Atiprimod is a novel anticancer and antiangiogenic
drug candidate which is currently being evaluated in patients with liver
carcinoid and
multiple myeloma. In this study, we report that
atiprimod selectively inhibited proliferation and induced apoptosis in HCC cells that expressed either hepatitis B virus (HBV) or hepatitis C virus, through deactivation of
protein kinase B (Akt) and signal transducers and activators of transcription 3 (STAT3) signaling. In HepG2 AD38 cells, which express HBV genome under the control of a
tetracycline-off promoter, both Akt and STAT3 were constitutively activated in response to HBV expression. However, this constitutive activation was not sensitive to
lamivudine, a
drug that inhibits HBV replication without affecting its gene expression, suggesting that HBV replication per se might not be responsible for the activation. Interestingly, the electrophoretic mobility of p-STAT3
protein bands on immunoblot was slower when AD38 cells were cultured in the absence of
tetracycline, suggesting a differential phosphorylation in response to HBV expression. In HCC cells,
interleukin 6 stimulates the phosphorylation of STAT3 both at
serine 727 and at
tyrosine 705 positions. The
interleukin 6-stimulated activation of STAT3 and Akt was inhibited not only by
atiprimod but also by
LY294002, a phosphoinositide-3-kinase-specific inhibitor, and by
NS398, a cyclooxygenase-2-selective inhibitor. The combination of these compounds did not produce any additive effect, implying that the mechanisms by which HBV activates Akt and STAT3 might also involve phosphoinositide-3-kinase and
cyclooxygenase-2. Collectively, these results suggest that
atiprimod could be useful as a multifunctional
drug candidate for the treatment of HCC in humans.