Abstract
Stemphol (STP) is a novel druggable phytotoxin triggering mixed apoptotic and non-apoptotic necrotic-like cell death in human acute myeloid leukemia (AML). Use of several chemical inhibitors highlighted that STP-induced non-canonical programmed cell death was Ca2+-dependent but independent of caspases, poly (ADP-ribose) polymerase-1, cathepsin, or calpains. Similar to thapsigargin, STP led to increased cytosolic Ca2+ levels and computational docking confirmed binding of STP within the thapsigargin binding pocket of the sarco/endoplasmic reticulum (ER) Ca2+-ATPase (SERCA). Moreover, the inositol 1,4,5-trisphosphate receptor is implicated in STP-modulated cytosolic Ca2+ accumulation leading to ER stress and mitochondrial swelling associated with collapsed cristae as observed by electron microscopy. Confocal fluorescent microscopy allowed identifying mitochondrial Ca2+ overload as initiator of STP-induced cell death insensitive to necrostatin-1 or cycloheximide. Finally, we observed that STP-induced necrosis is dependent of mitochondrial permeability transition pore (mPTP) opening. Importantly, the translational immunogenic potential of STP was validated by HMGB1 release of STP-treated AML patient cells. STP reduced colony and in vivo tumor forming potential and impaired the development of AML patient-derived xenografts in zebrafish.
Reference:
Ji S, Lee JY, Schrör J, Mazumder A, Jang DM, Chateauvieux S, Schnekenburger M, Hong CR, Christov C, Kang HJ, Lee Y, Han BW, Kim KW, Shin HY, Dicato M, Cerella C, König GM, Orlikova B, Diederich M. The dialkyl resorcinol stemphol disrupts calcium homeostasis to trigger programmed immunogenic necrosis in cancer. Cancer Lett. 2018 Mar 1;416:109-123. doi: 10.1016/j.canlet.2017.12.011.
Keywords: the dialkyl resorcinol stemphol, calcium homeostasis, programmed immunogenic necrosis, cancer, xenografts in zebrafish, HMGB1, mitochondrial permeability transition pore (mPTP) opening, mitochondrial Ca2+, sarco/endoplasmic reticulum (ER) Ca2+-ATPase (SERCA).
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