PKC412 Shows Strong Anti-myeloma effects in in-Vitro-Studies

Background. The protein kinase C (PKC) inhibitor PKC412 (N-benzylstaurosporine) is a derivate of the naturally occurring alkaloid staurosproine and has been shown to inhibit the conventional isoforms of PKC (alfa, beta1, beta2 and gamma). PKC412 has been shown to have an antitumor effect on non-small cell lung cancer and acute leukemia with FLT3 mutations, but little is known about its effect on multiple myeloma up to date.

Methods. Since PKC is also an inhibitor of a tyrosin kinase which is associated with VEGF, and inhibits the release of Interleukin-6, TNF alfa, and that of growth factor dependent C-FOS, we postulated that PKC412 might have also strong anti-myeloma features. Here we evaluated the anti-myeloma effect of PKC412 in the multiple myeloma cell lines INA-6, OPM-2 and RPMI 8226 by measuring its effect on their proliferation rate, the apoptosis rate and the Interleukin-6 mRNA expression.

Results. PKC412 showed strong anti-myeloma effects in all three celllines. 50nM of PKC412 was enough to drop the proliferation rate in all three cell lines under 10% compared to untreated cells(p<0.01). The apoptosis rate increased in INA cell line up to 2,5 times and in RPMI cell line up to 3 times (p<0.05), whereas only a moderate increase was observed in the OPM2 cell line with 500nM of PKC412. As expected, the IL-6 mRNA expression decreased after PKC412 treatment in all three cell lines more than 50%. The addition of Bevacizumab to PKC412 in RPMI and OPM-2 cell lines did not increased the apoptosis rate significantly, whereas the addition of short-interference RNA (RNAi) against VEGF increased the apoptosis rate in RPMI 8226 cells about 20% (p<0.05) and in OPM-2 cells up to 30% (p<0.01) compared to PKC412 alone, which was also associated concordantly with a further reduction of the proliferation rate in RPMI and OPM-2 cells up to 30%.

Conclusions. PKC412 shows strong anti-myeloma effects and might be effective also in the treatment of patients with multiple myeloma. These in-vitro studies might encourage to initiate clinical trials with PKC412 in patients with multiple myeloma.