Pharmacological reversal of histone methylation presensitizes pancreatic cancer cells to nucleoside drugs: in vitro optimization and novel nanoparticle delivery studies.
Pharmacological reversal of histone methylation presensitizes pancreatic cancer cells to nucleoside drugs: in vitro optimization and novel nanoparticle delivery studies.
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DOI：
10.1371/journal.pone.0071196
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Govindarajan R
中科院分区：
文献类型：
--
作者：
Hung SW;Mody H;Marrache S;Bhutia YD;Davis F;Cho JH;Zastre J;Dhar S;Chu CK;Govindarajan R
我们评估了研究中的组蛋白甲基化逆转剂3-去氮杂环素A(DZNep)在改善胰腺癌对核苷类似物(即吉西他滨)化疗敏感性方面的潜力。DZNep对胰腺癌细胞有延迟但选择性的细胞毒作用，不影响正常的人胰腺导管上皮细胞。联合应用DZNep和吉西他滨可通过增加细胞凋亡率，在高分化和低分化胰腺细胞系中诱导细胞毒的相加或协同作用。相反，DZNep与吉西他滨对HPDE细胞具有拮抗作用，与吉西他滨单独用药相比，细胞毒性显著降低。DZNep的细胞毒性轻微依赖于嘌呤核苷转运体，但其转运依赖可通过酰基衍生化来规避。药物暴露研究表明，在吉西他滨敏感和耐药的胰腺癌细胞中，用DZNep短期预注，然后吉西他滨治疗，而不是两种药物的联合治疗，可以产生最大的化疗增敏反应。DZNep分别以EZH2依赖和JMJD1A/2C依赖的方式快速且可逆地减少组蛋白H3赖氨酸27的三甲基化，而增加赖氨酸9的三甲基化。然而，核苷类似物化疗增敏的DZNep增强被发现与赖氨酸27的三甲基化变化而不是赖氨酸9的三甲基化变化有时间上的偶联。按时间顺序释放DZNep的聚合物纳米粒在吉西他滨之后产生了显著的化疗增敏和剂量降低效应。总之，我们的结果证实，优化的DZNep暴露可以通过逆转组蛋白甲基化来使胰腺癌细胞对抗癌核苷类似物预敏，强调了表观遗传逆转剂在未来胰腺癌联合治疗中的潜在临床应用。
We evaluated the potential of an investigational histone methylation reversal agent, 3-deazaneplanocin A (DZNep), in improving the chemosensitivity of pancreatic cancer to nucleoside analogs (i.e., gemcitabine). DZNep brought delayed but selective cytotoxicity to pancreatic cancer cells without affecting normal human pancreatic ductal epithelial (HPDE) cells. Co-exposure of DZNep and gemcitabine induced cytotoxic additivity or synergism in both well- and poorly-differentiated pancreatic cell lines by increased apoptosis. In contrast, DZNep exerted antagonism with gemcitabine against HPDE cells with significant reduction in cytotoxicity compared with the gemcitabine-alone regimen. DZNep marginally depended on purine nucleoside transporters for its cytotoxicity, but the transport dependence was circumvented by acyl derivatization. Drug exposure studies revealed that a short priming with DZNep followed by gemcitabine treatment rather than co-treatment of both agents to produce a maximal chemosensitization response in both gemcitabine-sensitive and gemcitabine-resistant pancreatic cancer cells. DZNep rapidly and reversibly decreased trimethylation of histone H3 lysine 27 but increased trimethylation of lysine 9 in an EZH2- and JMJD1A/2C-dependent manner, respectively. However, DZNep potentiation of nucleoside analog chemosensitization was found to be temporally coupled to trimethylation changes in lysine 27 and not lysine 9. Polymeric nanoparticles engineered to chronologically release DZNep followed by gemcitabine produced pronounced chemosensitization and dose-lowering effects. Together, our results identify that an optimized DZNep exposure can presensitize pancreatic cancer cells to anticancer nucleoside analogs through the reversal of histone methylation, emphasizing the promising clinical utilities of epigenetic reversal agents in future pancreatic cancer combination therapies.
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DOI：
10.1158/1078-0432.ccr-08-1013
发表时间：
2008-11-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Ougolkov AV;Bilim VN;Billadeau DD
通讯作者：
Billadeau DD
影响因子：
11.5
作者：
Chase, Andrew;Cross, Nicholas C. P.
通讯作者：
Cross, Nicholas C. P.
影响因子：
4.3
作者：
Bayraktar, Soley;Bayraktar, Ulas Darda;Rocha-Lima, Caio Max
通讯作者：
Rocha-Lima, Caio Max
影响因子：
3.7
作者：
Fussbroich B;Wagener N;Macher-Goeppinger S;Benner A;Fälth M;Sültmann H;Holzer A;Hoppe-Seyler K;Hoppe-Seyler F
通讯作者：
Hoppe-Seyler F
影响因子：
10.5
作者：
Mallen-St Clair, Jon;Soydaner-Azeloglu, Rengin;Bar-Sagi, Dafna
通讯作者：
Bar-Sagi, Dafna