Cetylpyridinium chloride is a potent AMP-activated kinase (AMPK) inducer and has therapeutic potential in cancer

Allen, Sonia; Datta, Sandipan; Sandoval, José Armando Pancorbo; Tomilov, Alexey; Sears, Thomas K.; Woolard, Kevin D.; Angelastro, James M.; Cortopassi, Gino A

doi:10.1016/j.mito.2019.09.009

Cited by 7 publications

(9 citation statements)

References 30 publications

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“…33 Previously, it has been reported that CPC kills glioblastoma cells with a higher efficacy than current standard temozollomide. 14 Our data confirmed a recent report on dose-dependent CPC cytotoxicity on MCF-7. 14 Unfortunately, this study did not evaluate the effect of CPC on non-tumorigenic cells.…”

Section: Discussionsupporting

confidence: 92%

Cetylpyridinium chloride inhibits human breast tumor cells growth in a no-selective way

García-Cuéllar

Hernandez-Delgadillo

Solís-Soto

et al. 2022

Journal of Applied Biomaterials & Functional Materials

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Objective: Analyze the antitumor capacity of cetylpyridinium chloride (CPC) on human breast tumor cells, and the possible action mechanism. Material and methods: The human breast tumor cells MCF-7 and no-tumor breast cells MCF-10A were exposed to CPC under various condition (concentration and duration). Cell viability was measured with MTT assay, the LIVE/DEAD assay, and fluorescence microscopy. Membrane permeability after CPC exposure was evaluated by Calcein AM assay, mitochondrial morphology with a MitoView staining, and genotoxicity with the comet assay and fluorescence microscopy. Results: CPC was cytotoxic to both MCF-7 and MCF-10A as of a 24-h exposure to 0.1 µM. Cytotoxicity was dose-dependent and reached 91% for MCF-7 and 78% for MCF-10A after a 24-h exposure to 100 µM CPC, which outperformed the positive control doxorubicin in effectiveness and selectivity. The LD50 of CPC on was 6 µM for MCF-7 and 8 µM for MCF-10A, yielding a selectivity index of 1.41. A time response analysis revealed 64% dead cells after only 5 min of exposure to 100 µM CPC. With respect to the action mechanisms, the comet assay did not reveal genome fragmentation. On the other hand, membrane damage was dose-dependent and may also affect mitochondrial morphology. Conclusion: Cetylpyridinium chloride inhibits MCF-7 cell growing in a non-selective way as of 5 min of exposure. The action mechanism of CPC on tumor cells involves cell membrane damage without change neither mitochondrial morphology nor genotoxicity.

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Section: Discussionsupporting

confidence: 92%

Cetylpyridinium chloride inhibits human breast tumor cells growth in a no-selective way

García-Cuéllar

Hernandez-Delgadillo

Solís-Soto

et al. 2022

Journal of Applied Biomaterials & Functional Materials

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“…Because CPC may be an electron transport chain (ETC) inhibitor (Chávez and Concepcion, 1982; Hess et al ., 2006; Datta et al ., 2017b), CPC’s mechanism may be related to its ETC inhibition: antimycin A and rotenone also induce donut formation, potentially via mitochondrial reactive oxygen species (ROS) generation (Plecita-Hlavata et al ., 2008; Giedt et al ., 2012; Ahmad et al ., 2013; Bulthuis et al ., 2019). Another potential mechanistic explanation for CPC-induced donuts involves CPC (3 & 10 μM; 2 hr) activation of AMP-activated protein kinase (AMPK), which has been demonstrated in liver cells (Allen et al ., 2020). Interestingly, inositol, which prevents aberrant AMPK activation, also prevents mitochondrial fission (Hsu et al ., 2021).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, inositol, which prevents aberrant AMPK activation, also prevents mitochondrial fission (Hsu et al ., 2021). Because CPC both activates AMPK (Allen et al ., 2020) and causes donut formation (Figure 5), AMPK stimulation may be involved in the mechanism underlying CPC formation of mitochondrial donuts.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of Antimicrobial Agent Cetylpyridinium Chloride Mitochondrial Toxicity in Rodent and Primary Human Cells: Super-resolution Microscopy Reveals Nanostructural Disruption

Weller

Burnell

Aho

et al. 2022

Preprint

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People are exposed to high concentrations of antibacterial agent cetylpyridinium chloride (CPC) via personal care and food products, despite little information regarding CPC effects on eukaryotes. CPC is used as an antibacterial agent via a detergent mechanism when above ~600-900 μM. While three previous studies suggested CPC mitochondrial toxicity, this phenomenon is not well-studied. Here, we show that low-micromolar CPC inhibits mitochondrial ATP production in primary human keratinocytes, mouse NIH-3T3 fibroblasts, and rat RBL-2H3 immune mast cells, in galactose media, which causes cells to produce ATP via mitochondria. ATP inhibition via CPC (EC50 1.7 μM) is nearly as potent as that caused by canonical mitotoxicant CCCP (EC50 1.2 μM). CPC inhibition of oxygen consumption rate (OCR) tracks with that of ATP: OCR is halved due to 1.75 μM CPC in RBL-2H3 cells and 1.25 μM in primary human keratinocytes. Here we demonstrate that CPC is more potent as a mitotoxicant than as an immune mast cell signaling inhibitor, an effect published previously. Mitochondrial [Ca2+] changes can cause mitochondrial dysfunction. Here we show, using a novel plate reader assay with reporter CEPIA2mt, that CPC causes mitochondrial Ca2+ efflux from mast cells via an ATP-inhibition mechanism. Using super-resolution microscopy (fluorescence photoactivation localization) in live cells, we have discovered that CPC causes mitochondrial nanostructural defects in fibroblasts, including the formation of spherical structures with donut-like cross section, as quantified by novel Fourier transform analysis. This work reveals CPC as a mitotoxicant despite widespread use, highlighting the importance of further research into its toxicological safety.

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“…Also, IF (30 mg/kg/day) significantly reduced the serum glucose and alanine aminotransferase in HFD group with no significant effects on aspartate aminotransferase. On the other hand, IF improved fatty acid metabolism in HFD group with an increase in the activity of adenosine monophosphate-activated protein kinase as a cell-protective enzyme versus the energy deficiency stress [139]. Pure IF also improved the phosphorylation of acetyl-CoA carboxylase and inhibited the expression of fatty acid synthase and hydroxyl-3-methylglutaryl coenzyme A reductase [27].…”

Section: Miscellaneous Effectsmentioning

confidence: 97%

Isofraxidin: Synthesis, Biosynthesis, Isolation, Pharmacokinetic and Pharmacological Properties

et al. 2020

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Isofraxidin (7-hydroxy-6, 8-dimethoxy coumarin) (IF) is a hydroxy coumarin with several biological and pharmacological activities. The plant kingdom is of the most prominent sources of IF, which, among them, Eleutherococcus and Fraxinus are the well-known genera in which IF could be isolated/extracted from their species. Considering the complex pathophysiological mechanisms behind some diseases (e.g., cancer, neurodegenerative diseases, and heart diseases), introducing IF as a potent multi-target agent, which possesses several herbal sources and the multiple methods for isolation/purification/synthesis, along with the unique pharmacokinetic profile and low levels of side effects, could be of great importance. Accordingly, a comprehensive review was done without time limitations until February 2020. IF extraction methods include microwave, mechanochemical, and ultrasound, along with other conventional methods in the presence of semi-polar solvents such as ethyl acetate (EtOAc). In addition to the isolation methods, related synthesis protocols of IF is also of great importance. From the synthesis point of view, benzaldehyde derivatives are widely used as precursors for IF synthesis. Along with the methods of isolation and biosynthesis, IF pharmacokinetic studies showed hopeful in vivo results of its rapid absorption after oral uses, leading to different pharmacological effects. In this regard, IF targets varieties of inflammatory mediators including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), tumor necrosis factor-α (TNF-α), and matrix metalloproteinases (MMPs). thereby indicating anticancer, cardioprotective, and neuroprotective effects. This is the first review on the synthesis, biosynthesis, isolation, and pharmacokinetic and pharmacological properties of IF in combating different diseases.

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Cetylpyridinium chloride is a potent AMP-activated kinase (AMPK) inducer and has therapeutic potential in cancer

Cited by 7 publications

References 30 publications

Cetylpyridinium chloride inhibits human breast tumor cells growth in a no-selective way

Cetylpyridinium chloride inhibits human breast tumor cells growth in a no-selective way

Mechanisms of Antimicrobial Agent Cetylpyridinium Chloride Mitochondrial Toxicity in Rodent and Primary Human Cells: Super-resolution Microscopy Reveals Nanostructural Disruption

Isofraxidin: Synthesis, Biosynthesis, Isolation, Pharmacokinetic and Pharmacological Properties

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