Combinatorial antitumor effect of HDAC and the PI3K-Akt-mTOR pathway inhibition in a Pten defecient model of prostate cancer.
Combinatorial antitumor effect of HDAC and the PI3K-Akt-mTOR pathway inhibition in a Pten defecient model of prostate cancer.
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DOI：
10.18632/oncotarget.1314
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发表时间：
2013-12
期刊：
影响因子：
--
通讯作者：
Pili R
中科院分区：
文献类型：
--
作者：
Ellis L;Ku SY;Ramakrishnan S;Lasorsa E;Azabdaftari G;Godoy A;Pili R
组蛋白脱乙酰酶(HDACs)的高表达和PI3K-Akt-mTORC1通路的激活是前列腺癌(PCa)常见的异常。因此，抑制这些靶点是开发治疗晚期PCa患者的新治疗策略的令人兴奋的途径。以往的报道表明，HDAC抑制剂(HDACi)增加了表达雄激素受体(AR)的PCa细胞系的DNA损伤和诱导更多的细胞凋亡。在这项研究中，我们利用AR阴性的PCa细胞株，观察到当PAN-DACI，Panobinostat(PAN)处理时，AR(PC3-AR)的重新表达导致更高水平的细胞凋亡。PAN介导的PC3和PC3-AR细胞的凋亡与双链DNA断裂水平的增加有关，p-ɣH_2AX表明。此外，在PC3-AR细胞中，PAN处理导致ATM-Akt-ERK DNA损伤反应通路的适度减弱。为此，我们将PAN与双重PI3K-mTOR抑制剂BEZ235联合使用。与单独使用PAN和BEZ235相比，PAN和BEZ235联合使用可显著降低DNA损伤修复蛋白ATM，并显著增强抗肿瘤活性。总体而言，PAN和BEZ235的联合抗肿瘤活性与AR状态无关。这些发现表明，这一治疗策略应该在临床试验中进一步发展。
Increased expression of histone deacetylases (HDACs) and activation of the PI3K-Akt-mTORC1 pathway are common aberrations in prostate cancer (PCa). For this reason, inhibition of such targets is an exciting avenue for the development of novel therapeutic strategies to treat patients with advanced PCa. Previous reports demonstrated that HDAC inhibitors (HDACi) increases DNA damage and induce greater apoptosis in PCa cell lines that express androgen receptor (AR). In this study we utilized the AR negative PCa cell line and observed that re-expression of AR (PC3-AR) results in greater levels of apoptosis when treated with the pan-DACi, panobinostat (PAN). PAN mediated apoptosis in PC3 and PC3-AR cells was associated with increased levels of double strand DNA breaks, indicated by p-ɣH2AX. Further, PAN treatment in PC3-AR cells resulted in moderate attenuation of the ATM-Akt-ERK DNA damage response pathway. For this reason, we combined PAN with the dual PI3K-mTOR inhibitor, BEZ235. Combination of PAN with BEZ235 resulted in significant attenuation of the DNA damage repair protein ATM and significantly increased anti-tumor activity compared to each single treatment. Overall, superior anti-tumor activity with combination of PAN with BEZ235 was independent of AR status. These findings suggest that this therapeutic strategy should be further developed in clinical trials.
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DOI：
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发表时间：
2011-06-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
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作者：
Haffner MC;De Marzo AM;Meeker AK;Nelson WG;Yegnasubramanian S
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DOI：
10.3390/ph3082441
发表时间：
2010-08-01
期刊：
Pharmaceuticals (Basel, Switzerland)
影响因子：
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作者：
Ellis L;Pili R
通讯作者：
Pili R