John D. Dingell VA Medical Center, Karmanos Cancer Institute, Wayne State University, VAMC, 4646 John R., Detroit, MI, 48201, USA.
Cancer Chemother Pharmacol. 2010 Aug;66(3):455-66. doi: 10.1007/s00280-009-1181-8. Epub 2009 Dec 4.
Thoracic malignancies and human breast cancer (HBC) continue to be aggressive solid tumors that are poor responders to the existing conventional standard chemotherapeutic approaches. Malignant pleural mesothelioma (MPM) is an asbestos-related tumor of the thoracic pleura that lacks effective treatment options. Altered ubiquitin proteasome pathway is frequently encountered in many malignancies including HBC and MPM and thus serves as an important target for therapeutic intervention strategies. Although proteasome inhibitor Velcade (Bortezomib) has been under clinical investigation for a number of cancers, limited preclinical studies with this agent have thus far been conducted in HBC and MPM malignancies.
To study the biological and molecular responses of MPM and HBC cells to Velcade treatments, and to identify mechanisms involved in transducing growth inhibitory effects of this agent.
Flow-cytometric analyses coupled with western immunoblotting and gene-array methodologies were utilized to determine mechanisms of Velcade-dependent growth suppression of five MPM (H2595, H2373, H2452, H2461, and H2714) and two breast cancer (MDA MB-468, SKBR-3) cell lines.
Our data revealed significant reduction in cell growth properties that were dose and time dependent. Velcade treatment resulted in G2M phase arrest, increased expression of cyclin-dependent kinase inhibitor p21 and pro-apoptotic protein Bax. Pretreatment of mesothelioma cells with Velcade showed synergistic effect with cisplatin combination regimens. High-throughput gene expression profiling among Velcade treated and untreated mesothelioma cell lines resulted in identification of novel transducers of apoptosis such as CARP-1, XAF1, and Troy proteins.
Velcade targets cell cycle and apoptosis signaling to suppress MPM and HBC growth in part by activating novel transducers of apoptosis. This pilot study has paved way for further in-depth analysis of the downstream target molecules associated with presensitization of mesothelioma cells in finding effective therapeutic treatment options for both mesothelioma and recalcitrant breast cancers.
胸部恶性肿瘤和人乳腺癌（HBC）仍然是对现有常规标准化疗方法反应不佳的侵袭性实体肿瘤。恶性胸膜间皮瘤（MPM）是一种与石棉有关的胸胸膜肿瘤，缺乏有效治疗方法。许多恶性肿瘤中经常出现异常的泛素蛋白酶体通路，包括 HBC 和 MPM，因此它是治疗干预策略的重要靶点。尽管蛋白酶体抑制剂硼替佐米（Bortezomib，Velcade）已在多种癌症的临床研究中进行了研究，但迄今为止，针对 HBC 和 MPM 恶性肿瘤的这种药物的临床前研究有限。
研究 MPM 和 HBC 细胞对 Velcade 治疗的生物学和分子反应，并确定介导该药物生长抑制作用的机制。
利用流式细胞术分析结合 Western 免疫印迹和基因阵列方法来确定五种 MPM（H2595、H2373、H2452、H2461 和 H2714）和两种乳腺癌（MDA MB-468、SKBR-3）细胞系中 Velcade 依赖性生长抑制的机制。
我们的数据显示，细胞生长特性明显降低，且呈剂量和时间依赖性。Velcade 治疗导致 G2M 期阻滞，细胞周期蛋白依赖性激酶抑制剂 p21 和促凋亡蛋白 Bax 的表达增加。用 Velcade 预处理间皮瘤细胞与顺铂联合方案显示协同作用。在 Velcade 处理和未处理的间皮瘤细胞系中进行高通量基因表达谱分析，确定了新型凋亡传感器，如 CARP-1、XAF1 和 Troy 蛋白。
Velcade 通过激活新型凋亡传感器来靶向细胞周期和凋亡信号通路，以抑制 MPM 和 HBC 的生长。这项初步研究为进一步深入分析与间皮瘤细胞预致敏相关的下游靶分子铺平了道路，以期为间皮瘤和难治性乳腺癌找到有效的治疗方法。
