Combining trail with PI3 kinase or HSP90 inhibitors enhances apoptosis in colorectal cancer cells via suppression of survival signaling.
Combining trail with PI3 kinase or HSP90 inhibitors enhances apoptosis in colorectal cancer cells via suppression of survival signaling.
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DOI：
10.18632/oncotarget.1162
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发表时间：
2013-08
期刊：
影响因子：
--
通讯作者：
Workman P
中科院分区：
文献类型：
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作者：
Saturno G;Valenti M;De Haven Brandon A;Thomas GV;Eccles S;Clarke PA;Workman P
TRAIL已被证明可以诱导癌细胞凋亡，但在某些情况下，它们对这种配体没有反应。我们探索了代表性的磷脂酰肌醇-3-激酶（PI3激酶）/mTOR和HSP90抑制剂通过增加结直肠癌模型中的细胞凋亡来克服TRAIL抗性的能力。我们测定了27例人结直肠癌和2例非转化结肠上皮细胞系对TRAIL治疗的敏感性。从用TRAIL与PI3激酶/mTOR抑制剂PI-103或HSP90抑制剂17-AAG（tanespimycin）组合治疗的组中选择对TRAIL具有一系列应答的癌细胞系的子集。选择两种TRAIL抗性细胞系用于与TRAIL和17-AAG的体内组合研究。我们发现13个结直肠癌细胞系和2个未转化的结肠上皮细胞系对TRAIL耐药。我们证明了TRAIL和PI-103或17-AAG的共处理是协同的或相加的，并且显著增强了结直肠癌细胞的凋亡。这与ERBB 2、AKT、IKK α和XIAP等生存蛋白生物标志物的表达或活性降低相关。相比之下，组合处理在非转化结肠细胞中的作用是最小的。我们在此首次表明，在两种TRAIL耐药的人结直肠癌异种移植模型中，与单一治疗相比，体内用TRAIL和17-AAG共同治疗导致显著更大的肿瘤生长抑制。我们提出，联合TRAIL与PI3激酶/mTOR或HSP90抑制剂在治疗TRAIL耐药的结直肠癌中具有治疗潜力。
TRAIL has been shown to induce apoptosis in cancer cells, but in some cases they fail to respond to this ligand. We explored the ability of representative phosphatidylinositol-3-kinase (PI3 Kinase)/mTOR and HSP90 inhibitors to overcome TRAIL resistance by increasing apoptosis in colorectal cancer models. We determined the sensitivity of 27 human colorectal cancer and 2 non-transformed colon epithelial cell lines to TRAIL treatment. A subset of the cancer cell lines with a range of responses to TRAIL was selected from the panel for treatment with TRAIL combined with the PI3 Kinase/mTOR inhibitor PI-103 or the HSP90 inhibitor 17-AAG (tanespimycin). Two TRAIL-resistant cell lines were selected for in vivo combination studies with TRAIL and 17-AAG. We found that 13 colorectal cancer cell lines and the 2 non-transformed colon epithelial cell lines were resistant to TRAIL. We demonstrated that co-treatment of TRAIL and PI-103 or 17-AAG was synergistic or additive and significantly enhanced apoptosis in colorectal cancer cells. This was associated with decreased expression or activity of survival protein biomarkers such as ERBB2, AKT, IKKα and XIAP. In contrast, the effect of the combination treatments in non-transformed colon cells was minimal. We show here for the first time that co-treatment in vivo with TRAIL and 17-AAG in two TRAIL-resistant human colorectal cancer xenograft models resulted in significantly greater tumor growth inhibition compared to single treatments. We propose that combining TRAIL with PI3 Kinase/mTOR or HSP90 inhibitors has therapeutic potential in the treatment of TRAIL-resistant colorectal cancers.