The combination of the farnesyl transferase inhibitor lonafarnib and the proteasome inhibitor bortezomib induces synergistic apoptosis in human myeloma cells that is associated with down-regulation of p-AKT

David, Ebenezer; Sun, Shi-Yong; Waller, Edmund K.; Chen, Jing; Khuri, Fadlo R.; Lonial, Sagar

doi:10.1182/blood-2005-06-2584

Cited by 54 publications

(35 citation statements)

References 42 publications

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“…We did not see decreased Akt phosphorylation with bortezomib alone at synergistic concentrations, which may be due to either cell linespecific effects or dose differences. Combining proteasome inhibitors with other agents, such as the farnesyl transferase inhibitor lonafarnib or the cyclin-dependent kinase inhibitor flavopiridol, also down-regulates phosphorylated Akt (39,40). Therefore, Akt seems to play a central role in mediating the cytotoxicity of proteasome inhibitors in combination with a diverse group of therapeutics.…”

Section: Discussionmentioning

confidence: 99%

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

Yu¹,

Friday²,

Lai³

et al. 2006

Molecular Cancer Therapeutics

104

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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]

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Section: Discussionmentioning

confidence: 99%

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

Yu¹,

Friday²,

Lai³

et al. 2006

Molecular Cancer Therapeutics

104

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“…5 In vitro co-treatment with proteasome inhibitors removes resistance and increases sensitivity to different types of anticancer drugs, including traditional antiblastics and g-irradiation, 2,3 as well as more novel therapeutics such as rituximab, histone deacetylase inhibitors, farnesyl transferase inhibitors, tyrosine kinase inhibitors and the cyclin-dependent kinase inhibitor flavopiridol (Bisping G et al Blood 2005; 106: 112; abstract). [24][25][26][27][28] In this context, we have demonstrated that proteasome inhibitors synergistically interact with recombinant TRAIL to overcome chemoresistance and induce apoptosis in chemoresistant Bcl-2-overexpressing lymphoma cells. 23 Interestingly, the cytotoxic effects of proteasome inhibitors have repeatedly been observed to depend on active protein synthesis within the cell, as the translation inhibitor cycloheximide typically blocks proteasome inhibitor-induced apoptosis at a very upstream stage.…”

Section: Mechanisms Of Anticancer Activity Of Proteasome Inhibitorsmentioning

confidence: 99%

Proteasome inhibitors: antitumor effects and beyond

et al. 2006

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Proteasome inhibitors are emerging as effective drugs for the treatment of multiple myeloma and possibly certain subtypes of non-Hodgkin's lymphoma. Bortezomib (Velcade) is the first proteasome inhibitor proven to be clinically useful and will soon be followed by a second generation of small molecule inhibitors with improved pharmacological properties. Although it is now understood that certain types of malignancies have an exquisite dependence on a functional proteasome for their survival, the underlying reason(s) remain unclear as of now. In this context, addiction to nuclear factor-jB (NF-jB)-induced survival signals, activation of the unfolded protein response as well as a reduced proteasomal activity in differentiated plasma cells have all been proposed to justify proteasome inhibitors' activity in susceptible tissues. The ubiquitin-proteasome pathway and its relevance to cancerThe ubiquitin-proteasome pathway (UPP) mediates the degradation of polyubiquitinated proteins and represents the main protein degradation pathway in eucaryotic cells. 1 It is estimated that more than 80% of intracellular proteins are degraded by the proteasome. Besides carrying out protein turnover, the UPP plays an essential role in regulating protein levels during cell cycle, apoptosis, response to cellular stress (i.e. DNA damage, hypoxia) and intracellular signal transduction, not to mention its importance for the generation of antigenic epitopes to be presented on human leukocyte antigen (HLA) molecules. It is now known that some types of cancer are exquisitely prone to undergo apoptosis in response to inhibition of the UPP pathway, a phenomenon that, at present, still lacks a precise explanation. 2,3 Intracellular proteins are targeted for degradation by the conjugation of polyubiquitin chains to lysine residues of the protein, a process carried out by ubiquitin-conjugating enzymes and antagonized by deubiquitinating proteases (revised by Nijman et al. 4 ). 1 Ubiquitination is performed by three enzymes: a ubiquitin-activating enzyme (E1), a ubiquitin-conjugating enzyme (E2) and a ubiquitin ligase (E3). E1 activates ubiquitin monomers by adenylation and transfers them to E2, which in turn works in conjunction with E3 to confer substrate specificity. Whereas E1 only exists in two isoforms derived from alternative splicing of the same messenger at least 25 E2 and hundreds of E3 enzymes exist. 1 A similar complexity is shared by the deubiquitinating enzymes, of which more than 500 are represented in the human genome, thus indicating the high complexity and specificity of this regulatory mechanism. 4 The proteasome is an enzymatic complex that recognizes ubiquitin-tagged proteins and catalyses their proteolytic degradation in an ATP-dependent fashion. 1-3 Proteasomes can be found both in the cytoplasm and in the nucleus of eucaryotic cells. The proteasome typically consists of a 20S component, which is normally associated to a 19S or to an 11S (inducible by interferon-g) regulator component. The 20S proteasome component is compris...

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“…With a wide range of investigational drugs that exploit essential PTM events commonly required by many tumors, combination therapy is being used with various other forms of treatment. These include the use of various PTM inhibitors with chemotherapeutic adjuvants such as taxanes, nucleoside analogs, and platinum agents (70 -72); radiation therapy (73); combination therapy with estrogen receptor antagonists (53); and finally combinations of drugs that inhibit different forms of PTM (74,75). In several cases prolongation of patient survival was found when these combination therapies were used.…”

Section: Ptms In Cancer Treatmentmentioning

confidence: 99%