Selenium supplementation protects cancer cells from the oxidative stress and cytotoxicity induced by the combination of ascorbate and menadione sodium bisulfite

Article

Author: Coppo, Lucia ; Arnér, Elias S J ; Ren, Xiaoyuan ; Gencheva, Radosveta

The combination of ascorbate (vitamin C) and menadione sodium bisulfite (MSB, vitamin K3), here called VC/VK3 (also named Apatone®, or M/A), has shown selective cytotoxicity in cancer cells and is under clinical investigation as a cancer therapy. However, the mechanisms of VC/VK3-induced cell death are not fully understood. In this in vitro study using human glioblastoma and non-transformed glial cell lines, we found that VC/VK3 caused higher toxicity in cancer cells in an H₂O₂- and iron-dependent manner, suggesting that ferroptosis may play a role in the cell death process. Furthermore, selenium supplementation significantly protected cancer cells from VC/VK3 treatment concomitantly with enhanced expression levels and enzymatic activity of antioxidant selenoproteins, including thioredoxin reductases (TXNRDs) and glutathione reductases (GPXs). We also found that VC/VK3 competes for electrons with thioredoxin (TXN), impairing peroxiredoxin 1 (PRDX1) in cells. Finally, chemically inhibiting TXNRDs or the glutathione-dependent antioxidant systems exaggerated the toxicity of VC/VK3. Overall, this study elucidated parts of the cell death mechanisms of VC/VK3 and identified combination strategies to overcome selenium-mediated resistance, advancing the translational potential of this prooxidant treatment.

25 Oct 2024·Science

Dietary pro-oxidant therapy by a vitamin K precursor targets PI 3-kinase VPS34 function

Article

Author: Williams, Roger L. ; Gong, Grace Q. ; Špokaitė, Saulė ; Nowak, Dawid G. ; Dessus, Antoine N. ; Trotman, Lloyd C. ; Minicozzi, Francesca ; Liu, Juan ; Cox, Hilary ; Alsudani, Habeeb ; Gineste, Charlotte ; Wee, Tse-Luen ; Swamynathan, Manojit M. ; Chakrabarty, Ram P. ; Reczek, Colleen R. ; Hicks, James B. ; Locasale, Jason W. ; Kuang, Shan ; Zhao, Xiang ; Park, Youngkyu ; Doherty, Mary R. ; Almeida, Ana S. ; Reiss, David ; Kendall, Jude ; Cheng, Eileen ; Wilkinson, John E. ; Gimotty, Phyllis A. ; Herzka, Tali ; Ghosh, Diya ; Chang, Kenneth ; Wigler, Michael ; Watrud, Kaitlin E. ; Egeblad, Mikala ; Diermeier, Sarah D. ; Klingbeil, Olaf ; Chandel, Navdeep S. ; Vakoc, Christopher R. ; Pappin, Darryl J. ; Mathew, Grinu ; Kim, Seung Tea ; Tuveson, David A. ; Cifani, Paolo ; Janowitz, Tobias ; Rivera, Keith ; Laporte, Jocelyn

Men taking antioxidant vitamin E supplements have increased prostate cancer (PC) risk. However, whether pro-oxidants protect from PC remained unclear. In this work, we show that a pro-oxidant vitamin K precursor [menadione sodium bisulfite (MSB)] suppresses PC progression in mice, killing cells through an oxidative cell death: MSB antagonizes the essential class III phosphatidylinositol (PI) 3-kinase VPS34—the regulator of endosome identity and sorting—through oxidation of key cysteines, pointing to a redox checkpoint in sorting. Testing MSB in a myotubular myopathy model that is driven by loss of MTM1 —the phosphatase antagonist of VPS34—we show that dietary MSB improved muscle histology and function and extended life span. These findings enhance our understanding of pro-oxidant selectivity and show how definition of the pathways they impinge on can give rise to unexpected therapeutic opportunities.

10 Oct 2024·Advanced Pharmaceutical Bulletin

Menadione Sodium Bisulfite Loaded Rhamnolipid Based Solid Lipid Nanoparticle as Skin Lightener Formulation: A Green Production Beside In Vitro/In Vivo Safety Index Evaluation

Article

Author: Asadpour Panbehchouleh, Fatemeh ; Amani, Hossein ; Saeedi, Majid

Purpose: In the current investigation, an ultrasonic approach was performed to produce menadione sodium bisulfite-loaded solid lipid nanoparticles (MSB-SLNs) with rhamnolipid as bio-surfactant, which aimed to increase the dermal delivery and anti-pigmentation effect. Methods: To achieve optimum delivery for MSB, the impact of the ratio of two surfactants (rhamnolipid: Tween) on nanoparticle attributes and the respective functions were evaluated. In vitro diffusion process, in vitro cytotoxicity assay, determination of melanin content of melanoma cells, L-DOPA auto-oxidation inhibitory test, and skin irritation studies carried out to investigate the suitability of MSB formulation in dermal application. Results: The optimized nanoparticles showed an average particle size, zeta potential, polydispersity index (PDI), and drug entrapment efficiency of 117.26±1.12 nm, -6.28±0.33 mV, 0.262±0.002, 83.34±0.75% respectively in hydrophilic-lipophilic balance (HLB) of 12. The in vitro diffusion process demonstrated that MSB-SLN gel had a prolonged release pattern. The levels of MSB in the cutaneous layers (52.192±2.730% or 961.59±50.313 μg/cm2 ) and the receiver compartment (23.721±1.803 % or 437.049± 33.236 μg/cm2 ) for the MSB-SLN gel was higher than MSB simple and showed no cutaneous irritancy and toxicity in rats. MSB-SLN inhibited melanin formation and was remarkably higher than free MSB. MSB-SLN inhibited L-3,4- dihydroxyphenylalanine (L-DOPA) auto-oxidation to a greater extent (95.14±1.46%) than MSB solution (72.28±0.83%). Conclusion: This study’s observations revealed that the produced MSB-SLN might be used as a potential nano-vehicle for MSB dermal administration, thereby opening up innovative options for the management of hyper-melanogenesis problems.

100 Deals associated with Menadione sodium bisulfite

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Indication	Highest Phase	Country/Location	Organization	Date
Congenital Structural Myopathy	Preclinical	United States	Cold Spring Harbor Biological Laboratory	25 Oct 2024
Prostatic Cancer	Preclinical	United States	Cold Spring Harbor Biological Laboratory	25 Oct 2024

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