The aggresome pathway as a target for therapy in hematologic malignancies.
Misfolded or unfolded proteins are often refolded with the help of chaperones or degraded by the 26S proteasome. An alternative fate of these proteins is the aggresome pathway. The microtubule-organizing center (MTOC) transports unfolded proteins to lysosomes and are degraded through autophagy. Histone deacetylase 6 (HDAC6) deacetylates alpha-tubulin, which is thought to be a component of the MTOC. Recently, two small molecule inhibitors of the aggresome pathway and HDAC6 have been described. One inhibitor, tubacin, prevents deacetylation of alpha-tubulin and produces accumulation of polyubiquitinated proteins and apoptosis. Tubacin acts synergistically with the proteasome inhibitor, bortezomib, to induce cytotoxicity in one type of hematologic malignancy, multiple myeloma. The other, LBH589, is a pan HDAC inhibitor and hydroxamic acid derivative that induces apoptosis of multiple myeloma cells resistant to conventional therapies. In this review, we summarize recent reports on targeting the aggresome pathway and HDAC6 in hematologic malignancies.
Simms-Waldrip
Tiffany
T
Division of Hematology-Oncology, Gwynne Hazen Cherry Memorial Laboratories, Mattel Children's Hospital UCLA, A2-412 MDCC CHS, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1752, USA.
Rodriguez-Gonzalez
Agustin
A
Lin
Tara
T
Ikeda
Alan K
AK
Fu
Cecilia
C
Sakamoto
Kathleen M
KM
D016503:Drug Delivery Systems / Q000379:methods; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D019337:Hematologic Neoplasms / Q000188:drug therapy*; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000502:physiology; D006801:Humans; D008954:Models, Biological; D018832:Molecular Chaperones / Q000502:physiology; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D017510:Protein Folding; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D054875:Ubiquitination / Q000502:physiology
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D018832:Molecular Chaperones; D046988:Proteasome Endopeptidase Complex; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases