Radiosensitization by non-nitro compounds

Wardman, Peter; Anderson, Robert F.; Hodgkiss, R.J.; Parrick, J.; Smithen, C. E.; Wallace, Raymond G.; Watts, M.E.

doi:10.1016/0360-3016(82)90647-2

Cited by 8 publications

(2 citation statements)

References 13 publications

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“…In addition, chemo- and radioresistant cells exhibit increased respiration rates 17 , 47 . A recent study showed that irradiated cells increase OXPHOS to favor DNA repair and cell survival 48 and inhibitors of electron transport complexes can enhance radiosensitivity 49 , 50 . In addition, mitochondrial translation has previously been identified as a therapeutic target in the treatment of acute myeloid leukemia 51 .…”

Section: Discussionmentioning

confidence: 99%

Targeting mitochondrial translation by inhibiting DDX3: a novel radiosensitization strategy for cancer treatment

et al. 2017

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DDX3 is a DEAD box RNA helicase with oncogenic properties. RK-33 is developed as a small molecule inhibitor of DDX3 and showed potent radiosensitizing activity in preclinical tumor models. This study aimed to assess DDX3 as a target in breast cancer and to elucidate how RK-33 exerts its anti-neoplastic effects. High DDX3 expression was present in 35% of breast cancer patient samples and correlated with markers of aggressiveness and shorter survival. With a quantitative proteomics approach, we identified proteins involved in the mitochondrial translation and respiratory electron transport pathways to be significantly downregulated after RK-33 or DDX3 knockdown. DDX3 localized to the mitochondria and DDX3 inhibition with RK-33 reduced mitochondrial translation. As a consequence, oxygen consumption rates and intracellular ATP concentrations decreased and reactive oxygen species (ROS) increased. RK-33 antagonized the increase in oxygen consumption and ATP production observed after exposure to ionizing radiation and reduced DNA repair. Overall, we conclude that DDX3 inhibition with RK-33 causes radiosensitization in breast cancer through inhibition of mitochondrial translation, which results in reduced oxidative phosphorylation capacity and increased ROS levels, culminating in a bioenergetic catastrophe.

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Section: Discussionmentioning

confidence: 99%

Targeting mitochondrial translation by inhibiting DDX3: a novel radiosensitization strategy for cancer treatment

et al. 2017

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“…Among the drugs tested have been nitroxyl compounds Cooke et al (1976), nitrofurans Chapman et al (1973), nitropyrroles Raleigh et al (1978), nitroimidazoles Asquith et al (1974), non-nitro compounds Wardman et al (1982), and indoles Infante et al (1980). Of the compounds examined, misonidazole (MISO) and desmethylmisonidazole, have entered clinical trials, but optimal doses of drug with each radiation dose fraction are not possible due to a cumulative neurotoxicity.…”

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confidence: 99%