Eribulin Induction of Immunogenic Cell Death (ICD): Comparison With Other Cytotoxic Agents and Temporal Relationship of ICD Biomarkers.

BACKGROUND/AIM: Preclinical studies were undertaken to investigate whether eribulin's known cytotoxic antimitotic effects are characterized by immunogenic cell death (ICD) as assessed by three established ICD biomarkers: extracellular released ATP, released HMGB1 and cell surface calreticulin.

MATERIALS AND

METHODS

Using BT-549, Hs578T and MCF-7 breast cancer cell lines, antiproliferative IC50's of eribulin, five other microtubule targeting agents (MTAs; ER-076349, vinblastine, vinorelbine, paclitaxel, docetaxel) and three DNA damaging agents (DDAs; doxorubicin, cisplatin, oxaliplatin) were determined.

RESULTS

Treatment of cells with 10×IC50 concentrations of all drugs in serum-free media resulted in time-dependent induction of cytotoxicity over DMSO controls. Measurement of ATP and HMGB1 released into conditioned media and appearance of cell surface calreticulin support eribulin's ability to induce ICD. Compared to the other agents tested, eribulin's potency as an ICD inducer was mid-range and shared with vinblastine, paclitaxel, doxorubicin and oxaliplatin. Interestingly, MTAs as a group appeared to be more potent inducers of ATP release compared to DDAs, whereas DDAs appeared to be more potent inducers of cell surface calreticulin compared to MTAs. Overall, drug effects on ATP release and cell surface calreticulin showed early peaking followed by rapid decline, while effects on HMGB1 release were generally slower and more prolonged.

CONCLUSION

Our results support the concept that eribulin's cytotoxic effects are associated with ICD. These findings provide impetus for investigating how eribulin-induced ICD may contribute to the larger spectrum of phenotypic and immunological effects by which eribulin exerts antitumor therapeutic benefits.