Simms-Waldrip Tiffany, Rodriguez-Gonzalez Agustin, Lin Tara, Ikeda Alan K, Fu Cecilia, Sakamoto Kathleen M
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.
Mol Genet Metab. 2008 Jul;94(3):283-6. doi: 10.1016/j.ymgme.2008.03.012. Epub 2008 May 9.
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.
错误折叠或未折叠的蛋白质通常会在伴侣蛋白的帮助下重新折叠，或者被26S蛋白酶体降解。这些蛋白质的另一种命运是进入聚集体途径。微管组织中心（MTOC）将未折叠的蛋白质转运到溶酶体，并通过自噬进行降解。组蛋白脱乙酰基酶6（HDAC6）使α-微管蛋白去乙酰化，而α-微管蛋白被认为是MTOC的一个组成部分。最近，已经描述了两种针对聚集体途径和HDAC6的小分子抑制剂。一种抑制剂tubacin可防止α-微管蛋白去乙酰化，并导致多聚泛素化蛋白的积累和细胞凋亡。Tubacin与蛋白酶体抑制剂硼替佐米协同作用，在一种血液系统恶性肿瘤——多发性骨髓瘤中诱导细胞毒性。另一种抑制剂LBH589是一种泛HDAC抑制剂和异羟肟酸衍生物，可诱导对传统疗法耐药的多发性骨髓瘤细胞凋亡。在这篇综述中，我们总结了近期关于在血液系统恶性肿瘤中靶向聚集体途径和HDAC6的报道。
