研究背景：前人研究發現，在許多固體及血液腫瘤中，組蛋白去乙醯酶 (Histone deacetylases, HDACs) 常有過度表現或活性增加的情況，但在正常細胞的基礎表現量卻很低，因此HDACs為極具潛力的癌症治療標靶。現行的組蛋白去乙醯酶抑制劑已證實具有多種抑癌能力並使用於血液腫瘤臨床治療上；然而，組蛋白去乙醯酶抑制劑對於固體腫瘤的治療效果仍須進一步研究。
研究目的：藉由人類肺癌細胞及動物實驗模式，評估新穎的組蛋白去乙醯酶抑制劑－HTPB (全名N-Hydroxy-4-(4- phenylbutyryl-amino) benzamide）及Nano-HTPB（HTPB硒化鎘/硫化鋅奈米粒子衍生物）的抗癌能力。
研究方法及結果：本研究將Nano-HTPB處理不同肺癌細胞株，於6~48小時後觀察到Nano-HTPB有進入到細胞核的情況，顯示可以成功的將奈米粒子作為HTPB藥物傳遞載體。本研究進一步發現，Nano-HTPB及HTPB對不同肺癌細胞株的毒殺能力顯著高於現行臨床用藥SAHA，且對正常肺細胞沒有明顯毒殺影響。其中，Nano-HTPB具有nM程度之IC50，毒殺效果高於HTPB數百倍。本研究亦觀察到，Nano-HTPB及HTPB促使細胞滯留在G2/M時期，並透過活化凋亡相關蛋白及內在粒線體途徑中的caspase-3/9而誘導癌細胞凋亡。由組蛋白去乙醯酶螢光活性實驗顯示，Nano-HTPB及HTPB屬於廣泛型組蛋白去乙醯酶抑制劑，並有效促使組蛋白及非組蛋白的乙醯化。此外，Nano-HTPB及HTPB可透過降低基質金屬蛋白酶(matrix metalloproteinases) 活性、抑制RhoA活性、焦點黏著複合體(focal adhesion complex) 的活化、及F-actin細胞骨架的聚集，而抑制癌細胞遷移的能力。由異位移植腫瘤動物模式實驗顯示，無論以腹腔注射或口服給藥方式，Nano-HTPB及HTPB在動物活體也能有效抑制腫瘤生長，且沒有明顯副作用的出現。此外，HTPB明顯抑制小鼠乳癌4T1細胞轉移至肺臟的能力。
結論：細胞及動物實驗結果顯示，Nano-HTPB及HTPB可以有效抑制肺癌腫瘤生長及細胞移動，為具潛力及臨床發展價值的肺癌治療藥物。目前我們已著手進行Nano-HTPB與HTPB對於腫瘤轉移抑制的效果，以及於動物體內之藥物代謝及動力學探討。

Background: Overexpression and/or increased activity of histone deacetylases (HDACs) in hematologic and solid malignancies make HDACs a potential therapeutic target for cancer treatment. HDAC inhibitors have shown pleiotropic anticancer activities in hematological cancers. However, validated HDAC inhibitors for the treatment of solid tumors remain to be developed.
Purpose: To develop novel HDAC inhibitors to treat solid tumor, the current study evaluated the antitumor effects of novel HDAC inhibitors, N-Hydroxy-4-(4- phenylbutyryl-amino) benzamide HTPB and its nanoparticle-conjugated derivative Nano-HTPB by in vitro and in vivo models of human lung cancer.
Results: We found that Nano-HTPB delivered to cell nucleus at 6~48 hours in various lung cancer cell lines, indicating that HTPB conjugated with quantum dot nanoparticles was a feasible strategy for cancer cell delivery. In addition, Nano-HTPB and HTPB significantly induced cytotoxicity more potent than FDA-approved HDAC inhibitor SAHA in various lung cancer cells, without showing apparent cytotoxicity towards normal lung cells. Nano-HTPB was more potent than HTPB in IC50 values, which were in nM ranges. Nano-HTPB and HTPB induced G2/M arrest and led to apoptotic DNA ladder accompanied with induction of proapoptotic-related proteins and mitochondria-specific caspase-3/9 activities. The data from HDAC fluorometric activity assay suggested that Nano-HTPB and HTPB were pan-HDAC inhibitors, and they stimulated acetylation of histone and non-histone proteins in dose-dependent and time-dependent manners. In addition, Nano-HTPB and HTPB inhibited cancer cell migration at non-cytotoxic doses, which through inhibiting activity of matrix metalloproteinases, RhoA, and focal adhesion complex. Furthermore, the data from confocal microscopy analysis indicated that the polymerization of F-actin stress fiber was dramatically inhibited after Nano-HTPB or HTPB treatment. Finally, Nano-HTPB and HTPB efficiently inhibited tumor growth in xenograft animal models without significant side effects. In addition, HTPB significantly inhibited metastasis of 4T1-luc cells in vivo.
Conclusions: Our findings suggest that Nano-HTPB and HTPB are potent HDAC inhibitors and have clinical value in lung cancer treatment because they inhibit tumor growth and cell migration. The in vivo anti-metastasis effect, in vivo metabolic effects, and pharmacokinetics of Nano-HTPB and HTPB are under investigation.

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