Marchese Melissa, La Regina Gilda, Amato Rachele, Bertoni Gianmarco, Ruzzolini Jessica, Martinucci Daniele, Papucci Laura, Peppicelli Silvia, Bianchini Francesca
Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Viale GB Morgagni 50, 50134, Florence, Italy.
Sci Rep. 2025 Aug 1;15(1):28071. doi: 10.1038/s41598-025-13584-1.
Melanoma is still one of the most aggressive cancers, with global incidence and mortality rates expected to rise significantly by 2040. Surgical excision with adequate safety margins remains the standard treatment for primary cutaneous melanoma. However, the therapeutic approach to treat advanced stages or disease recurrence in melanoma is still challenging. Although initial responses to combined targeted therapies and immune checkpoint inhibitors often achieve clinical success, disease progression remains difficult to manage. Thus, there is an urgent need for novel and unexplored therapeutic strategies. Pirfenidone (PFD) is an antifibrotic drug approved for Idiopathic Pulmonary Fibrosis, with anti-inflammatory, and anti-oxidant properties. Its primary mechanism involves Transforming Growth Factorβ signalling downregulation, alongside with the suppression of cytokine and reactive oxygen species (ROS) release. Recently, it has been suggested that PFD may function as furin convertase enzyme inhibitor. Furin is involved in many physiological and pathological processes such as BRAF oncogene activation. In this study, we investigated the mechanisms of antitumoral effect of PFD in BRAF mutated human melanoma cell lines. Docking analysis revealed a close interaction between PFD and furin convertase active site. In vitro studies revealed that PFD reduced cell proliferation, clonogenicity, and invasiveness. Interestingly, the early antioxidant effect observed during PFD treatment was later replaced by a marked increase in ROS levels, along with p21 upregulation and induction of apoptosis. This multi-angle approach highlights a key role of furin in melanoma cell aggressiveness. Although, the present study lacks clinical data from melanoma patients, our observations suggest that PFD may represent a treatment option for metastatic melanoma cases that are resistant to conventional therapeutic interventions, through a drug repurposing approach.
黑色素瘤仍然是最具侵袭性的癌症之一，预计到2040年全球发病率和死亡率将显著上升。采用足够安全切缘的手术切除仍然是原发性皮肤黑色素瘤的标准治疗方法。然而，治疗黑色素瘤晚期或疾病复发的治疗方法仍然具有挑战性。尽管联合靶向治疗和免疫检查点抑制剂的初始反应常常取得临床成功，但疾病进展仍然难以控制。因此，迫切需要新的未被探索的治疗策略。吡非尼酮（PFD）是一种被批准用于特发性肺纤维化的抗纤维化药物，具有抗炎和抗氧化特性。其主要机制涉及转化生长因子β信号下调，同时抑制细胞因子和活性氧（ROS）释放。最近，有人提出PFD可能作为弗林蛋白酶抑制剂发挥作用。弗林蛋白酶参与许多生理和病理过程，如BRAF癌基因激活。在本研究中，我们研究了PFD在BRAF突变的人黑色素瘤细胞系中的抗肿瘤作用机制。对接分析显示PFD与弗林蛋白酶活性位点之间存在密切相互作用。体外研究表明，PFD可降低细胞增殖、克隆形成能力和侵袭性。有趣的是，PFD治疗期间观察到的早期抗氧化作用后来被ROS水平的显著升高所取代，同时p21上调并诱导细胞凋亡。这种多角度方法突出了弗林蛋白酶在黑色素瘤细胞侵袭性中的关键作用。虽然本研究缺乏黑色素瘤患者的临床数据，但我们的观察结果表明，通过药物重新利用方法，PFD可能代表对传统治疗干预有抗性的转移性黑色素瘤病例的一种治疗选择。
