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XRT and mitochondrial demise in head and neck cancer

Discussion in 'Mitochondrial Rx' started by Jack Kruse, Apr 9, 2021.

  1. Jack Kruse

    Jack Kruse Administrator

  2. Mitochondria-targeted antioxidant protects against irradiation-induced salivary gland hypofunction - https://www.nature.com/articles/s41598-021-86927-3

    Consequences of ionizing radiation in any tissue is DNA damage as well as substantial increase in cellular levels of reactive oxygen species (ROS).

    MitoTEMP was developed and administered with a specific protocol for treatment on mice with the mitochondrially targeted ROS scavenger.

    MitoTEMPO is a combination of the antioxidant piperidine nitroxide TEMPO with the lipophilic cation triphenylphosphonium, giving MitoTEMPO the ability to pass through lipid bilayers with ease and accumulate several hundred-fold in mitochondria.

    Nitroxide 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPOL) - this nitroxide proved to be significantly more effective in inhibiting the growth of neoplastic. The Chemistry and Biology of Nitroxide Compounds - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1991293/

    Cyclic nitroxides are a diverse range of stable free radicals that have unique antioxidant properties.

    Triphenylphosphonium is a modified paclitaxel nanocrystal -> chemotherapy drug

    The substituent groups on the ring (denoted by R-) produce a diverse range of compounds that can be directed to specific hydrophilic or hydrophobic regions in the cellular microenvironment.
    Nitroxide radicals have long been utilized as biophysical tools for electron paramagnetic resonance (EPR) spectroscopic studies such as spin label/oxymetry and spin trapping because of their stability and their paramagnetic nature.

    Nitroxide compounds are found in vivo in an equilibrium between the nitroxide radical form which is detected by EPR, and the reduced form, known as the hydroxylamine, which is not detected. This equilibrium is dependent on the oxygen status and redox-status of the tissue milieu. Cellular redox processes convert the compound between the two states, thus the ratio of the two states is determined by the redox activity within the cell.

    There is protective effect of nitroxides on cellular. These are:
    • Nitroxides mimetics the enzyme superoxide dismutase
    • It inhibits lipid peroxidation
    • It has a peroxidase action
    • It inhibits the fenton reactions
    • It has a protective effect agains radiation-induced radicals.

    In conclusion, a severe consequence of radiation therapy in patients with head and neck cancer is persistent salivary gland hypofunction which causes xerostomia and oral infections. We know from previous studies that irradiation (IR) of salivary glands in mice triggers initial transient increases in ROSmt, [Ca2+]mt and caspase-3 activation but persistent loss of salivary secretion.

    MitoTEMPO treatment prevented radiation-induced decrease in STIM1, consequently protecting store-operated calcium entry which is essential for saliva secretion. Together, these findings identify initial increase in ROSmt induced by irradiation as a critical driver of persistent salivary gland hypofunction.

    So what's the lesson in this? -> Perhaps it can be found in the quantitative chaos of our current scientific endeavors; that is, there is a higher probability in the potential of publishing, funding and status recognition for your drug delivery if you include a chemotherapeutic into the mix.

    Last edited: Apr 9, 2021

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