Gowda Raghavendra, Sharma Arati, Robertson Gavin P
Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, United states; The Penn State Melanoma Center, The Pennsylvania State University College of Medicine, Hershey, PA 17033, United states; Penn State Melanoma Therapeutics Program, The Pennsylvania State University College of Medicine, Hershey, PA 17033, United states; Foreman Foundation for Melanoma Research, The Pennsylvania State University College of Medicine, Hershey, PA 17033, United states.
Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, United states.
Cancer Lett. 2017 Jan 28;385:243-250. doi: 10.1016/j.canlet.2016.10.016. Epub 2016 Oct 18.
Melanoma is a highly drug resistant cancer. To circumvent this problem, a class of synergistically acting drug combinations, which inhibit multiple key pathways in melanoma cells, could be used as one approach for long-term treatment of this deadly disease. A screen has been undertaken on cell lines to identify those that could be combined to synergistically kill melanoma cells. Plumbagin and Celecoxib are two agents that were identified to synergistically kill melanoma cells by inhibiting the COX-2 and STAT3 pathways, which are constitutively activated in up to 70% of melanomas. The combination of these two drugs was more effective at killing melanoma cells than normal cells and decreased cellular proliferation as well as induced apoptosis of cultured cells. The drug combination inhibited development of xenograft melanoma tumors by up to 63% without affecting animal weight or blood biomarkers of organ function, suggesting negligible toxicity. Mechanistically, combination of Celecoxib and Plumbagin decreased melanoma cell proliferation and retarded vascular development of tumors mediated by inhibition of COX-2 and STAT3 leading to decreased levels of key cyclins key on which melanoma cell were dependent for survival.
黑色素瘤是一种具有高度耐药性的癌症。为了解决这个问题，一类协同作用的药物组合可作为治疗这种致命疾病的长期方法之一，这类组合能抑制黑色素瘤细胞中的多个关键通路。已对细胞系进行筛选，以确定哪些细胞系可以联合起来协同杀死黑色素瘤细胞。白花丹素和塞来昔布是两种经鉴定可通过抑制COX - 2和STAT3通路协同杀死黑色素瘤细胞的药物，在高达70%的黑色素瘤中，这两条通路处于持续激活状态。这两种药物的组合在杀死黑色素瘤细胞方面比正常细胞更有效，可降低细胞增殖并诱导培养细胞凋亡。该药物组合可使异种移植黑色素瘤肿瘤的生长抑制高达63%，且不影响动物体重或器官功能的血液生物标志物，表明其毒性可忽略不计。从机制上讲，塞来昔布和白花丹素的组合通过抑制COX - 2和STAT3降低了黑色素瘤细胞增殖并延缓了肿瘤的血管生成，导致黑色素瘤细胞赖以生存的关键细胞周期蛋白水平降低。
