硼替佐米在恶性间皮瘤中的抗肿瘤作用：体外轻度内质网应激和体内 T 细胞反应激活的证据。

Antitumoral effects of Bortezomib in malignant mesothelioma: evidence of mild endoplasmic reticulum stress in vitro and activation of T cell response in vivo.

机构信息

Department of Clinical Sciences and Translational Medicine, University of Rome "Tor Vergata", Rome, Italy.

Saint Camillus International, University of Health and Medical Sciences, Rome, Italy.

出版信息

Biol Direct. 2023 Apr 17;18(1):17. doi: 10.1186/s13062-023-00374-w.

DOI:10.1186/s13062-023-00374-w

PMID:37069690

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10111665/

Abstract

BACKGROUND

Malignant mesothelioma (MM) is a rare tumor with a dismal prognosis. The low efficacy of current treatment options highlights the urge to identify more effective therapies aimed at improving MM patients' survival. Bortezomib (Bor) is a specific and reversible inhibitor of the chymotrypsin-like activity of the 20S core of the proteasome, currently approved for the treatment of multiple myeloma and mantle cell lymphoma. On the other hand, Bor appears to have limited clinical effects on solid tumors, because of its low penetration and accumulation into tumor tissues following intravenous administration. These limitations could be overcome in MM through intracavitary delivery, with the advantage of increasing local drug concentration and decreasing systemic toxicity.

METHODS

In this study, we investigated the effects of Bor on cell survival, cell cycle distribution and modulation of apoptotic and pro-survival pathways in human MM cell lines of different histotypes cultured in vitro. Further, using a mouse MM cell line that reproducibly forms ascites when intraperitoneally injected in syngeneic C57BL/6 mice, we investigated the effects of intraperitoneal Bor administration in vivo on both tumor growth and the modulation of the tumor immune microenvironment.

RESULTS

We demonstrate that Bor inhibited MM cell growth and induced apoptosis. Further, Bor activated the Unfolded Protein Response, which however appeared to participate in lowering cells' sensitivity to the drug's cytotoxic effects. Bor also affected the expression of EGFR and ErbB2 and the activation of downstream pro-survival signaling effectors, including ERK1/2 and AKT. In vivo, Bor was able to suppress MM growth and extend mice survival. The Bor-mediated delay of tumor progression was sustained by increased activation of T lymphocytes recruited to the tumor microenvironment.

CONCLUSIONS

The results presented herein support the use of Bor in MM and advocate future studies aimed at defining the therapeutic potential of Bor and Bor-based combination regimens for this treatment-resistant, aggressive tumor.

摘要

背景

恶性间皮瘤（MM）是一种罕见的肿瘤，预后较差。目前治疗选择的疗效较低，突显了迫切需要寻找更有效的治疗方法，以改善 MM 患者的生存。硼替佐米（Bor）是一种蛋白酶体 20S 核心糜蛋白酶样活性的特异性和可逆抑制剂，目前已被批准用于治疗多发性骨髓瘤和套细胞淋巴瘤。另一方面，由于静脉给药后 Bor 进入肿瘤组织的穿透和积累有限，因此其对实体瘤的临床疗效有限。通过腔内给药，这些局限性在 MM 中可以得到克服，其优势在于增加局部药物浓度和降低全身毒性。

方法

在这项研究中，我们研究了 Bor 对体外培养的不同组织型人 MM 细胞系的细胞存活、细胞周期分布以及凋亡和存活途径的调节作用。此外，我们使用一种可在同基因 C57BL/6 小鼠体内腹膜内注射时重现形成腹水的小鼠 MM 细胞系，研究了腹腔内给予 Bor 对体内肿瘤生长和肿瘤免疫微环境调节的影响。

结果

我们证明 Bor 抑制 MM 细胞生长并诱导细胞凋亡。此外，Bor 激活了未折叠蛋白反应，但这似乎参与降低了细胞对药物细胞毒性作用的敏感性。Bor 还影响 EGFR 和 ErbB2 的表达以及下游存活信号效应物的激活，包括 ERK1/2 和 AKT。在体内，Bor 能够抑制 MM 生长并延长小鼠的存活。Bor 介导的肿瘤进展延迟与募集到肿瘤微环境中的 T 淋巴细胞的激活增加有关。