The Akt inhibitor ISC-4 synergizes with cetuximab in 5-FU-resistant colon cancer.
The Akt inhibitor ISC-4 synergizes with cetuximab in 5-FU-resistant colon cancer.
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DOI：
10.1371/journal.pone.0059380
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
El-Deiry WS
中科院分区：
文献类型：
--
作者：
Allen JE;Gallant JN;Dicker DT;Amin S;Irby RB;Sharma AK;El-Deiry WS
异硒氰酸苯丁酯（ISC-4）是一种Akt抑制剂，对黑色素瘤和结肠癌具有临床前疗效。在这项研究中，我们试图通过确定与FDA批准的抗癌疗法的协同组合，用于测试的相关和适当的疾病环境以及反应的生物标志物来提高ISC-4的临床效用。我们测试了ISC-4和19种FDA批准的抗癌剂单独或组合对SW 480和RKO人结肠癌细胞系的活性。在一组额外的结肠癌细胞系中鉴定并验证了与西妥昔单抗的协同相互作用，以及协同作用的动力学。ISC-4与西妥昔单抗的组合协同降低了具有野生型而非突变型KRAS基因的人结肠癌细胞的活力。进一步的分析表明，联合治疗协同降低细胞周期进程，增加半胱天冬酶依赖性凋亡，并减少磷酸化Akt在响应肿瘤细胞。ISC-4和西妥昔单抗之间的协同作用在人结肠癌细胞中独立于对5-FU的获得性耐药性。该组合在体内表现出协同抗肿瘤作用，没有毒性，并且面对5-FU的耐药性。这些结果表明，ISC-4和西妥昔单抗联合应用应在携带野生型KRAS的5-FU耐药结肠癌患者中进行探索。
Phenylbutyl isoselenocyanate (ISC-4) is an Akt inhibitor with demonstrated preclinical efficacy against melanoma and colon cancer. In this study, we sought to improve the clinical utility of ISC-4 by identifying a synergistic combination with FDA-approved anti-cancer therapies, a relevant and appropriate disease setting for testing, and biomarkers of response. We tested the activity of ISC-4 and 19 FDA-approved anticancer agents, alone or in combination, against the SW480 and RKO human colon cancer cell lines. A synergistic interaction with cetuximab was identified and validated in a panel of additional colon cancer cell lines, as well as the kinetics of synergy. ISC-4 in combination with cetuximab synergistically reduced the viability of human colon cancer cells with wild-type but not mutant KRAS genes. Further analysis revealed that the combination therapy cooperatively decreased cell cycle progression, increased caspase-dependent apoptosis, and decreased phospho-Akt in responsive tumor cells. The synergism between ISC-4 and cetuximab was retained independently of acquired resistance to 5-FU in human colon cancer cells. The combination demonstrated synergistic anti-tumor effects in vivo without toxicity and in the face of resistance to 5-FU. These results suggest that combining ISC-4 and cetuximab should be explored in patients with 5-FU-resistant colon cancer harboring wild-type KRAS.
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影响因子：
2.8
作者：
Festuccia, Claudio;Gravina, Giovanni Luca;Bologna, Mauro
通讯作者：
Bologna, Mauro
DOI：
10.1158/1078-0432.ccr-08-2214
发表时间：
2009-03-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Sharma A;Sharma AK;Madhunapantula SV;Desai D;Huh SJ;Mosca P;Amin S;Robertson GP
通讯作者：
Robertson GP
影响因子：
64.8
作者：
Misale, Sandra;Yaeger, Rona;Hobor, Sebastijan;Scala, Elisa;Janakiraman, Manickam;Liska, David;Valtorta, Emanuele;Schiavo, Roberta;Buscarino, Michela;Siravegna, Giulia;Bencardino, Katia;Cercek, Andrea;Chen, Chin-Tung;Veronese, Silvio;Zanon, Carlo;Sartore-Bianchi, Andrea;Gambacorta, Marcello;Gallicchio, Margherita;Vakiani, Efsevia;Boscaro, Valentina;Medico, Enzo;Weiser, Martin;Siena, Salvatore;Di Nicolantonio, Federica;Solit, David;Bardelli, Alberto
通讯作者：
Bardelli, Alberto
DOI：
10.1158/1078-0432.ccr-10-2370
发表时间：
2011-07-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Sharma AK;Kline CL;Berg A;Amin S;Irby RB
通讯作者：
Irby RB
影响因子：
--
作者：
Allen, Joshua E;El-Deiry, Wafik S
通讯作者：
El-Deiry, Wafik S