Cytotoxic synergy between the multikinase inhibitor sorafenib and the proteasome inhibitor bortezomib in vitro: induction of apoptosis through Akt and c-Jun NH2-terminal kinase pathways

Abstract

This study was undertaken to characterize preclinical cytotoxic interactions for human malignancies between the multikinase inhibitor sorafenib (BAY 43-9006) and proteasome inhibitors bortezomib or MG132. Multiple tumor cell lines of varying histiotypes, including A549 (lung adenocarcinoma), 786-O (renal cell carcinoma), HeLa (cervical carcinoma), MDA-MB-231 (breast), K562 (chronic myelogenous leukemia), Jurkat (acute T-cell leukemia), MEC-2 (B-chronic lymphocytic leukemia), and U251 and D37 (glioma), as well as cells derived from primary human glioma tumors that are likely a more clinically relevant model were treated with sorafenib or bortezomib alone or in combination. Sorafenib and bortezomib synergistically induced a marked increase in mitochondrial injury and apoptosis, reflected by cytochrome c release, caspase-3 cleavage, and poly(ADPribose) polymerase degradation in a broad range of solid tumor and leukemia cell lines. These findings were accompanied by several biochemical changes, including decreased phosphorylation of vascular endothelial growth factor receptor-2, platelet-derived growth factor receptor-B, and Akt and increased phosphorylation of stress-related c-Jun NH 2 -terminal kinase (JNK). Inhibition of Akt was required for synergism, as a constitutively active Akt protected cells against apoptosis induced by the combination. Alternatively, the JNK inhibitor SP600125 could also protect cells from apoptosis induced by the combination, indicating that both inhibition of Akt and activation of JNK were required for the synergism. These findings show that sorafenib interacts synergistically with bortezomib to induce apoptosis in a broad spectrum of neoplastic cell lines and show an important role for the Akt and JNK pathways in mediating synergism. Further clinical development of this combination seems warranted. [Mol Cancer Ther 2006;5(9):2378 -87]

Tanshinone IIA arrests cell cycle and induces apoptosis in 786-O human renal cell carcinoma cells

“…Moreover, Tan IIA treatment led to a concentration-dependent increase in the levels of p53, paralleling the accumulation of p21. These results suggest that the observed p21 accumulation may be due to p53 activation, since p53 (wild-type) upregulates p21 expression (16). It should be noted that it is possible that the level of p21 was altered via a p53-independent pathway.…”

Sorafenib induces cell death in chronic lymphocytic leukemia by translational downregulation of Mcl-1

“…This may certainly depend on the drugpartner combined with sorafenib. A synergism between sorafenib and bortezomib has been demonstrated in the CLL cell line MEC-2 30 , but it still needs to be experimentally explored whether this can be translated to primary CLL cells.…”

Role of ATF4 in regulation of autophagy and resistance to drugs and hypoxia

“…68,94 Interaction between inhibitors of the proteasome and HDAC inhibitors have been investigated, showing synergistic effect, in different types of cancer and future clinical applications of this combination should be considered. [95][96][97][98][99] Synergistic effects were shown for BZ in combination with tubacin and SAHA that inhibits HDAC6 resulting in a marked accumulation of ubiquitinated proteins. 100,101 Moreover, recent studies showed that disruption of autophagy, resulted in accumulation of ubiquitinated proteins and HDACs inhibitors, like Vorinostat, potentiates aggregates formation, super oxide generation and apoptosis.…”

“…100,101 Moreover, recent studies showed that disruption of autophagy, resulted in accumulation of ubiquitinated proteins and HDACs inhibitors, like Vorinostat, potentiates aggregates formation, super oxide generation and apoptosis. 96,98,102,103 …”