Melanoma prevention using topical PBISe.
Melanoma prevention using topical PBISe.
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DOI：
10.1158/1940-6207.capr-10-0202
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发表时间：
2011-06
期刊：
影响因子：
--
通讯作者：
Robertson GP
中科院分区：
文献类型：
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作者：
Chung CY;Madhunapantula SV;Desai D;Amin S;Robertson GP
恶性黑色素瘤是最致命的皮肤癌，以其耐药性和高转移潜力而闻名。PI 3和MAP激酶通路失调促进早期黑素细胞病变发展并产生耐药性。不存在靶向这些失调的途径以防止皮肤非侵袭性黑色素细胞或侵袭性黑色素瘤发展成更具侵袭性的广泛播散的转移性疾病的药剂。在这项研究中，含硒的PBIT [S，S′-1，4-亚苯基双（1，2-乙二基）双异硫醚]的电子等排类似物PBISe [Se，Se′-1，4-亚苯基双（1，2-乙二基）双异硒醚]被证明可以调节这两个主要的信号通路，以防止皮肤黑色素细胞损伤或黑色素瘤的发展。PBISe的局部应用在实验室产生的皮肤中延缓了70-80%的黑素细胞病变发展，在动物皮肤中延缓了100%。从机制上讲，由于Akt 3信号传导减少，导致MAP激酶途径活性增加至抑制水平，从而预防了病变发展。靶向这些途径的组合效应导致细胞增殖减少和凋亡性细胞死亡增加，从而防止黑色素瘤发展。因此，局部施用的PBISe治疗具有预防皮肤中的非侵入性黑色素细胞病变和侵入性转移性黑色素瘤发展的潜力。
Malignant melanoma is the deadliest form of skin cancer, known for its drug resistance and high metastatic potential. Deregulated PI3 and MAP kinase pathways promote early melanocytic lesion development and confer drug resistance. No agent exists to target these deregulated pathways to prevent cutaneous non-invasive melanocytic cells or invasive melanomas from developing into more aggressive widely disseminated metastatic disease. In this study, a selenium containing isosteric analogue of PBIT [S,S′-1,4-phenylenebis(1,2-ethanediyl)bis-isothiourea] called PBISe [Se,Se′-1,4-phenylenebis(1,2-ethanediyl)bis-isoselenourea] is shown to moderate these two major signaling pathways to prevent cutaneous melanocytic lesion or melanoma development. Topical application of PBISe retarded melanocytic lesion development in laboratory-generated skin by 70-80% and in animal skin by ∼50%. Mechanistically, prevention of lesion development occurred due to decreased Akt3 signaling, which increased MAP kinase pathway activity to inhibitory levels. The combined effect of targeting these pathways led to decreased cell proliferation and increased apoptotic cell death thereby preventing melanoma development. Thus, topically applied PBISe treatment has potential to prevent non-invasive melanocytic lesion and invasive metastatic melanoma development in skin.