Baeta Jefferson Viktor de Paula Barros, Rocha E Oliveira Maria Aparecida Braga, Nascimento Fernada Rodrigues, de Oliveira Marcos Rodrigo, Pizziolo Virgínia Ramos, de Oliveira Mendes Tiago Antônio, Diaz-Muñoz Gaspar, Dos Santos Anésia Aparecida, Diaz Marisa Alves Nogueira
Departments of Biochemistry and Molecular Biology.
Medicine, Universidade Federal de Viçosa, Viçosa.
Anticancer Drugs. 2025 Sep 1;36(8):607-621. doi: 10.1097/CAD.0000000000001730. Epub 2025 Jun 17.
This study investigated 2-allyl-1,3-diphenyl-1,3-propanedione (DPAP), a dibenzoylmethane derivative, as a potentially more effective and safer alternative to dacarbazine for melanoma treatment. The antitumor activity of DPAP was assessed through comprehensive in-vitro, in-silico, and in-vivo experiments. In-vitro assays evaluated DPAP's IC 50 values against melanoma cells, benchmarking its efficacy against dacarbazine. Molecular analyses explored apoptosis mechanisms, emphasizing the roles of FAS receptors and caspase pathways. In-silico absorption, distribution, metabolism, excretion, and toxicity analysis provided insights into DPAP's pharmacokinetic profile, including absorption, distribution, metabolism, and toxicity. In-vivo studies examined its effects on tumor volume, vascular endothelial growth factor (VEGF) levels, and the histopathology of the liver, kidney, and lymph nodes. DPAP demonstrated significantly enhanced antitumor activity, reflected by markedly lower IC 50 values compared with dacarbazine, underscoring its superior efficacy and specificity toward tumor cells. Molecular assays confirmed that DPAP induces apoptosis through modulation of FAS receptors and activation of caspase pathways. In-silico results revealed favorable pharmacokinetic properties, including high intestinal absorption and good tissue distribution, with no evidence of carcinogenic potential. Notably, in-vivo experiments showed that DPAP effectively reduced tumor volume and VEGF levels, while also preventing hepatotoxicity and nephrotoxicity. In addition, it inhibited the migration of tumor cells to lymph nodes. These findings position DPAP as a promising candidate for melanoma treatment, particularly as a topical therapeutic, offering enhanced efficacy and safety compared with existing treatments. DPAP is a promising candidate for melanoma treatment, particularly through topical application, offering a safer and more effective alternative to current treatments.
本研究调查了二苯甲酰甲烷衍生物2-烯丙基-1,3-二苯基-1,3-丙二酮（DPAP），作为一种对黑色素瘤治疗可能更有效、更安全的达卡巴嗪替代物。通过全面的体外、计算机模拟和体内实验评估了DPAP的抗肿瘤活性。体外试验评估了DPAP对黑色素瘤细胞的半数抑制浓度（IC50）值，以此为基准衡量其相对于达卡巴嗪的疗效。分子分析探索了凋亡机制，着重研究了FAS受体和半胱天冬酶途径的作用。计算机模拟的吸收、分布、代谢、排泄和毒性分析提供了有关DPAP药代动力学特征的见解，包括吸收、分布、代谢和毒性。体内研究考察了其对肿瘤体积、血管内皮生长因子（VEGF）水平以及肝脏、肾脏和淋巴结组织病理学的影响。与达卡巴嗪相比，DPAP的IC50值显著降低，表明其抗肿瘤活性显著增强，突出了其对肿瘤细胞的卓越疗效和特异性。分子试验证实，DPAP通过调节FAS受体和激活半胱天冬酶途径诱导凋亡。计算机模拟结果显示出良好的药代动力学特性，包括高肠道吸收率和良好的组织分布，且无致癌潜力的迹象。值得注意的是，体内实验表明，DPAP有效降低了肿瘤体积和VEGF水平，同时还预防了肝毒性和肾毒性。此外，它还抑制了肿瘤细胞向淋巴结的迁移。这些发现表明DPAP是黑色素瘤治疗的一个有前景的候选药物，特别是作为一种局部治疗药物，与现有治疗方法相比，疗效和安全性更高。DPAP是黑色素瘤治疗的一个有前景的候选药物，特别是通过局部应用，为当前治疗提供了一种更安全、更有效的替代方案。
