Giannotti Laura, Di Chiara Stanca Benedetta, Spedicato Francesco, Vergara Daniele, Stanca Eleonora, Damiano Fabrizio, Siculella Luisa
Department of Experimental Medicine, University of Salento, 73100 Lecce, Italy.
Institute of Polymers, Composites and Biomaterials, National Research Council (IPCB-CNR), 80125 Naples, Italy.
Antioxidants (Basel). 2024 Dec 26;14(1):18. doi: 10.3390/antiox14010018.
Cannabinoids include both endogenous endocannabinoids and exogenous phytocannabinoids, such as cannabidiol (CBD), and have potential as therapeutic agents in cancer treatment due to their selective anticancer activities. CBD exhibits both antioxidant and pro-oxidant effects depending on its concentration and cell types. These properties allow CBD to influence oxidative stress responses and potentially enhance the efficacy of antitumor therapies. In this study, we treated U87MG glioma cells with low dose (1 μM) CBD and evaluated its molecular effects. Our findings indicate that CBD reduced cell viability by 20% ( < 0.05) through the alteration of mitochondrial membrane potential. The alteration of redox status by CBD caused an attempt to rescue mitochondrial functionality through nuclear localization of the GABP transcription factor involved in mitochondria biogenesis. Moreover, CBD treatment caused an increase in autophagic flux, as supported by the increase in Beclin-1 and the ratio of LC3-II/LC3-I. Due to mitochondria functionality alteration, pro-apoptotic proteins were induced without activating apoptotic effectors Caspase-3 or Caspase-7. The study of the transcription factor NRF2 and the ubiquitin-binding protein p62 expression revealed an increase in their levels in CBD-treated cells. In conclusion, low-dose CBD makes U87MG cells more vulnerable to cytotoxic effects, reducing cell viability and mitochondrial dynamics while increasing autophagic flux and redox systems. This explains the mechanisms by which glioma cells respond to CBD treatment. These findings highlight the therapeutic potential of CBD, suggesting that modulating NRF2 and autophagy pathways could represent a promising strategy for glioblastoma treatment.
大麻素包括内源性内源性大麻素和外源性植物大麻素，如大麻二酚（CBD），由于其选择性抗癌活性，在癌症治疗中具有作为治疗剂的潜力。CBD根据其浓度和细胞类型表现出抗氧化和促氧化作用。这些特性使CBD能够影响氧化应激反应，并可能增强抗肿瘤治疗的疗效。在本研究中，我们用低剂量（1μM）CBD处理U87MG胶质瘤细胞，并评估其分子效应。我们的研究结果表明，CBD通过改变线粒体膜电位使细胞活力降低了20%（<0.05）。CBD引起的氧化还原状态改变导致试图通过参与线粒体生物发生的GABP转录因子的核定位来挽救线粒体功能。此外，CBD处理导致自噬通量增加，这得到了Beclin-1增加以及LC3-II/LC3-I比率增加的支持。由于线粒体功能改变，诱导了促凋亡蛋白，但未激活凋亡效应物半胱天冬酶-3或半胱天冬酶-7。对转录因子NRF2和泛素结合蛋白p62表达的研究表明，在CBD处理的细胞中它们的水平有所增加。总之，低剂量CBD使U87MG细胞更容易受到细胞毒性作用，降低细胞活力和线粒体动力学，同时增加自噬通量和氧化还原系统。这解释了胶质瘤细胞对CBD治疗作出反应的机制。这些发现突出了CBD的治疗潜力，表明调节NRF2和自噬途径可能是胶质母细胞瘤治疗的一种有前景的策略。
