Cotreatment with Suberanoylanilide Hydroxamic Acid and 17-Allylamino 17-demethoxygeldanamycin Synergistically Induces Apoptosis in Bcr-Abl⁺Cells Sensitive and Resistant to STI571 (Imatinib Mesylate) in Association with Down-Regulation of Bcr-Abl, Abrogation of Signal Transducer and Activator of Transcription 5 Activity, and Bax Conformational Change

Abstract

Interactions between the histone deacetylase (HDAC) inhibitors suberanoylanilide hydroxamic acid (SAHA) and sodium butyrate (SB) and the heat shock protein (Hsp) 90 antagonist 17-allylamino 17-demethoxygeldanamycin (17-AAG) have been examined in Bcr-Abl ϩ human leukemia cells (K562 and LAMA84), including those sensitive and resistant to STI571 (imatinib mesylate). Cotreatment with 17-AAG and SAHA or SB synergistically induced mitochondrial dysfunction (cytochrome c and apoptosis-inducing factor release), caspase-3 and -8 activation, apoptosis, and growth inhibition. Similar effects were observed in LAMA84 cells and K562 cells resistant to STI571, as well as in CD34 ϩ cells isolated from the bone marrows of three patients with chronic myelogenous leukemia. These events were associated with increased binding of BcrAbl, Raf-1, and Akt to Hsp70, and inactivation of extracellular signal-regulated kinase 1/2 and Akt. In addition, 17-AAG/SAHA abrogated the DNA binding and the transcriptional activities of signal transducer and activator of transcription (STAT) 5 in K562 cells, including those ectopically expressing a constitutively active STAT5A construct. Cotreatment with 17-AAG and SAHA also induced down-regulation of Mcl-1, Bcl-xL, and BRaf; up-regulation of Bak; cleavage of 14-3-3 proteins; and a profound conformational change in Bax accompanied by translocation to the membrane fraction. Moreover, ectopic expression of Bcl-2 attenuated cell death induced by this regimen, implicating mitochondrial injury in the lethality observed. Together, these findings raise the possibility that combining HDAC inhibitors with the Hsp90 antagonist 17-AAG may represent a novel strategy against Bcr-Abl ϩ leukemias, including those resistant to STI571.17-Allylamino 17-demethoxygeldanamycin (17-AAG), a derivative of the ansamycin antibiotic geldanamycin, has shown promising preclinical activity against a variety of tumor cell types and is currently undergoing phase II clinical evaluation (Dunn, 2002). 17-AAG antineoplastic activity has been attributed to binding to the ATP/ADP binding pocket of the heat shock protein (Hsp) 90, thereby inhibiting its function as a molecular chaperone. Hsp90 plays a key role in the intracellular trafficking and maturation of diverse cell signaling proteins, including those involved in cell survival such as Bcr-Abl, Raf-1, ErbB2, and Akt.

Histone deacetylase inhibitors induce FPGS mRNA expression and intracellular accumulation of long-chain methotrexate polyglutamates in childhood acute lymphoblastic leukemia: implications for combination therapy

“…[39][40][41] Consequently, SAHA is currently being evaluated in several phase-II studies of patients with hematologic and solid-tumor malignancies. 42 SAHA also has shown synergism in hematological malignancies when combined with a wide variety of agents such as the Src kinase-family inhibitor dasatinib; 43 the heat-shock protein 90 antagonist 17-allylamino-17-demethoxygeldanamycin; 44 the cyclin-dependent kinase inhibitor flavopiridol; 45 the nuclear factor-kB inhibitor Bay 11-7082; 46 the Bcr/Abl TK inhibitors imatinib and MK-0457; 47,48 the MEK1/2 inhibitor PD184352; 49 the proteasome inhibitor bortezomib 50,51 and DNA topoisomerase-II inhibitors, 52 among others.…”

Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer

“…The combination of HDACi with DNA-demethylating agents should be more carefully analysed in murine models of tumours, with a view to optimizing the design of clinical studies. HDACi might also work synergistically with HSP90 inhibitors; this would further inhibit the capacity of HSP90 to chaperone oncoproteins that are required for the survival of tumour cells 121 .…”

Targeting HSP90 for cancer therapy

“…Therefore, HSP90 inhibitors targets BCR-ABL for degradation and suppresses cell proliferation (Nimmanapalli et al, 2001). Furthermore, HDAC inhibitors shown to effectively induce apoptosis in both imatinib-sensitive and -resistant BCR-ABL myeloid leukaemia cells can be used in combination with HSP90 inhibitors to synergistically induce apoptosis and inhibit cell growth (Rahmani et al, 2005).…”