背景:伏立诺他(SAHA)是一种组蛋白脱乙酰酶抑制剂,已显示出对晚期皮肤T细胞淋巴瘤(CTCL)的临床疗效。然而,只有一部分CTCL患者(30-35%)对SAHA有反应,而且这种反应并不总是可持续的.因此,了解这种癌症中规避耐药的潜在机制是提高当前疗法疗效的未满足的医学需求.
目的:本研究旨在确定CTCL中导致SAHA耐药性的因素以及减轻该耐药性的方法。
结果:在这项研究中,我们证明了减弱的活性氧(ROS)诱导白细胞介素(IL)-2Rα的表达,IL-2受体之一,驱动CTCL中SAHA的阻力。我们还确定,斑驳素可以通过ROS依赖性方式阻断IL-2Rα相关信号来克服SAHA对CTCL的抗性。机械上,由于SAHA抗性CTCL中ROS水平降低,IL-2Rα的加速翻译有助于过度的IL-2Rα蛋白形成。同时,IL-2Rβ与IL-2Rγ和Janus激酶/信号转导子和转录分子激活子的相互作用增强,并通过增加蛋白激酶B(AKT)/mTOR和丝裂原激活的蛋白激酶信号传导的表达。此外,cantharidin,中药中使用的Mylabris的活性成分,ROS水平显著增加,从而抑制IL-2Rα的翻译,导致SAHA抗性细胞中下游途径的抑制。还发现斑潜素与SAHA协同作用,并在体外和体内通过IL-2R信号传导触发SAHA抗性细胞死亡。
结论:我们的研究揭示了获得性SAHA耐药的一种新的分子机制,并且还表明使用斑蒿苷是克服CTCL治疗耐药的一种潜在方法。我们的发现是斑疹素治疗CTCL的潜在治疗价值的基础。
BACKGROUND: Vorinostat (SAHA) is a histone deacetylase inhibitor that has shown clinical efficacy against advanced cutaneous T-cell lymphoma (CTCL). However, only a subset of patients with CTCL (30-35%) respond to SAHA and the response is not always sustainable. Thus, understanding the mechanisms underlying evasive resistance in this cancer is an unmet medical need to improve the efficacy of current therapies.
OBJECTIVE: This study aims to identify factors contributing to resistance against SAHA in CTCL and ways to mitigate it.
RESULTS: In this study, we demonstrated that attenuated reactive oxygen species (ROS) induces the expression of interleukin (IL)-2Rα, one of the IL-2 receptors, which drives resistance to SAHA in CTCL. We also determined that
cantharidin could overcome SAHA resistance to CTCL by blocking IL-2Rα-related signaling via ROS-dependent manner. Mechanistically, accelerated translation of IL-2Rα contributes to excessive IL-2Rα protein formation as a result of reduced ROS levels in SAHA-resistant CTCL. At the same time, amplified IL-2R signals are evidenced by strengthened interaction of IL-2Rβ with IL-2Rγ and Janus kinase/signal transducer and activator of transcription molecules, and by increased expression of protein kinase B (AKT)/mTOR and mitogen-activated protein kinase signaling. Moreover,
cantharidin, an active constituent of Mylabris used in traditional Chinese medicine, markedly increased ROS levels, and thereby restrained IL-2Rα translation, resulting in suppression of downstream pathways in SAHA-resistant cells.
Cantharidin is also found to synergize with SAHA and triggers SAHA-resistant cell death via IL-2R signaling both in vitro and in vivo.
CONCLUSIONS: Our study uncovers a novel molecular mechanism of acquired SAHA resistance and also suggests that using
cantharidin is a potential approach to overcome CTCL therapy resistance. Our findings underlie the therapeutic potential of
cantharidin in treating CTCL.