Subverting ER-stress towards apoptosis by nelfinavir and curcumin coexposure augments docetaxel efficacy in castration resistant prostate cancer cells.
Subverting ER-stress towards apoptosis by nelfinavir and curcumin coexposure augments docetaxel efficacy in castration resistant prostate cancer cells.
复制标题
DOI：
10.1371/journal.pone.0103109
复制
发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Mondal D
中科院分区：
文献类型：
--
作者：
Mathur A;Abd Elmageed ZY;Liu X;Kostochka ML;Zhang H;Abdel-Mageed AB;Mondal D
尽管有副作用，多西他赛（DTX）仍然是去势抵抗性前列腺癌（CRPC）的一线治疗药物。因此，迫切需要提高其抗肿瘤功效并减少其副作用的策略。靶向癌细胞中的组成型内质网（ER）应激作为一种化学增敏方法正在研究中。我们推测，同时诱导ER应激和抑制PI 3 K/AKT存活通路将是一种更有效的方法。在CRPC细胞系C4-2B中，我们观察到在共暴露于毒胡萝卜素和AKT抑制剂后，DTX诱导的细胞毒性显著增强（p<0.005）。然而，由于这两种药物尚未获得临床批准，我们研究了已知靶向这两种代谢途径的奈非那韦（NFR）和姜黄素（CUR）的组合是否可以类似地增加CRPC细胞中的DTX细胞毒性。在暴露于生理浓度的NFR（5 μM）和CUR（5 μM）后24小时内，低浓度的DTX（10 nM）的细胞毒性明显显著增强（p<0.005）。这3种药物的组合迅速增加了侵袭性C4-2B细胞的凋亡，但在RWPE-1细胞或原代前列腺上皮细胞（PrEC）中没有。比较分子研究显示，与RWPE-1细胞相比，该3种药物组合在C4-2B细胞中引起更明显的磷酸化AKT抑制和更高的磷酸化eIF 2 α诱导。急性暴露（3-9小时）于该3种药物组合增强了ER应激诱导的促凋亡标志物，即ATF 4、CHOP和TRIB 3。在低得多的浓度下，慢性（3周）暴露于这三种药物大大减少了C4-2B细胞的集落形成单位（CFU）。使用含有C4-2B肿瘤异种移植物的小鼠的体内研究显示，在共暴露于NFR（20 mg/kg）和CUR（100 mg/kg）后，DTX（10 mg/kg）的抗肿瘤功效显著增强（p<0.05）。肿瘤切片的免疫组织化学（IHC）分析表明，在暴露于3种药物组合的小鼠中，Ki-67染色减少，TUNEL强度增加。因此，使用NFR和CUR的辅助疗法将ER-应激逆转为细胞凋亡可以使CRPC细胞对DTX疗法化学敏感。
Despite its side-effects, docetaxel (DTX) remains a first-line treatment against castration resistant prostate cancer (CRPC). Therefore, strategies to increase its anti-tumor efficacy and decrease its side effects are critically needed. Targeting of the constitutive endoplasmic reticulum (ER) stress in cancer cells is being investigated as a chemosensitization approach. We hypothesized that the simultaneous induction of ER-stress and suppression of PI3K/AKT survival pathway will be a more effective approach. In a CRPC cell line, C4-2B, we observed significant (p<0.005) enhancement of DTX-induced cytotoxicity following coexposure to thapsigargin and an AKT-inhibitor. However, since these two agents are not clinically approved, we investigated whether a combination of nelfinavir (NFR) and curcumin (CUR), known to target both these metabolic pathways, can similarly increase DTX cytotoxicity in CRPC cells. Within 24 hrs post-exposure to physiologic concentrations of NFR (5 µM) and CUR (5 µM) a significantly (p<0.005) enhanced cytotoxicity was evident with low concentration of DTX (10 nM). This 3-drug combination rapidly increased apoptosis in aggressive C4-2B cells, but not in RWPE-1 cells or in primary prostate epithelial cells (PrEC). Comparative molecular studies revealed that this 3-drug combination caused a more pronounced suppression of phosphorylated-AKT and higher induction in phosphorylated-eIF2α in C4-2B cells, as compared to RWPE-1 cells. Acute exposure (3–9 hrs) to this 3-drug combination intensified ER-stress induced pro-apoptotic markers, i.e. ATF4, CHOP, and TRIB3. At much lower concentrations, chronic (3 wks) exposures to these three agents drastically reduced colony forming units (CFU) by C4-2B cells. In vivo studies using mice containing C4-2B tumor xenografts showed significant (p<0.05) enhancement of DTX’s (10 mg/kg) anti-tumor efficacy following coexposure to NFR (20 mg/kg) & CUR (100 mg/kg). Immunohistochemical (IHC) analyses of tumor sections indicated decreased Ki-67 staining and increased TUNEL intensity in mice exposed to the 3-drug combination. Therefore, subverting ER-stress towards apoptosis using adjuvant therapy with NFR and CUR can chemosensitize the CRPC cells to DTX therapy.
登录
查看更多内容
影响因子：
21.3
作者：
通讯作者：
--
影响因子：
9.7
作者：
He, Hai-Ning;Wang, Xia;Lin, Yong
通讯作者：
Lin, Yong
影响因子：
9.7
作者：
Chen, Thomas C.;Wang, Weijun;Schoenthal, Axel H.
通讯作者：
Schoenthal, Axel H.
影响因子：
11.5
作者：
Gills, JoellJ.;Lo Piccolo, Jaclyn;Dennis, Phillip A.
通讯作者：
Dennis, Phillip A.
影响因子：
7.2
作者：
Mhaidat, Nizar M.;Thorne, Rick;Hersey, Peter
通讯作者：
Hersey, Peter