Hideshima Teru, Podar Klaus, Chauhan Dharminder, Ishitsuka Kenji, Mitsiades Constantine, Tai Yu-Tzu, Hamasaki Makoto, Raje Noopur, Hideshima Hiromasa, Schreiner George, Nguyen Aaron N, Navas Tony, Munshi Nikhil C, Richardson Paul G, Higgins Linda S, Anderson Kenneth C
Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Mayer 557, 44 Binney Street, Boston, MA 02115, USA.
Oncogene. 2004 Nov 18;23(54):8766-76. doi: 10.1038/sj.onc.1208118.
Although PS-341 (bortezomib) is a promising agent to improve multiple myeloma (MM) patient outcome, 65% of patients with relapsed and refractory disease do not respond. We have previously shown that heat shock protein (Hsp)27 is upregulated after PS-341 treatment, that overexpression of Hsp27 confers PS-341 resistance, and that inhibition of Hsp27 overcomes PS-341 resistance. Since Hsp27 is a downstream target of p38 mitogen-activated protein kinase (MAPK)/MAPK-mitogen-activated protein kinase-2 (MAPKAPK2), we hypothesized that inhibition of p38 MAPK activity could augment PS-341 cytotoxicity by downregulating Hsp27. Although p38 MAPK inhibitor SCIO-469 (Scios Inc, CA, USA) alone did not induce significant growth inhibition, it blocked baseline and PS-341-triggered phosphorylation of p38 MAPK as well as upregulation of Hsp27, associated with enhanced cytotoxicity in MM.1S cells. Importantly, SCIO-469 enhanced phosphorylation of c-Jun NH2-terminal kinase (JNK) and augmented cleavage of caspase-8 and poly(ADP)-ribose polymerase. Moreover, SCIO-469 downregulated PS-341-induced increases in G2/M-phase cells, associated with downregulation of p21Cip1 expression. Importantly, SCIO-469 treatment augmented cytotoxicity of PS-341 even against PS-341-resistant cell lines and patient MM cells. These studies therefore provide the framework for clinical trials of SCIO-469 to enhance sensitivity and overcome resistance to PS-341, thereby improving patient outcome in MM.
尽管PS - 341（硼替佐米）是一种有望改善多发性骨髓瘤（MM）患者预后的药物，但65%复发和难治性疾病患者对此无反应。我们之前已经表明，热休克蛋白（Hsp）27在PS - 341治疗后上调，Hsp27的过表达赋予PS - 341耐药性，并且抑制Hsp27可克服PS - 341耐药性。由于Hsp27是p38丝裂原活化蛋白激酶（MAPK）/MAPK丝裂原活化蛋白激酶-2（MAPKAPK2）的下游靶点，我们推测抑制p38 MAPK活性可通过下调Hsp27增强PS - 341的细胞毒性。尽管单独使用p38 MAPK抑制剂SCIO - 469（美国加利福尼亚州Scios公司）不会诱导显著的生长抑制，但它可阻断p38 MAPK的基线和PS - 341触发的磷酸化以及Hsp27的上调，这与MM.1S细胞中细胞毒性增强相关。重要的是，SCIO - 469增强了c - Jun氨基末端激酶（JNK）的磷酸化，并增加了半胱天冬酶-8和聚（ADP）-核糖聚合酶的裂解。此外，SCIO - 469下调了PS - 341诱导的G2/M期细胞增加，这与p21Cip1表达下调相关。重要的是，SCIO - 469治疗增强了PS - 341对PS - 341耐药细胞系和患者MM细胞的细胞毒性。因此，这些研究为SCIO - 469的临床试验提供了框架，以增强对PS - 341的敏感性并克服对其的耐药性，从而改善MM患者的预后。
