The sphingosine kinase 2 inhibitor ABC294640 displays anti-non-small cell lung cancer activities in vitro and in vivo.
The sphingosine kinase 2 inhibitor ABC294640 displays anti-non-small cell lung cancer activities in vitro and in vivo.
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鞘氨醇激酶 2 抑制剂 ABC294640 在体外和体内表现出抗非小细胞肺癌活性
DOI：
10.1002/ijc.31234
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发表时间：
2018-05-15
影响因子：
6.4
通讯作者：
Qin Z
中科院分区：
文献类型：
--
作者：
Dai L;Smith CD;Foroozesh M;Miele L;Qin Z
非小细胞肺癌（NSCLC）约占肺癌病例的85-90%，是美国癌症中的第一大杀手。大多数肺癌患者对传统化疗和/或放疗的反应不佳治疗方案，5年生存率约为15%。最近引入的靶向治疗和免疫治疗给NSCLC患者带来了新的希望，但即使使用这些药物，也不是所有患者都有反应，而且反应很少是完全的。因此，仍然迫切需要确定新的NSCLC治疗靶点并开发新的抗癌药物。鞘氨醇激酶2（SphK 2）是鞘脂代谢的关键酶之一。SphK 2表达预测NSCLC患者的生存率较差，并与吉非替尼耐药相关。在这项研究中，ABC 294640的抗NSCLC活性进行了探索，ABC 294640是唯一的一类口服SphK 2抑制剂。所获得的结果表明，ABC 294640治疗在体外和体内引起显著的NSCLC细胞凋亡、细胞周期停滞和肿瘤生长抑制。此外，脂质组学分析揭示了在有或没有ABC 294640处理的NSCLC细胞系中神经酰胺和二氢（dh）-神经酰胺种类的完整特征。这些结果表明，鞘脂代谢靶向治疗可能是一个有前途的战略，对非小细胞肺癌。
Non-small cell lung cancer (NSCLC) accounts for about 85–90% of lung cancer cases, and is the number one killer among cancers in the U.S. The majority of lung cancer patients do not respond well to conventional chemo- and/or radio-therapeutic regimens, and have a dismal 5-year survival rate of ~15%. The recent introduction of targeted therapy and immunotherapy gives new hopes to NSCLC patients, but even with these agents, not all patients respond, and responses are rarely complete. Thus, there is still an urgent need to identify new therapeutic targets in NSCLC and develop novel anti-cancer agents. Sphingosine kinase 2 (SphK2) is one of the key enzymes in sphingolipid metabolism. SphK2 expression predicts poor survival in NSCLC patients, and is associated with Gefitinib-resistance. In this study, the anti-NSCLC activities of ABC294640, the only first-in-class orally available inhibitor of SphK2, were explored. The results obtained indicate that ABC294640 treatment causes significant NSCLC cell apoptosis, cell cycle arrest, and suppression of tumor growth in vitro and in vivo. Moreover, lipidomics analyses revealed the complete signature of ceramide and dihydro(dh)-ceramide species in the NSCLC cell-lines with or without ABC294640 treatment. These findings indicate that sphingolipid metabolism targeted therapy may be developed as a promising strategy against NSCLC.
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影响因子：
4.7
作者：
Oaks J;Ogretmen B
通讯作者：
Ogretmen B
影响因子：
--
作者：
McNaughton M;Pitman M;Pitson SM;Pyne NJ;Pyne S
通讯作者：
Pyne S
DOI：
10.1158/1078-0432.ccr-16-2363
发表时间：
2017-08-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Britten CD;Garrett-Mayer E;Chin SH;Shirai K;Ogretmen B;Bentz TA;Brisendine A;Anderton K;Cusack SL;Maines LW;Zhuang Y;Smith CD;Thomas MB
通讯作者：
Thomas MB
影响因子：
3.2
作者：
Johnson, KR;Johnson, KY;Obeid, LM
通讯作者：
Obeid, LM
影响因子：
3
作者：
Aureli, Massimo;Murdica, Valentina;Sonnino, Sandro
通讯作者：
Sonnino, Sandro