associated with drug administration.

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The therapeutic potential of mitochondrial toxins

Cited by 4 publications

References 76 publications

Oxphos Targeting of Mycn-Amplified Neuroblastoma

Oxphos Targeting of Mycn-Amplified Neuroblastoma

Effects of Phytotoxic Nonenolides, Stagonolide A and Herbarumin I, on Physiological and Biochemical Processes in Leaves and Roots of Sensitive Plants

Molecular Recognition Study toward the Mitochondrial Electron Transport Chain Inhibitor Mubritinib and Human Serum Albumin

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