Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.659198
Title: Investigations into the mechanism of action of antitumour quinols
Author: Matthews, Charles S.
Awarding Body: University of Nottingham
Current Institution: University of Nottingham
Date of Award: 2011
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Abstract:
Antitumour quinols containing the 4-hydroxycyclohexa-2,5-dienone pharmacophore potently inhibit human tumour cell growth in vitro and in vivo. This activity is postulated to occur via inhibition of the thioredoxin/thioredoxin reductase (TrxlTrxR) redox system which reduces numerous substrates involved in cellular proliferation, signal transduction, redox homeostasis and apoptosis. Similar to the archetypal quinol, PMX 464, its eventual successor, PMX 290, induced caspase-dependent apoptosis, cell cycle arrest and oxidative stress in sensitive tumour cells whilst depletion of glutathione increased tumour cell sensitivity to PMX 290. The ability of PMX 464 and PMX 290 to induce cellular responses understood to occur downstream of TrxlTrxR inhibition that could account for their antitumour activity were investigated. Quinol activity was shown to be independent of oxidative stress. Colon cancer cells stably overexpressing catalase retained sensitivity to PMX 464 and PMX 290 yet were resistant to hydrogen peroxide whilst the use of radical scavengers failed to abrogate quinol activity. Trx binds to and inhibits apoptosis signalling kinase 1 (ASK1), a mitogen activated protein kinase (MAPK) kinase kinase responsible for stress-induced apoptosis via sustained activation of the MAPKs c-jun N-terminal kinase (JNK) and p38. PMX 464 and PMX 290 disrupted cellular ASK1 :Trx1 complexes and induced sustained JNKlp38 phosphorylation yet overexpression of dominant negative ASK1 or pharmacological inhibition of JNKlp38 did not prevent quinol-induced apoptosis. Additionally, knockdown of Trx1 using siRNA did not impact quinol activity suggesting additional mechanisms of action. PMX 290 induced endoplasmic reticulum (ER) stress at apoptosis-inducing concentrations below those required to inhibit cellular TrxlTrxR. Upregulation of ER stress proteins, translation-inactivating phosphorylation events and ER distension occurred in response to PMX 290 alongside the accumulation/aggregation of ubiquitinated proteins prior to the onset of apoptosis. Proteasome inhibition was not responsible for these effects. A definitive cellular target for PMX 290 was not identified, however, useful tools have been generated which could be applied to investigate the actions of other redox homeostasis modulating therapies.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.659198  DOI: Not available
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