The cytotoxic and pro-apoptotic activities of the novel fluoropyrimidine F10 towards prostate cancer cells are enhanced by Zn(2+) -chelation and inhibiting the serine protease Omi/HtrA2.
The cytotoxic and pro-apoptotic activities of the novel fluoropyrimidine F10 towards prostate cancer cells are enhanced by Zn(2+) -chelation and inhibiting the serine protease Omi/HtrA2.
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DOI：
10.1002/pros.22922
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发表时间：
2015-03-01
期刊：
影响因子：
2.8
通讯作者：
Balaji, K. C.
中科院分区：
文献类型：
--
作者：
Gmeiner, William H.;Boyacioglu, Olcay;Stuart, Christopher H.;Jennings-Gee, Jamie;Balaji, K. C.
细胞内 Zn2+ 水平在前列腺癌进展过程中降低，调节细胞内 Zn2+ 的药物通过不完全描述的机制对前列腺癌细胞具有细胞毒性。 F10 是一种新型聚合氟嘧啶候选药物，在前列腺癌和其他恶性肿瘤的临床前模型中显示出强大的活性和最小的全身毒性。研究了外源 Zn2+ 或 Zn2+ 螯合对增强 F10 细胞毒性的作用，以及 Omi/HtrA2 的作用，Omi/HtrA2 是一种丝氨酸蛋白酶，可响应细胞应激促进细胞凋亡。为了检验 F10 的促凋亡作用可以通过调节细胞内 Zn2+ 来增强的假设，我们研究了细胞渗透性和细胞不可渗透性 Zn2+ 螯合剂和外源 Zn2+，并评估了去势抵抗性前列腺癌 (CRPC; PC3、C4-2) 细胞模型中的细胞活力和凋亡。通过药理学抑制和蛋白质印迹评估 Omi/HtrA2 调节细胞凋亡的作用。外源 Zn2+ 最初会降低前列腺癌细胞的活力，但这些作用是短暂的，并且不能有效增强 F10 细胞毒性。细胞渗透性 Zn2+-螯合剂四-(2-吡啶甲基)乙二胺 (TPEN) 诱导前列腺癌细胞凋亡并增强 F10 的促凋亡作用。通过抑制 Omi/HtrA2，Zn2+ 螯合与 F10 治疗相结合的促凋亡作用得到增强，表明这种丝氨酸蛋白酶是前列腺癌治疗的新靶点。 Zn2+ 螯合增强了 F10 的促凋亡作用，可能有助于增强 F10 治疗晚期前列腺癌的有效性。丝氨酸蛋白酶 Omi/HtrA2 调节前列腺癌细胞中 Zn2+ 依赖性细胞凋亡，代表了治疗 CRPC 的新靶点。
Intracellular Zn2+ levels decrease during prostate cancer progression and agents that modulate intracellular Zn2+ are cytotoxic to prostate cancer cells by an incompletely described mechanism. F10 is a new polymeric fluoropyrimidine drug-candidate that displays strong activity with minimal systemic toxicity in pre-clinical models of prostate cancer and other malignancies. The effects of exogenous Zn2+ or Zn2+ chelation for enhancing F10 cytotoxicity are investigated as is the role of Omi/HtrA2, a serine protease that promotes apoptosis in response to cellular stress. To test the hypothesis that the pro-apoptotic effects of F10 could be enhanced by modulating intracellular Zn2+ we investigated cell-permeable and cell-impermeable Zn2+ chelators and exogenous Zn2+ and evaluated cell viability and apoptosis in cellular models of castration-resistant prostate cancer (CRPC; PC3, C4-2). The role of Omi/HtrA2 for modulating apoptosis was evaluated by pharmacological inhibition and Western blotting. Exogenous Zn2+ initially reduced prostate cancer cell viability but these effects were transitory and were ineffective at enhancing F10 cytotoxicity. The cell-permeable Zn2+-chelator tetrakis-(2-pyridylmethl)ethylenediamine (TPEN) induced apoptosis in prostate cancer cells and enhanced the pro-apoptotic effects of F10. The pro-apoptotic effects of Zn2+-chelation in combination with F10 treatment were enhanced by inhibiting Omi/HtrA2 implicating this serine protease as a novel target for prostate cancer treatment. Zn2+-chelation enhances the pro-apoptotic effects of F10 and may be useful for enhancing the effectiveness of F10 for treatment of advanced prostate cancer. The serine protease Omi/HtrA2 modulates Zn2+-dependent apoptosis in prostate cancer cells and represents a new target for treatment of CRPC.
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影响因子：
10.6
作者：
Franz, M-C;Anderle, P.;Buerzle, M.;Suzuki, Y.;Freeman, M. R.;Hediger, M. A.;Kovacs, G.
通讯作者：
Kovacs, G.
影响因子：
2.4
作者：
Prasad AS;Mukhtar H;Beck FW;Adhami VM;Siddiqui IA;Din M;Hafeez BB;Kucuk O
通讯作者：
Kucuk O
影响因子：
4.4
作者：
Ghosh S;Salsbury FR Jr;Horita DA;Gmeiner WH
通讯作者：
Gmeiner WH
影响因子：
12.4
作者：
Makhov, P.;Golovine, K.;Uzzo, R. G.;Rothman, J.;Crispen, P. L.;Shaw, T.;Scoll, B. J.;Kolenko, V. M.
通讯作者：
Kolenko, V. M.
影响因子：
50.5
作者：
Huan, SD;Aitken, SE;Stewart, DJ
通讯作者：
Stewart, DJ