PBISe, a novel seennium-containing drug for the treatment of malignant melanoma
PBISe, a novel seennium-containing drug for the treatment of malignant melanoma
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DOI：
10.1158/1535-7163.mct-07-2267
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发表时间：
2008-05-01
影响因子：
5.7
通讯作者：
Robertson, Gavin P.
中科院分区：
文献类型：
--
作者：
Madhunapantula, SubbaRao V.;Desai, Dhimant;Robertson, Gavin P.
恶性黑色素瘤是最致命的皮肤癌形式，由于其高度转移的性质。非靶向疗法对于治疗转移性疾病是无效的，导致特异性抑制黑素瘤中失调的蛋白质或途径的药剂的开发。诱导型一氧化氮合酶（WOS）的失调是发生在黑色素瘤中的一个事件，与生存率低相关。目前的WOS抑制剂，如PBIT [S，S ′-1，4-亚苯基双（1，2-乙二基）双异硫醚]，需要高浓度的临床功效，导致全身毒性。为了开发在显著较低浓度下有效的更有效的药剂，合成了一种新型的PBIT的电子等排类似物，称为PBISe [SS '-1，4-亚苯基双（1，2-乙二基）双-异硒杂环丁烷]，其中硫被硒取代。PBISe比PBIT更有效地杀死黑素瘤细胞>10倍，并且培养的癌细胞比正常细胞更敏感2至5倍。与PBIT一样，PBISe靶向NOS，但也具有新的抑制特性，作为Akt 3途径抑制剂和有丝分裂原活化蛋白激酶（MAPK）级联激活剂，可导致癌细胞增殖减少和细胞凋亡增加。PBISe介导的细胞增殖抑制诱导G（2）-M期细胞周期阻滞，这与过高的MAPK活性有关，导致细胞周期蛋白D1降低和p21以及p27水平升高。PBISe通过抑制Akt 3信号传导、升高裂解的半胱天冬酶-3和PARP水平来促进细胞凋亡。与PBIT相比，PBISe在小鼠中使肿瘤发展减少30%至50%，诱导细胞凋亡增加2倍，而相关的全身毒性可忽略不计。总的来说，这些结果表明PBISe是一种有效的化疗剂，具有能够靶向iNOS、Akt 3和MAPK信号传导的新特性，从而促进黑素瘤细胞凋亡和抑制增殖。
Malignant melanoma is the most deadly form of skin cancer due to its highly metastatic nature. Untargeted therapies are ineffective for treating metastatic disease, leading to the development of agents specifically inhibiting proteins or pathways deregulated in melanoma. The deregulation of inducible nitric oxide synthase (WOS) is one such event occurring in melanoma, and is correlated with poor survival. Current WOS inhibitors, such as PBIT [S,S'-1,4-phenylenebis(1,2-ethanediyl)bis-isothiourea], require high concentrations for clinical efficacy causing systemic toxicity. To develop more potent agents effective at significantly lower concentrations, a novel isosteric analogue of PBIT was synthesized, called PBISe [SS'-1,4-phenylenebis(1,2-ethanediyl)bis-isoselenourea], in which sulfur was replaced with selenium. PBISe kills melanoma cells >10-fold more effectively than PBIT, and cultured cancer cells are 2- to 5-fold more sensitive than normal cells. Like PBIT, PBISe targets NOS but also has new inhibitory properties acting as an Akt3 pathway inhibitor and mitogen-activated protein kinase (MAPK) cascade activator, which causes decreased cancer cell proliferation and increased apoptosis. Inhibition of cellular proliferation mediated by PBISe induced a G(2)-M phase cell cycle block linked to excessively high MAPK activity causing decreased cyclin D1 and increased p21 as well as p27 levels. PBISe promotes apoptosis by inhibiting Akt3 signaling, elevating cleaved caspase-3 and PARP levels. Compared with PBIT, PBISe reduced tumor development by 30% to 50% in mice inducing a 2-fold increase in apoptosis with negligible associated systemic toxicity. Collectively, these results suggest that PBISe is a potent chemotherapeutic agent with novel properties enabling the targeting of iNOS, Akt3, and MAPK signaling, thereby promoting melanoma cell apoptosis and inhibition of proliferation.