Notch activator cyclopiazonic acid induces apoptosis in HL-60 cells through calcineurin activation

We screened a library of microbial extracts and compounds library using our constructed assay cells and found pulicatins F ( 1 ) and G ( 2 ), and cyclopiazonic acid (CPA) ( 3 ) as Notch activators. Pulicatin F ( 1 ) and (±)-pulicatin G were synthesized and their activities were evaluated. Notch activation of CPA ( 3 ) was investigated using Western blot and RT-PCR. CPA ( 3 ) increased protein level of HES1 and mRNA expression of HES1. Also, the expression of FMS-like tyrosine kinase 3 (FLT3), which was known to inhibit apoptosis, was also inhibited by CPA ( 3 ) addition. The Notch activation by CPA ( 3 ) and cytotoxicity against HL-60 were clearly canceled by addition of FK506, which is an inhibitor of calcineurin (CaN). In addition, it was revealed that CPA ( 3 ) induced apoptosis in HL-60 cells.