Srivastava Ankita, Moorthy Anbalagan
School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India 632014.
School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India 632014,
Front Biosci (Schol Ed). 2019 Mar 1;11(1):193-202. doi: 10.2741/S534.
Vemurafenib is a B-raf inhibitor which is widely used in treatment of melanoma patients with B-RAF V600E mutation. Majority of patients treated with vemurafenib develop resistance against the drug. Here, we asssessed the effectiveness of a combination drug therapy in vemurafenib resistant melanoma cells. Vemurafenib resistant A375 melanoma cells (A375Res cells) were developed by growing parental cells in increasing concentrations of the drug. The A375Res cells were 50 times more resistant (higher IC value), had reduced cell doubling time, were less responsive to the antiproliferative activity of Vemurafenib and showed increased tumor forming potential as compared to the parental cells. Vemurafenib inhibited phosphorylation of MEK 1/2 and ERK 1/2 at the concentrations far less than those that were effective in parental cells. Compared to the other drugs sorafenib in combination with vemurafenib significantly inhibited proliferation of A375Res cells. These findings show that Sorafenib, in combination with Vemurafenib, is a more effective method for treatment of melanoma with B-Raf 600E mutation.
维莫非尼是一种B-raf抑制剂，广泛用于治疗携带B-RAF V600E突变的黑色素瘤患者。大多数接受维莫非尼治疗的患者会对该药物产生耐药性。在此，我们评估了联合药物疗法对维莫非尼耐药黑色素瘤细胞的有效性。通过在不断增加药物浓度的条件下培养亲代细胞，培育出了维莫非尼耐药的A375黑色素瘤细胞（A375Res细胞）。与亲代细胞相比，A375Res细胞的耐药性高50倍（IC值更高），细胞倍增时间缩短，对维莫非尼的抗增殖活性反应较弱，且肿瘤形成潜力增加。维莫非尼在远低于对亲代细胞有效的浓度下就能抑制MEK 1/2和ERK 1/2的磷酸化。与其他药物相比，索拉非尼与维莫非尼联合使用能显著抑制A375Res细胞的增殖。这些研究结果表明，索拉非尼与维莫非尼联合使用是治疗携带B-Raf 600E突变黑色素瘤的更有效方法。
