Targeting argininosuccinate synthetase negative melanomas using combination of arginine degrading enzyme and cisplatin.
Targeting argininosuccinate synthetase negative melanomas using combination of arginine degrading enzyme and cisplatin.
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DOI：
10.18632/oncotarget.3370
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发表时间：
2015-03-20
期刊：
影响因子：
--
通讯作者：
Feun LG
中科院分区：
文献类型：
--
作者：
Savaraj N;Wu C;Li YY;Wangpaichitr M;You M;Bomalaski J;He W;Kuo MT;Feun LG
黑色素瘤中精氨酸琥珀酸合成酶（ASS）表达的丧失使得这些肿瘤细胞容易受到精氨酸剥夺的影响。聚乙二醇化精氨酸脱亚胺酶 (ADI-PEG20) 可将精氨酸降解为瓜氨酸和氨，已在临床上使用，并已注意到部分反应和稳定疾病且毒性最小。为了提高ADI-PEG20的治疗效果，我们将ADI-PEG20与DNA损伤剂顺铂联合使用。我们已经证明，与单独使用 ADI-PEG20 或单独使用顺铂相比，两种药物的组合在 4 种黑色素瘤细胞系中显着提高了治疗效果，无论其 BRAF 突变如何。体内研究也表现出与体外相同的效果，单独使用任何一种药物都没有增加毒性。潜在的机制很复杂，但由于 DNA 修复蛋白、FANCD2、ATM 和 CHK1/2 减少，精氨酸剥夺后 DNA 损伤增加，很可能导致细胞凋亡增加。促凋亡蛋白 NOXA 的增加和抗凋亡蛋白 SURVIVIN、BCL2 和 XIAP 的减少进一步增强了这种作用。 ADI-PEG20 治疗后保护细胞免于凋亡的自噬过程也会在顺铂给药后减弱。因此，精氨酸剥夺和顺铂的组合协同作用来杀死不表达ASS的肿瘤细胞，而不增加对正常细胞的毒性。
Loss of argininosuccinate synthetase (ASS) expression in melanoma makes these tumor cells vulnerable to arginine deprivation. Pegylated arginine deiminase (ADI-PEG20) which degrades arginine to citrulline and ammonia has been used clinically and partial responses and stable disease have been noted with minimal toxicity. In order to improve the therapeutic efficacy of ADI-PEG20, we have combined ADI-PEG20 with a DNA damaging agent, cisplatin. We have shown that the combination of the two drugs together significantly improved the therapeutic efficacy when compared to ADI-PEG20 alone or cisplatin alone in 4 melanoma cell lines, regardless of their BRAF mutation. In-vivo study also exhibited the same effect as in-vitro with no added toxicity to either agent alone. The underlying mechanism is complex, but increased DNA damage upon arginine deprivation due to decreased DNA repair proteins, FANCD2, ATM, and CHK1/2 most likely leads to increased apoptosis. This action is further intensified by increased proapoptotic protein, NOXA, and decreased antiapoptotic proteins, SURVIVIN, BCL2 and XIAP. The autophagic process which protects cells from apoptosis upon ADI-PEG20 treatment also dampens upon cisplatin administration. Thus, the combination of arginine deprivation and cisplatin function in concert to kill tumor cells which do not express ASS without added toxicity to normal cells.
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影响因子：
11.2
作者：
Kim, Randie H.;Coates, Jodi M.;Bowles, Tawnya L.;McNerney, Gregory P.;Sutcliffe, Julie;Jung, Jae U.;Gandour-Edwards, Regina;Chuang, Frank Y. S.;Bold, Richard J.;Kung, Hsing Jien
通讯作者：
Kung, Hsing Jien
影响因子：
45.3
作者：
Ascierto, PA;Scala, S;Logan, TF
通讯作者：
Logan, TF
影响因子：
8
作者：
Hassan, M.;Alaoui, A.;Hengge, U. R.
通讯作者：
Hengge, U. R.
影响因子：
--
作者：
Ding, Zhen-Yu;Liu, Gui-Hong;Sun, Xiao-Feng
通讯作者：
Sun, Xiao-Feng
影响因子：
56.9
作者：
Matsuoka, Shuhei;Ballif, Bryan A.;Elledge, Stephen J.
通讯作者：
Elledge, Stephen J.