Targeting Akt3 signaling in malignant melanoma using isoselenocyanates.
Targeting Akt3 signaling in malignant melanoma using isoselenocyanates.
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DOI：
10.1158/1078-0432.ccr-08-2214
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发表时间：
2009-03-01
期刊：
影响因子：
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通讯作者：
Robertson GP
中科院分区：
文献类型：
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作者：
Sharma A;Sharma AK;Madhunapantula SV;Desai D;Huh SJ;Mosca P;Amin S;Robertson GP
黑色素瘤是最具侵袭性和致命性的皮肤癌。很少有药物可用于治疗晚期疾病以实现患者的长期生存，这推动了对抑制导致黑色素瘤的失调途径的新化合物的探索。 Akt3 是黑色素瘤的重要靶标，因为其活性在约 70% 的肿瘤中增加，减少细胞凋亡以促进肿瘤发生。由于天然产物可以成为有效的抗癌剂，因此筛选了一个库来鉴定 Akt3 途径抑制剂。异硫氰酸盐被确定为候选物，但其效力低，需要高浓度才能达到治疗效果，因此不适合。因此，使用异硫氰酸酯主链，但增加烷基链长度并用硒代替硫，创建了称为异硒氰酸酯的更有效的类似物。通过量化增殖、凋亡、血管生成、毒性和 Akt3 通路抑制来测量对培养细胞和肿瘤的功效。异硒氰酸盐显着降低培养的黑色素瘤细胞和肿瘤中的 Akt3 信号传导。具有 4-6 个碳烷基侧链并用硒取代硫的化合物（分别称为 ISC-4 和 ISC-6）与相应的异硫氰酸盐相比，可减少约 60% 的肿瘤发展，而异硫氰酸盐没有效果。使用异硒氰酸盐，没有观察到动物体重或血液参数发生指示肝脏、肾脏或心脏相关毒性的变化。从机制上讲，异硒氰酸盐 ISC-4 和 ISC-6 通过导致细胞凋亡增加约 3 倍来减少黑色素瘤的发生。合成异硒氰酸酯通过靶向 Akt3 信号传导来增加黑色素瘤细胞的凋亡，从而在治疗上有效抑制黑色素瘤肿瘤的发展，且相关的全身毒性可忽略不计。
Melanoma is the most invasive and deadly form of skin cancer. Few agents are available for treating advanced disease to enable long-term patient survival, which is driving the search for new compounds inhibiting deregulated pathways causing melanoma. Akt3 is an important target in melanomas since its activity is increased in ~70% of tumors, decreasing apoptosis in order to promote tumorigenesis. Since naturally occurring products can be effective anti-cancer agents, a library was screened to identify Akt3 pathway inhibitors. Isothiocyanates were identified as candidates but low potency requiring high concentrations for therapeutic efficacy made them unsuitable. Therefore, more potent analogs called isoselenocyanates were created using the isothiocyanate backbone but increasing the alkyl chain length and replacing sulfur with selenium. Efficacy was measured on cultured cells and tumors by quantifying proliferation, apoptosis, angiogenesis, toxicity and Akt3 pathway inhibition. Isoselenocyanates significantly decreased Akt3 signaling in cultured melanoma cells and tumors. Compounds having 4–6 carbon alkyl side chains with selenium substituted for sulfur, called ISC-4 and ISC-6 respectively, decreased tumor development by ~60% compared to corresponding isothiocyanates, which had no effect. No changes in animal body weight or in blood parameters indicative of liver, kidney or cardiac related toxicity were observed with isoselenocyanates. Mechanistically, isoselenocyanates ISC-4 and ISC-6 decreased melanoma tumorigenesis by causing an ~3-fold increase in apoptosis. Synthetic isoselenocyanates are therapeutically effective for inhibiting melanoma tumor development by targeting Akt3 signaling to increase apoptosis in melanoma cells with negligible associated systemic toxicity.