二亞硝基鐵錯合物（DNIC）在血管增生、傷口癒合及抗癌活性探討

Application of Dinitrosyl Iron Complex (DNIC) in Angiogenesis, Wound Healing and Anticancer Activity

陳以柏(Yi-Po Chen) ； 陳念爵(Nien-Chueh Chen) ； 王雲銘(Yun-Ming Wang)

《化學》 77卷4期 (2019/12) Pp. 365-378

https://doi.org/10.6623/chem.201912_77(4).006

摘要

一氧化氮（NO）是重要的細胞信號傳導分子，可調節各種生理活動，在實驗和臨床研究中都已經探索了NO釋放劑促進血管生成活性。先前的研究中，在血管中加入一氧化氮衍生的細胞錯合物{Fe(NO)_2}^9二亞硝基鐵化合物（DNIC），DNIC在體內作為天然的NO載體，在許多研究中表明其作為NO載體潛在的藥物活性。在這項研究中，合成三種水溶性的DNIC以用作NO釋放劑，並各自探討其潛在的藥物活性。通過細胞活性分析、細胞刮痕癒合分析及小鼠活體內血管新生分析，確定DNIC－1和DNIC－2促進細胞增生的能力，且結果顯示，DNIC－1在劑量濃度7.8μM時，比起血管內皮生長因子（VEGF）及市售一氧化氮釋放劑（Spermine NONOate及MAHMA NONOate）有更佳的細胞增生及傷口癒合之能力，且從下肢缺血糖尿病鼠實驗結果顯示，DNIC－1可促進糖尿病鼠表現血管新生相關蛋白質，促使受損的下肢的血管修復與新生。綜合上述，DNIC－1具備使細胞增生、傷口癒合及血管新生的效果，因此可認為其應用於傷口癒合及血管新生治療藥物的潛力。通過細胞活性分析、Annexin－V／PI染色法及蛋白質印跡法確定DNIC－3透過凋亡途徑抑制腫瘤細胞的生長並誘導腫瘤死亡，再由皮下移植PC－3腫瘤的裸鼠評估DNIC－3體內的抗腫瘤活性。

關鍵字

一氧化氮（NO） ； 二亞硝基鐵錯合物（DNIC） ； 抗腫瘤（anti-tumor） ； 血管增生（angiogenesis） ； 傷口癒合（wound healing）

並列摘要

Nitric oxide (NO) is an important cell signaling molecule that regulates various physiological activities. The angiogenic activity of NO donor drugs has been explored in both experimental and clinical studies using the dinitrosoferric iron complex (DNIC) as a NO carrier. In this study, three water-soluble DNICs were synthesized and used as NO-releasing agents. Each agent has been thoroughly studied to determine their potential biological activities. Cell viability, cell scratch healing assay, and angiogenesis in vivo analyses were carried out to determine the potential abilities of DNIC-1 DNIC-2 on biological applications. The cell viability studies demonstrated the cell proliferation results and the results indicated that DNIC-1 has better cell proliferation and wound healing abilities when compared to vascular endothelial growth factor (VEGF) and commercially available nitric oxide release agents (Spermine NONOate and MAHMA NONOate) at a dose concentration of 7.8 μM. The experimental results from lower extremity ischemic diabetic mice showed that DNIC-1 can promote the expression of angiogenesis- related proteins in diabetic mice and promote vascular repair and regeneration of damaged lower limbs. Collectively, on comparing the experimental results of DNIC-1, DNIC-2, and DNIC-3, DNIC-1 displayed greater effects when subjected to cell proliferation, wound healing and angiogenesis studies. The results of cell viability analysis, Annexin-V / PI staining, and western blotting studies revealed that DNIC-3 inhibits the growth of cancer cells and induces cell death via the apoptotic pathway. Besides, the antitumor ability of DNIC-3 was evaluated using nude mice implanted subcutaneously with PC-3 cancer cells, in vivo.

並列關鍵字

Nitric oxide (NO) ； Dinitrosyl iron complex (DNIC) ； Anti-tumor ； Angiogenesis ； Wound healing