The alkaloid, soyauxinium chloride, displays remarkable cytotoxic effects towards a panel of cancer cells, inducing apoptosis, ferroptosis and necroptosis

The cytotoxic potential of a naturally occurring indoloquinazoline alkaloid, soyauxinium chloride (SCHL), was determined on a broad panel of animal and human cancer cell lines, including various sensitive and drug-resistant phenotypes. The cytotoxicity, SCHL-induced autophagic, ferroptotic, and necroptotic cell death were evaluated by the resazurin reduction assay (RRA). Caspase-Glo assay was used to detect the activity of caspases using spectrophotometric analysis. Flow cytometry was applied for cell cycle analysis (PI staining), apoptosis (annexin V/PI staining), mitochondrial membrane potential (MMP) (JC-1) and reactive oxygen species (ROS) (H2DCFH-DA). SCHL and doxorubicin (reference molecule) exhibited cytotoxic effects towards the 18 cancer cell lines tested. The IC50 values obtained ranged from 3.64 μM (towards CCRF-CEM leukemia cells) to 16.86 μM (against the BRAF-wildtype SKMel-505 melanoma cells for SCHL). Collateral sensitivity of the resistant HCT116 p53−/− colon adenocarcinoma cells to SCHL was observed as well as the normal sensitivity of CEM/ADR5000 leukemia cells, MDA-MB-231-BCRP breast adenocarcinoma cells and U87. MGΔEGFR glioblastoma cells. SCHL induced apoptosis in CCRF-CEM cells via caspases 3/7-, 8- and 9-activation, MMP alteration and increased ROS production, and otherwise ferroptosis and necroptosis. SCHL is a prominent cytotoxic alkaloid that should be further studied to develop a novel drug to combat cancers including refractory phenotypes. Soyauxinium chloride (SCHL) had good cytotoxic effects with IC50 values below 10 μM towards 14 of the 18 cancer cell lines tested. SCHL induced apoptosis in CCRF-CEM cells via caspases 3/7-, 8- and 9-activation, MMP alteration and increased ROS production; SCHL also induced ferroptosis and necroptosis. [Display omitted] •The cytotoxicity of an indoloquinazoline alkaloid, soyauxinium chloride (SCHL), was evaluated.•SCHL exerted cytotoxic effects towards the 18 cancer cell lines tested including animal and human cell lines.•SCHL induced apoptosis, ferroptosis and necroptosis in CCRF-CEM cells.