Arsenic trioxide and proteasome inhibitor bortezomib synergistically induce apoptosis in leukemic cells: the role of protein kinase Cδ

Abstract

Arsenic trioxide (ATO) and proteasome inhibitor bortezomib have been successfully applied to treat acute promyelocytic leukemia (APL) and multiple myeloma (MM), respectively. Their synergistic effects with other anticancer drugs have been widely studied. Here, we investigated the potential synergy of bortezomib and ATO on Bcr-Abl þ leukemic K562 cells. The results showed that cotreatment of bortezomib at 32 nM, a half concentration for growth arrest, and ATO at 1 lM, a dose with no significant cytotoxic effect, synergistically induced apoptosis in the cell line, followed by enhanced mitochondrial dysfunction, release of cytochrome c and apoptosis-inducing factor, caspase-3 cleavage and degradation of poly-adenosine diphosphate-ribose polymerase together with the decreased Bcr-Abl protein. These two drugs synergistically induced proteolytic activation of protein kinase Cd (PKCd) with enhanced activation of two mitogen-activated protein kinases phospho-c-Jun NH 2 -terminal kinase and p38. The specific PKCd inhibitor rottlerin markedly decreased bortezomib plus ATO-induced apoptosis, suggesting that PKCd plays an important role in bortezomib plus ATO-induced apoptosis. Moreover, apoptosis synergy of bortezomib and ATO could also be seen in some kinds of acute leukemic cell lines and primary cells. Totally, our results indicate that combined regimen of bortezomib and ATO might be a potential therapeutic remedy for the treatment of leukemia.

Bortezomib induces apoptosis in primitive chronic myeloid leukemia cells including LTC-IC and NOD/SCID repopulating cells

“…There is published evidence that BCR-ABL expression is associated with increased proteasome activity; primitive CML cells express higher levels of BCR-ABL than their more mature counterparts and BCR-ABL ϩ cell lines are susceptible to PI. 18,22,39,40 We have extended this work to demonstrate that CD34-enriched samples taken at diagnosis from patients with CP CML undergo apoptosis in SFMϮ5GF with bortezomib exposure. This effect was replicated in 7 different patient samples and the drug was consistent in its effect.…”

“…These studies used BCR-ABL ϩ cell lines both sensitive and resistant to IM and demonstrated antiproliferative and apoptotic effects. [39][40][41] In addition, the PI Z-Ile-Glu(OtBu)-Ala-Leucinal selectively inhibits colony formation by CD34 ϩ BCR-ABL ϩ progenitor cells. 41 Despite promising in vitro effects, there are little in vivo data.…”

Bortezomib decreases Rb phosphorylation and induces caspase-dependent apoptosis in Imatinib-sensitive and -resistant Bcr-Abl1-expressing cells

“…Most of them use Btz in combination with other drugs (Yu et al, 2003;Dai et al, 2004;Dasmahapatra et al, 2006;Yan et al, 2007) or lack the use of control cells (Gatto et al, 2003). In our case, we have used Btz alone at a dose that has no effect on BaF/3 cells that do not express Bcr-Abl1, showing that Btz alone is sufficient to arrest the cell cycle and induce apoptosis specifically in Bcr-Abl1-expressing cells.…”

Protein Kinase C (PKC) Isozymes and Cancer

“…Expression of PKC in AML cells induces cell death through the downregulation of heterogeneous nuclear ribonucleoprotein K [380], phosphorylation of eIF2 [381] and -actin [382], and activation of MAPKs (JNK and p38) [383] and caspase-3 [384,385]. In addition, when wogonin, a natural monoflavonoid, is added to AML U937 cells, cell differentiation and G 1 phase arrest are induced through PKC -mediated upregulation of p21 proteins [386].…”