Abstract
Owing to lagging or insufficient neo-angiogenesis, hypoxia is a feature of most solid tumors. Hypoxic tumor regions contribute to resistance against antiproliferative chemotherapeutics, radiotherapy and immunotherapy. Targeting cells in hypoxic tumor areas is therefore an important strategy for cancer treatment. 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. By using tumor spheroids in hypoxic conditions as screening system, we identified a set of compounds, including the phenothiazine antipsychotic Fluphenazine, as hits with novel mode of action. Fluphenazine functionally inhibits acid sphingomyelinase and causes cellular sphingomyelin accumulation, which induces cancer cell death specifically in hypoxic tumor spheroids. Moreover, we found that functional inhibition of acid sphingomyelinase leads to overactivation of hypoxia stress-response pathways and that hypoxia-specific cell death is mediated by the stress-responsive transcription factor ATF4. Taken together, the here presented data suggest a novel, yet unexplored mechanism in which induction of sphingolipid stress leads to the overactivation of hypoxia stress-response pathways and thereby promotes their pro-apoptotic tumor-suppressor functions to specifically kill cells in hypoxic tumor areas.
Highlights
IntroductionRapid cell growth and high metabolic rates of cancer cells in combination with insufficient or disorganized neovascularization can lead to the development of hypoxic or anoxic tumor regions.[1,2,3] Intratumoral hypoxia is a common feature of most solid tumors[2,4,5] and inversely correlates with clinical efficacy of cancer therapies and clinical outcome.[5,6,7,8,9,10,11] targeting cancer cells in hypoxic tumor areas is an important strategy for cancer treatment
By deep sequencing we show that Fluphenazine induces overactivity of hypoxia stressresponse pathways and causes hypoxia-specific cell death via the stress-response transcription factor ATF4
Hypoxic and nutrient-depleted conditions found in tumor tissue can be mimicked in a 3D cell culture setting and tumor spheroids are being increasingly used to better reflect physiological conditions of tumor cell growth in vitro
Summary
Rapid cell growth and high metabolic rates of cancer cells in combination with insufficient or disorganized neovascularization can lead to the development of hypoxic or anoxic tumor regions.[1,2,3] Intratumoral hypoxia is a common feature of most solid tumors[2,4,5] and inversely correlates with clinical efficacy of cancer therapies and clinical outcome.[5,6,7,8,9,10,11] targeting cancer cells in hypoxic tumor areas is an important strategy for cancer treatment. One of the main strategies for targeting hypoxic tumor cells is to inhibit or modulate hypoxia-survival pathways. Four highly hypoxia-selective compounds with novel mode of action were identified that induce cell death in hypoxic spheroids and show no effects in spheroids cultured under normoxia. Of these substances, Fluphenazine, an antipsychotic phenothiazine drug, could be validated as novel hypoxia-selective cell death inducer. Fluphenazine acts differently than known lysosomal-disrupting agents[17,18] or inhibitors of lysosomal acidification.[19] by deep sequencing we show that Fluphenazine induces overactivity of hypoxia stressresponse pathways and causes hypoxia-specific cell death via the stress-response transcription factor ATF4
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