Dibenzyl trisulfide induces caspase-independent death and lysosomal membrane permeabilization of triple-negative breast cancer cells

The Petiveria alliacea L. (P. alliacea) plant is traditionally used in folklore medicine throughout tropical regions of the world to treat arthritis, asthma, and cancer. Dibenzyl trisulfide (DTS) is one of the active ingredients within the P. alliacea plant. Triple-negative breast cancer (TNBC) is associated with a poor prognosis, particularly among women of West African ancestry, due in part to limited effective therapy. Though potent anticancer actions of DTS have been reported in a TNBC cell line, the mechanism of DTS-mediated cytotoxicity and cell death remains ill-defined. In the current study, we show that DTS exhibits cytotoxicity in a panel of triple-negative breast cancer (TNBC) cells derived from patients of European and West African ancestry. We found that DTS inhibits proliferation and migration of CRL-2335 cells derived from a patient of West African ancestry. DTS induces the expression of pro-apoptotic genes BAK1, GADD45a, and LTA in CRL2335 cells though it primarily promotes caspase-independent CRL-2335 cell death. DTS also promotes destabilization of the lysosomal membrane resulting in cathepsin B release in CRL-2335 cells. Finally, Kaplan-Meier survival curves reveal that higher expression of BAK1 and LTA in tumors from patients with TNBC is associated with longer relapse-free survival. Collectively, our data suggest that DTS confers promising antitumor efficacy in TNBC, in part, via lysosomalmediated, caspase-independent cell death to warrant furthering its development as an anticancer agent.