17AAG 治疗可加速多柔比星诱导的细胞衰老:Hsp90干扰肿瘤细胞的强制衰老

IF 2 Q3 PHARMACOLOGY & PHARMACY Drug Target Insights Pub Date : 2012-01-01 Epub Date: 2012-08-06 DOI:10.4137/DTI.S9943
Upasana Sarangi, Khande Rao Paithankar, Jonnala Ujwal Kumar, Vaidyanathan Subramaniam, Amere Subbarao Sreedhar
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引用次数: 0

摘要

Hsp90 合子已被确定为一种有吸引力的抗癌药物靶点。然而,一些转移性肿瘤要么对 Hsp90 抑制剂无反应,要么出现恢复,这就需要采取不可逆的治疗策略。为此,有人提出了一种替代策略--强迫衰老。在这里,我们证明了用 17AAG 抑制 Hsp90 会使人类神经母细胞瘤对 DNA 损伤反应介导的细胞衰老敏感。在单药和联合用药治疗中,17AAG预处理后再用多柔比星治疗表现出类似衰老的特征,如细胞核与细胞质比率增加、细胞周期停滞、SA-β-gal染色和SAHF持续增加。多柔比星诱导的衰老信号由 p53-p21(CIP/WAF-1)介导,并在缺乏功能性 Hsp90 的情况下加速。与端粒酶激活不受影响相关的p16(INK4a)和H3K4me3的持续表达使复制性衰老无效,并评估了应激诱导的衰老。尽管[(ROS)i]和[(Ca(2+))i]有所增加,但细胞抗氧化防御系统的同时增加表明衰老的激活与氧化无关。存活激酶(Akt)和增殖激酶(ERK1/2)的持续激活可促进细胞的稳健性。用生长因子激活衰老细胞或用 mTOR 或 PI3 激酶抑制剂窥探衰老细胞会影响细胞存活,但不会影响衰老。有趣的是,衰老细胞的衰老相关分泌因子在神经母细胞瘤中表现出成熟的衰老,这为我们的方法提供了临床优势。我们的研究探讨了Hsp90的肿瘤选择性功能,并讨论了在抗癌治疗中抑制Hsp90的无可辩驳的策略。
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17AAG Treatment Accelerates Doxorubicin Induced Cellular Senescence: Hsp90 Interferes with Enforced Senescence of Tumor Cells.

Hsp90 chaperone has been identified as an attractive pharmacological target to combat cancer. However, some metastatic tumors either fail to respond to Hsp90 inhibition or show recovery necessitating irreversible therapeutic strategies. In response to this enforced senescence has been proposed as an alternate strategy. Here, we demonstrate that inhibiting Hsp90 with 17AAG sensitizes human neuroblastoma to DNA damage response mediated cellular senescence. Among individual and combination drug treatments, 17AAG pre-treatment followed by doxorubicin treatment exhibited senescence-like characteristics such as increased nucleus to cytoplasm ratio, cell cycle arrest, SA-β-gal staining and the perpetual increase in SAHF. Doxorubicin induced senescence signaling was mediated by p53-p21(CIP/WAF-1) and was accelerated in the absence of functional Hsp90. Sustained p16(INK4a) and H3K4me3 expressions correlating with unaffected telomerase activation annulled replicative senescence and appraised stress induced senescence. Despite increases in [(ROS)i] and [(Ca(2+))i], a concomitant increase in cellular antioxidant defense system suggested oxidation independent senescence activation. Sustained activation of survival (Akt) and proliferative (ERK1/2) kinases fosters robustness of cells. Invigorating senescent cells with growth factor or snooping with mTOR or PI3 kinase inhibitors compromised cell survival but not senescence. Intriguingly, senescence-associated secretory factors from the senescence cells manifested established senescence in neuroblastoma, which offers clinical advantage to our approach. Our study discusses tumor selective functions of Hsp90 and discusses irrefutable strategies of Hsp90 inhibition in anticancer treatments.

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来源期刊
Drug Target Insights
Drug Target Insights PHARMACOLOGY & PHARMACY-
CiteScore
2.70
自引率
0.00%
发文量
5
审稿时长
8 weeks
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