Shringarpure Reshma, Catley Laurence, Bhole Deepak, Burger Renate, Podar Klaus, Tai Yu-Tzu, Kessler Benedikt, Galardy Paul, Ploegh Hidde, Tassone Pierfrancesco, Hideshima Teru, Mitsiades Constantine, Munshi Nikhil C, Chauhan Dharminder, Anderson Kenneth C
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Br J Haematol. 2006 Jul;134(2):145-56. doi: 10.1111/j.1365-2141.2006.06132.x.
The proteasome inhibitor bortezomib has shown impressive clinical activity alone and in combination with conventional and other novel agents for the treatment of multiple myeloma (MM). Although bortezomib is known to be a selective proteasome inhibitor, the downstream mechanisms of cytotoxicity and drug resistance are poorly understood. However, resistance to bortezomib as a single agent develops in the majority of patients, and activity in other malignancies has been less impressive. To elucidate mechanisms of bortezomib resistance, we compared differential gene expression profiles of bortezomib-resistant SUDHL-4 and bortezomib-sensitive SUDHL-6 diffuse large B-cell lymphoma lines in response to bortezomib. At concentrations that effectively inhibited proteasome activity, bortezomib induced apoptosis in SUDHL-6 cells, but not in SUDHL-4 cells. We showed that overexpression of activating transcription factor 3 (ATF3), ATF4, ATF5, c-Jun, JunD and caspase-3 is associated with sensitivity to bortezomib-induced apoptosis, whereas overexpression of heat shock protein (HSP)27, HSP70, HSP90 and T-cell factor 4 is associated with bortezomib resistance.
蛋白酶体抑制剂硼替佐米单独使用以及与传统药物和其他新型药物联合使用时，在治疗多发性骨髓瘤（MM）方面已显示出令人瞩目的临床活性。尽管硼替佐米是一种选择性蛋白酶体抑制剂，但其细胞毒性和耐药性的下游机制仍知之甚少。然而，大多数患者会对硼替佐米单药产生耐药性，且其在其他恶性肿瘤中的活性也不那么显著。为了阐明硼替佐米耐药的机制，我们比较了硼替佐米耐药的SUDHL - 4和硼替佐米敏感的SUDHL - 6弥漫性大B细胞淋巴瘤细胞系在硼替佐米作用下的差异基因表达谱。在有效抑制蛋白酶体活性的浓度下，硼替佐米可诱导SUDHL - 6细胞凋亡，但不能诱导SUDHL - 4细胞凋亡。我们发现，激活转录因子3（ATF3）、ATF4、ATF5、c - Jun、JunD和半胱天冬酶 - 3的过表达与硼替佐米诱导的凋亡敏感性相关，而热休克蛋白（HSP）27、HSP70、HSP90和T细胞因子4的过表达与硼替佐米耐药相关。
