Identification of hypoxia-specific anti-cancer drugs using an in vitro spheroid model
Abstract
Cancer is among the leading causes of morbidity and mortality worldwide and the effectiveness of novel treatment approaches is often limited by the development of drug resistance. Owing to the rapid growth, high metabolic rates and lagging or insufficient neo-angiogenesis, many solid tumors are characterized by large regions of hypoxia. Tumor hypoxia is a main determinant for resistance development and treatment failure and is therefore an important target for cancer therapy. Most approaches for targeting hypoxic cells focus on the inhibition of hypoxia adaption pathways but only a limited number of compounds with the potential to specifically target hypoxic tumor regions have been identified. Therefore, a tumor spheroid model that mimics regions of severe hypoxia in tumors was used to perform a high-content screen for the identification of hypoxia-sensitizing compounds that specifically induce cell death in hypoxic tumor spheroids. Using this unbiased phenotypic screening system, a set of compounds including the antipsychotic phenothiazine drug fluphenazine were identified as highly hypoxia-selective hits that act via a novel, yet unreported mode of action. It was discovered that fluphenazine functionally inhibits the lysosomal enzyme acid sphingomyelinase and induces cancer cell death in hypoxic tumor spheroids by sphingomyelin accumulation. Moreover, fluphenazine potentiates the transcriptional activity of hypoxia stress response pathways and causes hypoxia specific cell…
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Evidence Hub reads this as a thesis, done in cell cultures (in vitro), not in people. Its evidence level is 5 of 5 (Very low · case / narrative / animal / in vitro / in silico). Case reports, narrative reviews, and animal, cell or computer-model studies give the weakest evidence for human health.
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