Mitochondrial toxicity

Pyraclostrobin is one of the most heavily used fungicides that inhibits mitochondrial complex III of fungal and mammalian cells.

Polyphyllin D induces apoptosis via the mitochondrial apoptotic pathway as evidenced by decreased Bcl-2 expression levels, disruption of MMP and increased Bax, cytochrome C, and cleaved-caspase-3 levels. Polyphyllin D has an anti-angiogenic effect. Polyphyllin D has toxicity in human RBCs as well as its underlying mechanism for the hemolysis and eryptosis/erythroptosis. Polyphyllin D has strong anticancer activity, can overcome drug resistance in R-HepG2 cells and elicit programmed cell death via mitochondrial dysfunction.

Metacavir (PNA) is a novel nucleoside reverse transcriptase inhibitor, a deoxyguanosine analog, with anti-hepatitis B virus (HBV) activity and mitochondrial toxicity, which can be used to study HBV infection.

1. Oxyresveratro can inhibit tyrosinase activity. 2. Oxyresveratro is useful to trauma models, as toxicity to glia could be beneficial by inhibiting reactive gliosis. 3. Oxyresveratrol (trans-Oxyresveratrol) has antioxidant activity, can reduce neuronal oxidative damage and protect hepatocytes against oxidative stress and mitochondrial dysfunction, which may be associated with activation of Nrf2.

Pyrroloquinoline quinone (PQQ), as a well-known redox enzyme cofactor, PQQ can protect NS/PCs against glutamate toxicity associated with ROS-mediated mitochondrial pathway,

Quinine sulfate dihydrate plays a major role in potassium channel blockers. It is also used as an antimalarial, anticholinergic, antihypertensive and a hypoglycemic agent. It inhibits mitochondrial ATP-regulated potassium channel. It is also used to study the metabolism of biocrystalized heme, hemozoin, in malarial parasites and to study the toxicity of heme (FP)-complexes.

RLX (PD 139530) is a PI3K/Akt/FoxO3a signal inhibitor with anticancer activity against tumour cell lines such as colon cancer, inducing sub-G1 arrest and mitochondrial potential loss, thereby inhibiting tumour growth. RLX also exhibits antitussive and anti-asthmatic activity, reducing eosinophils and total lymphocytes in bronchoalveolar lavage (BAL) fluid, and exhibits toxicity toward A549 cells.

Aftin-4, an amyloid forty-two inducer, activates γ-secretase, promoting the generation of amyloid-β-1-42 (Aβ1-42) from amyloid-β protein precursor. Aftin-4(Aftin4) increased Aβ-1-42, but not Aβ-1-40 in mouse hipppocampus, accompanied by learning deficits and mitochondrial ultrastructural changes similar to those found in the brains of patients with AD. Aftin-4(Aftin4) can thus be used to induce a rapid, acute Alzheimer's disease-like toxicity in the rodent brain.

LDCA is a double-hit metabolic regulator that exhibits potent anti-proliferative activity. lDCA competitively inhibits LDH-A enzyme activity, alters mitochondrial hyperpolarization and simultaneously subverts apoptosis. lDCA has a pronounced effect in cancer cells and does not show toxicity.

Trifluralin (Treflan) is an agricultural herbicide with mild toxicity. Trifluralin is a novel pollutant that can interfere with mitochondrial respiration.

Apoptosisinducer 24 (Compound 4) inhibits the proliferation of gastric cancer cells with an IC50 range of 1.2-4.8 μM. It arrests the cell cycle at the G2 M phase, induces apoptosis in BGC-823 cells, and causes mitochondrial dysfunction. In mice, Apoptosisinducer 24 exhibits antitumor activity without significant toxicity, having an LD50 of 91.2 mg kg.

IDOi-Pt(IV) prodrug-1 (Compound 10) is an IDOi-Pt(IV) prodrug that suppresses IDO expression. It induces apoptosis, reduces mitochondrial membrane potential, and inhibits tumor cell migration and invasion. Additionally, IDOi-Pt(IV) prodrug-1 triggers reactive oxygen species-mediated endoplasmic reticulum stress and the secretion of damage-associated molecular patterns (DAMPs), leading to immunogenic cell death (ICD). Compared to cisplatin, IDOi-Pt(IV) prodrug-1 exhibits relatively high efficiency and low toxicity in its antitumor activity.

IPH10 is an anticancer agent with strong antitumor effects in vivo and exhibits no liver or kidney toxicity. It significantly increases the reactive oxygen species (ROS) levels in tumor cells, decreases mitochondrial membrane potential, and induces apoptosis (apoptosis) in these cells.

Tubulin inhibitor 50 (compound 07) is a microtubule protein inhibitor that enhances mitochondrial reactive oxygen species levels. It exhibits anticancer activity in HeLa cells with an IC50 value of 0.46 μM, while showing low toxicity in normal cell lines.

Mitochondrial-IN (C458) is a potent inhibitor of mitochondrial complex I. It offers significant protection against Aβ toxicity, exhibits favorable pharmacokinetic properties, and has minimal off-target effects.

COE-PNH2 exhibits antibacterial activity against Mycobacterium abscessus (Mab) with an MIC90 of 26 μM. It disrupts bacterial cell wall and membrane integrity, possesses intracellular permeability, and lacks mitochondrial toxicity.

NF-κB-IN-16 (compound 9) is a complex of an NF-κB inhibitor and Cisplatin (Pt(IV) complex) with potent and low-toxicity antitumor activity. It can cause DNA damage, induce mitochondrial dysfunction, generate reactive oxygen species, and trigger apoptosis via mitochondrial pathways and endoplasmic reticulum stress. NF-κB-IN-16 effectively inhibits the NF-κB/MAPK signaling pathway and disrupts PI3K/AKT signal transduction. Additionally, it demonstrates excellent in vivo antitumor efficacy and low toxicity in A549 or A549/CDDP xenograft models.

RC363 is an inhibitor of ferroptosis and a derivative of the antioxidant and hypocholesterolemic agent probucol .1It reduces 2,2-diphenyl-1-picrylhydrazyl radicals by approximately 40% in a cell-free assay when used at a concentration of 25 μM. RC363 prevents glutamate-induced toxicity in HT22 cultured hippocampal cells (IC50= 234.5 nM) but does not reduce oxidant levels in these cells. It increases the levels of glutathione peroxidase 1 (GPX1) and the activity of GPX in glutamate-challenged HT22 cells when used at a concentration of 3 μM. RC363 inhibits ferroptosis induced by the GPX4 inhibitor RSL3 in HT22 cells (IC50= 173.6 nM). 1.Bueno, D.C., Canto, R.F.S., de Souza, V., et al.New probucol analogues inhibit ferroptosis, improve mitochondrial parameters, and induce glutathione peroxidase in HT22 cellsMol. Neurobiol.57(8)3273-3290(2020)

TFM is a piscicide.1It is toxic to sea lamprey (P. marinus) with LC50values ranging from 1.97 to 2.11 and 2.05 to 2.21 mg/L for sac and swim-up fry, respectively, 1.6 to 2.45 mg/L for juveniles, and 1.6 to 1.63 mg/L for adults. It is also toxic to juvenile lake sturgeon (A. fulvescens) less than 100 mm in size but not to a variety of other fish species. TFM (50 μM) uncouples oxidative phosphorylation by 22 and 28% in isolated sea lamprey and rainbow trout (O. mykiss) liver, respectively.2Formulations containing TFM have been used as lampricides in the control of larval sea lamprey populations. 1.Boogaard, M.A., Bills, T.D., and Johnson, D.A.Acute toxicity of TFM and a TFM/niclosamide mixture to selected species of fish, including lake sturgeon (Acipenser fulvescens) and mudpuppies (Necturus maculosus), in laboratory and field exposuresJ. Great Lakes Res.29(Suppl 1)529-541(2003) 2.Birceanu, O., McClelland, G.B., Wang, Y.S., et al.The lampricide 3-trifluoromethyl-4-nitrophenol (TFM) uncouples mitochondrial oxidative phosphorylation in both sea lamprey (Petromyzon marinus) and TFM-tolerant rainbow trout (Oncorhynchus mykiss)Comp. Biochem. Physiol. C. Toxicol. Pharmacol.153(3)342-349(2011)

TRi-1 is irreversible inhibitor of cytosolic thioredoxin reductase 1 (TXNRD1), with an IC50 of 12 nM. TRi-1 has little mitochondrial toxicity for anticancer therapy

1. Neferine ((-)-Neferine) has anti-tumor activities , Metabolic activation mediated by CYP3A4 and GSH depletion enhanced Neferine-induced cytotoxicity. 2. Neferine can be helpful to increase the efficacy of DOX and to achieve anticancer synergism by curbing the toxicity. 3. Neferine inhibited high glucose-induced endothelial apoptosis via blocking ROS/Akt/NF-κB pathway, which provides the evidence for using Neferine to treat diabetic vasculopathy. 4. Neferine induced apoptosis in a dose-dependent manner with the hypergeneration of reactive oxygen species, activation of MAPKs, lipid peroxidation, depletion of cellular antioxidant pool, loss of mitochondrial membrane potential, and intracellular calcium accumulation.

Sciadopitysin may prevent the development of diabetic osteopathy, it exerts its therapeutic effects via upregulation of mitochondrial biogenesis.Sciadopitysin shows protective effects on antimycin A-induced toxicity in osteoblastic MC3T3-E1 cells, it may

PI3Kα-IN-6 (Compound 5b) is a PI3Kα inhibitor that demonstrates anticancer properties without harming normal cells, by increasing ROS production, decreasing mitochondrial membrane potential, and inducing apoptosis.

Antiproliferative agent-4 showed good anti-proliferative effects on some cancer cells. antiproliferative agent-4 inhibited tumour growth in nude mice and showed low toxicity. antiproliferative agent-4 reduced the mitochondrial membrane potential of EC109 cells and increased Antiproliferative agent-4 reduced the mitochondrial membrane potential of EC109 cells and increased the apoptosis rate and ROS level.