Roman Andrea, Motoc Andrei, Marcovici Iasmina, Dehelean Cristina, Nicolescu Laura, Boru Casiana
Faculty of Medicine, "Vasile Goldis" Western University of Arad, 94 Revolutiei Blvd., 310130 Arad, Romania.
Faculty of Medicine, "Victor Babes" University of Medicine and Pharmacy, Eftimie Murgu Square No. 2, 300041 Timisoara, Romania.
Medicina (Kaunas). 2025 Apr 25;61(5):798. doi: 10.3390/medicina61050798.
Cutaneous melanoma (CM) poses a continuous challenge in oncology due to the developing resistance to available treatments. Doxorubicin (DOX) is noted as one of the most effective chemotherapeutics, although associated toxicity and resistance limit its use in CM treatment. Consequently, DOX has become a promising candidate for combination therapies targeting this neoplasm. Genistein (GEN) gathered significant attention due to its anti-neoplastic properties and ability to enhance the effects of DOX against several cancers, yet this association remains underexplored in CM. Therefore, this study investigated the combination therapy regimen comprising GEN and DOX in terms of anti-melanoma activity and safety profile. : The in vitro experiments were performed on SK-MEL-28 and HaCaT cells. Cell viability was determined using MTT assay. Cell morphology and confluence were inspected microscopically. Nuclear and cytoskeletal aspects were assessed via immunofluorescence. Apoptosis and oxidative stress were quantified through caspase activity and intracellular reactive oxygen species (ROS) production, respectively. The irritant effect was evaluated on the chorioallantoic membrane. : The results revealed that the combination of GEN 10 µM with DOX (0.5 and 1 µM) provided augmented cytotoxic events (e.g., reduced cell viability, altered cell morphology and confluence, apoptotic-like impairments in nuclear shape and cytoskeletal network, increased caspases-3/7 and -9 activity, and elevated ROS) in SK-MEL-28 cells, compared to individual treatments, and exerted a strong synergistic interaction. Simultaneously, GEN 10 µM efficiently surpassed the toxic effects (e.g., viability and confluence loss, hypertrophy, and cytoskeletal condensation) of DOX (0.5 and 1 µM) in HaCaT cells. In ovo, GEN 10 µM + DOX 1 µM treatment was classified as non-irritant. : These findings stand as one of the first contributions revealing the beneficial therapeutic interplay between GEN and DOX at physiologically achievable concentrations that resulted in elevated anti-tumor properties in CM cells and alleviated toxicity in keratinocytes.
由于对现有治疗方法产生耐药性，皮肤黑色素瘤（CM）在肿瘤学领域一直是一项持续的挑战。阿霉素（DOX）被认为是最有效的化疗药物之一，尽管其相关毒性和耐药性限制了它在CM治疗中的应用。因此，DOX已成为针对这种肿瘤的联合治疗的一个有前景的候选药物。染料木黄酮（GEN）因其抗肿瘤特性以及增强DOX对多种癌症的治疗效果的能力而备受关注，但这种联合在CM中的研究仍不充分。因此，本研究从抗黑色素瘤活性和安全性方面研究了GEN与DOX的联合治疗方案。：体外实验在SK-MEL-28和HaCaT细胞上进行。使用MTT法测定细胞活力。通过显微镜检查细胞形态和汇合度。通过免疫荧光评估细胞核和细胞骨架方面。分别通过半胱天冬酶活性和细胞内活性氧（ROS）产生来量化细胞凋亡和氧化应激。在鸡胚尿囊膜上评估刺激作用。：结果显示，与单独治疗相比，10 μM的GEN与DOX（0.5和1 μM）联合在SK-MEL-28细胞中产生了增强的细胞毒性事件（例如，细胞活力降低、细胞形态和汇合度改变、细胞核形状和细胞骨架网络出现凋亡样损伤、半胱天冬酶-3/7和-9活性增加以及ROS升高），并表现出强烈的协同相互作用。同时，10 μM的GEN有效超过了DOX（0.5和1 μM）在HaCaT细胞中的毒性作用（例如，活力和汇合度丧失、肥大以及细胞骨架凝聚）。在鸡胚中，10 μM的GEN + 1 μM的DOX治疗被归类为无刺激性。：这些发现是首批揭示GEN和DOX在生理可达到浓度下有益的治疗相互作用的研究之一，这种相互作用导致CM细胞中的抗肿瘤特性增强，并减轻了角质形成细胞中的毒性。
