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OSU-03012 interacts with lapatinib to kill brain cancer cells

机译：OSU-03012与拉帕替尼相互作用以杀死脑癌细胞

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We have further defined mechanism(s) by which the drug OSU-03012 (OSU) kills brain cancer cells. OSU toxicity was enhanced by the HSP 90 inhibitor 17-N-Allylamino-17-demethoxygeldanamycin (17AA G) that correlated with reduced expression of ERBB1 and ERBB2. Inhibition of the extrinsic apoptosis pathway blocked the interaction between 17AA G and OSU. OSU toxicity was enhanced by the inhibitor of ERBB1/2/4, lapatinib. Knock down of ERBB1/2/4 in a cell line specific fashion promoted OSU toxicity. Combined exposure of cells to lapatinib and OSU resulted in reduced AKT and ERK1/2 activity; expression of activated forms of AKT and to a lesser extent MEK1 protected cells from the lethal effects of the drug combination. Knock down of PTEN suppressed, and expression of PTEN enhanced, the lethal interaction between OSU and lapatinib. Downstream of PTEN, inhibition of mTOR recapitulated the effects of lapatinib. Knock down of CD95, NOXA, PUMA, BIK or AIF, suppressed lapatinib and OSU toxicity. Knock down of MCL-1 enhanced, and overexpression of MCL-1 suppressed, drug combination lethality. Lapatinib and OSU interacted in vivo to suppress the growth of established tumors. Collectively our data argue that the inhibition of ERBB receptor function represents a useful way to enhance OSU lethality in brain tumor cells.
机译：我们进一步定义了药物OSU-03012（OSU）杀死脑癌细胞的机制。 HSP 90抑制剂17-N-烯丙基氨基-17-脱甲氧基格尔德霉素（17AA G）可增强OSU毒性，这与ERBB1和ERBB2的表达降低有关。外源性凋亡途径的抑制阻止了17AA G和OSU之间的相互作用。 ERBB1 / 2/4抑制剂拉帕替尼可增强OSU毒性。以细胞系特异性方式敲低ERBB1 / 2/4可促进OSU毒性。细胞与拉帕替尼和OSU的联合暴露导致AKT和ERK1 / 2活性降低; AKT活化形式的表达和MEK1在较小程度上保护细胞免受药物组合的致死作用。抑制PTEN的敲低，增强PTEN的表达，是OSU和拉帕替尼之间的致命相互作用。在PTEN下游，对mTOR的抑制概括了拉帕替尼的作用。击倒CD95，NOXA，PUMA，BIK或AIF可抑制拉帕替尼和OSU毒性。 MCL-1的基因敲除增强，MCL-1的过表达抑制，药物联合杀伤力。拉帕替尼和OSU在体内相互作用以抑制已建立肿瘤的生长。总体而言，我们的数据认为，抑制ERBB受体功能代表了一种增强脑肿瘤细胞OSU致死率的有用方法。

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