Background: Bortezomib, a proteasome inhibitor (PI), has excellent clinical activity in patients with multiple myeloma and mantle cell lymphoma. Our previous study has shown that down-regulation of phospho-Akt (P-Akt) plays a key role in determining the sensitivity of hepatocellular carcinoma cells to bortezomib-induced apoptosis. (Cancer Res, 2008). Here, we further examined whether P-Akt is associated with the drug sensitivity of hematological malignant cells toward bortezomib. Methods: Several hematological malignant cell lines were used for in vitro studies. Apoptosis was examined by both flow cytometry and Western blot. Signal transduction pathways in cells were assessed by Western Blot. Gene silencing was done by small interference RNA (siRNA). Results: Bortezomib induced apoptosis in association with down-regulation of P-Akt in a dose- and time-dependent manner in sensitive cells (HL-60) but not in resistant K562 cells. Down-regulation of Akt1 by small interference RNA overcame the apoptotic resistance to bortezomib in K562 cells whereas a constitutively activated Akt1 protected HL-60 cells from bortezomib-induced apoptosis. Importantly, bortezomib showed the similar inhibition of the proteasome activity in both sensitive and resistant cells, suggesting that bortezomib-induced apoptotic effect may not depend on its proteasome inhibitory effect. Conclusions: Down-regulation of P-Akt plays an important role in bortezomib-induced apoptosis in hematological malignancies. Targeting on Akt signaling, either directly or through upstream regulation, provides an attractive approach to overcome bortezomib resistance in certain hematological malignancies. Supported by VGHTPE 99DHA0100332

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1575.