Hanson Kimberley, Robinson Stephen D, Al-Yousuf Karamallah, Hendry Adam E, Sexton Darren W, Sherwood Victoria, Wheeler Grant N
School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK.
School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK.
Oncotarget. 2017 Dec 17;9(3):3815-3829. doi: 10.18632/oncotarget.23378. eCollection 2018 Jan 9.
Cutaneous melanoma, which develops from the pigment producing cells called melanocytes, is the most deadly form of skin cancer. Unlike the majority of other cancers, the incidence rates of melanoma are still on the rise and the treatment options currently available are being hindered by resistance, limited response rates and adverse toxicity. We have previously shown that an FDA approved drug leflunomide, used for rheumatoid arthritis (RA), also holds potential therapeutic value in treating melanoma especially if used in combination with the mutant BRAF inhibitor, vemurafenib. We have further characterized the function of leflunomide and show that the drug reduces the number of viable cells in both wild-type and mutant melanoma cell lines. Further experiments have revealed leflunomide reduces cell proliferation and causes cells to arrest in G1 of the cell cycle. Cell death assays show leflunomide causes apoptosis at treatment concentrations of 25 and 50 µM. To determine if leflunomide could be used combinatorialy with other anti-melanoma drugs, it was tested in combination with the MEK inhibitor, selumetinib. This combination showed a synergistic effect in the cell lines tested. This drug combination led to an enhanced decrease in tumor size when tested compared to either drug alone, demonstrating its potential as a novel combinatorial therapy for melanoma.
皮肤黑色素瘤由名为黑素细胞的色素生成细胞发展而来，是最致命的皮肤癌形式。与大多数其他癌症不同，黑色素瘤的发病率仍在上升，目前可用的治疗方案受到耐药性、有限的缓解率和不良毒性的阻碍。我们之前已经表明，一种用于类风湿性关节炎（RA）的FDA批准药物来氟米特，在治疗黑色素瘤方面也具有潜在的治疗价值，特别是与突变型BRAF抑制剂维莫非尼联合使用时。我们进一步对来氟米特的功能进行了表征，结果表明该药物可减少野生型和突变型黑色素瘤细胞系中的活细胞数量。进一步的实验表明，来氟米特可降低细胞增殖并使细胞停滞在细胞周期的G1期。细胞死亡分析表明，来氟米特在25和50 µM的治疗浓度下可导致细胞凋亡。为了确定来氟米特是否可以与其他抗黑色素瘤药物联合使用，我们将其与MEK抑制剂司美替尼联合进行了测试。这种联合在测试的细胞系中显示出协同作用。与单独使用任何一种药物相比，这种药物组合在测试时导致肿瘤大小的下降更为显著，证明了其作为黑色素瘤新型联合治疗方法的潜力。
