Applied Biomedical Research & Training Center "Marianthi Simou", Department of Critical Care & Pulmonary Services, General Hospital "Evangelismos", National and Kapodistrian University of Athens, Greece.
Mol Cancer. 2010 Mar 10;9:56. doi: 10.1186/1476-4598-9-56.
We have previously shown that nuclear factor (NF)-kappaB activation of mouse Lewis lung carcinoma (LLC) specifically promotes the induction of malignant pleural effusions (MPE) by these cells. In the present studies we hypothesized that treatment of immunocompetent mice with bortezomib tailored to inhibit cancer cell NF-kappaB activation and not proliferation specifically inhibits MPE formation by LLC cells.
Treatment of LLC cells with low concentrations of bortezomib (100 ng/ml) inhibited NF-kappaB activation and NF-kappaB-dependent transcription, but not cellular proliferation. Bortezomib treatment of immunocompetent C57BL/6 mice bearing LLC-induced subcutaneous tumors and MPEs significantly blocked tumor-specific NF-kappaB activation. However, bortezomib treatment did not impair subcutaneous LLC tumor growth, but was effective in limiting LLC-induced MPE. This specific effect was evidenced by significant reductions in effusion accumulation and the associated mortality and was observed with both preventive (beginning before MPE formation) and therapeutic (beginning after MPE establishment) bortezomib treatment. The favorable impact of bortezomib on MPE was associated with suppression of cardinal MPE-associated phenomena, such as inflammation, vascular hyperpermeability, and angiogenesis. In this regard, therapeutic bortezomib treatment had identical favorable results on MPE compared with preventive treatment, indicating that the drug specifically counteracts effusion formation.
These studies indicate that proteasome inhibition tailored to block NF-kappaB activation of lung adenocarcinoma specifically targets the effusion-inducing phenotype of this tumor. Although the drug has limited activity against advanced solid lung cancer, it may prove beneficial for patients with MPE.
我们之前已经表明，核因子（NF）-κB 对小鼠 Lewis 肺癌（LLC）的激活特异性地促进了这些细胞诱导恶性胸腔积液（MPE）。在本研究中，我们假设用硼替佐米治疗免疫功能正常的小鼠，专门抑制癌细胞 NF-κB 激活而不是增殖，可特异性抑制 LLC 细胞形成 MPE。
低浓度硼替佐米（100ng/ml）处理 LLC 细胞可抑制 NF-κB 激活和 NF-κB 依赖性转录，但不抑制细胞增殖。硼替佐米治疗携带 LLC 诱导的皮下肿瘤和 MPE 的免疫功能正常的 C57BL/6 小鼠可显著阻断肿瘤特异性 NF-κB 激活。然而，硼替佐米治疗并未损害皮下 LLC 肿瘤生长，但可有效限制 LLC 诱导的 MPE。这一特定效果的证据是胸腔积液积累及其相关死亡率的显著降低，并在预防性（在 MPE 形成之前开始）和治疗性（在 MPE 建立后开始）硼替佐米治疗中均观察到。硼替佐米对 MPE 的有利影响与抑制主要的 MPE 相关现象有关，如炎症、血管通透性增加和血管生成。在这方面，与预防性治疗相比，治疗性硼替佐米治疗对 MPE 具有相同的有利结果，表明该药物特异性地对抗胸腔积液形成。
这些研究表明，针对肺腺癌 NF-κB 激活的蛋白酶体抑制专门针对该肿瘤的胸腔积液诱导表型。尽管该药物对晚期实体肺癌的活性有限，但它可能对 MPE 患者有益。
Zotero 插件
