Copeland Robert L, Das Jharna R, Bakare Oladapo, Enwerem Nkechi M, Berhe Solomon, Hillaire Kenguele, White Douglas, Beyene Desta, Kassim Olakunle O, Kanaan Yasmine M
Department of Pharmacology, College of Medicine and Cancer Center, Howard University, Washington, DC 20059, USA.
Anticancer Res. 2007 May-Jun;27(3B):1537-46.
Prostate cancer ranks third worldwide in cancer incidence and sixth in cancer mortality among men. A number of 1,4-naphthoquinone derivatives have been found to possess significant pharmacological effects associated with marked antimicrobial and antitumor activities. In the present study the in vitro effect of 2,3-dichloro-5,8-dimethoxy-1,4-naphthoquinone (DCDMNQ) was evaluated on androgen-dependent (LNCaP, CWR-22) and androgen-independent (PC-3. DU-145) human prostate cancer cell lines, and/or a normal bone marrow cell line (HS-5). Moreover, the in vitro activity of this compound on cell cycle regulation and apoptosis was evaluated.
Established methods of cell viability, cell cycle, Western blot and apoptosis were used.
The effect of DCDMNQ on LNCaP, CWR-22, PC-3, DU-145 and HS-5 cells revealed significant anti-tumor activities with IC50s, of 1, 3. 1.5, 3 and 10 microM respectively. Cell cycle analysis showed that DCDMNQ inhibited progression through the cell cycle in PC-3 and DU-145 cell lines in a time-dependent manner. The result for the CWR-22 cell line showed that DCDMNQ arrested cells in the G -phase of the cell cycle with the greatest proportion of cells in the G1-phase by day 5; however, the LNCaP cell line was inconsistent. The compound showed no effect on the cell cycle progression in the bone marrow HS-5 cell line. These findings were further validated using Western blot analysis. Furthermore, DCDMNQ induced apoptosis in the androgen-independent cells, preferentially over that of the androgen-dependent cell lines, in a time-dependent manner.
Although the mechanism of action of this compound has not been completely elucidated, the effect on the cell cycle and the induction of apoptosis in different prostate cancer cell lines prompted us to carry out a more in-depth preclinical evaluation of it. This study suggests that DCDMNQ may have an impact on treatment of prostate cancer while protecting the bone marrow.
前列腺癌在全球男性癌症发病率中排名第三，在癌症死亡率中排名第六。已发现多种1,4 -萘醌衍生物具有与显著抗菌和抗肿瘤活性相关的重要药理作用。在本研究中，评估了2,3 -二氯-5,8 -二甲氧基-1,4 -萘醌（DCDMNQ）对雄激素依赖性（LNCaP、CWR - 22）和雄激素非依赖性（PC - 3、DU - 145）人前列腺癌细胞系以及/或正常骨髓细胞系（HS - 5）的体外作用。此外，还评估了该化合物对细胞周期调控和凋亡的体外活性。
采用已建立的细胞活力、细胞周期、蛋白质免疫印迹和凋亡检测方法。
DCDMNQ对LNCaP、CWR - 22、PC - 3、DU - 145和HS - 5细胞的作用显示出显著的抗肿瘤活性，其IC50分别为1、3、1.5、3和10微摩尔。细胞周期分析表明，DCDMNQ以时间依赖性方式抑制PC - 3和DU - 145细胞系的细胞周期进程。CWR - 22细胞系的结果显示，到第5天时，DCDMNQ使细胞停滞在细胞周期的G1期，且处于G1期的细胞比例最大；然而，LNCaP细胞系的结果并不一致。该化合物对骨髓HS - 5细胞系的细胞周期进程无影响。这些发现通过蛋白质免疫印迹分析得到进一步验证。此外，DCDMNQ以时间依赖性方式诱导雄激素非依赖性细胞凋亡，且优先于雄激素依赖性细胞系。
尽管该化合物的作用机制尚未完全阐明，但它对不同前列腺癌细胞系的细胞周期和凋亡诱导作用促使我们对其进行更深入的临床前评估。本研究表明，DCDMNQ可能在保护骨髓的同时对前列腺癌治疗产生影响。
