Multiple myeloma is a clonal
malignancy of plasma cells that invariably progresses to a chemoresistant state. The PI3K/Akt pathway mediates signals downstream of several
growth factors involved in myeloma pathogenesis, and constitutive activation of Akt was observed in myeloma cells. We now report that a
staurosporine derivative, N-benzoylated
staurosporine or
PKC412, induces cell death in myeloma cell lines (RPMI8226S, U266, MM1S and MM1R) with loss of mitochondrial membrane potential Delta psi m,
caspase 3 and PARP cleavage.
ZVAD.fmk, but not
interleukin-6, rescued these cells from
PKC412 effects. Upstream of the mitochondria,
PKC412 inhibited Bad phosphorylation and attenuated Akt
kinase activity by suppressing its phosphorylation on
serine residue in its activation loop. Reduced phosphorylation of downstream Akt substrates GSK3 alpha/beta and FKHR was also noted. Stable transfection of 8226S cells with constitutively active Akt (8226S-myAkt) partially protected against
PKC412 cytotoxicity. Primary myeloma cells isolated from refractory myeloma patients (n=4), were equally sensitive to
PKC412 treatment. More importantly,
PKC412 did not affect CFU-GM or BFU-E colony formation. In summary, our results demonstrate that
PKC412 suppresses Akt
kinase activation and induces apoptosis in myeloma cell lines, as well as primary resistant cells.
PKC412 is an appropriate candidate for novel treatment protocols for
multiple myeloma.