Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran.
Department of Laboratory Sciences, School of Paramedical Sciences, Mashhad University of Medical Sciences, Mashhad, Iran.
Arch Iran Med. 2018 Jun 1;21(6):251-259.
Prostate cancer is one of the leading causes of cancer related deaths in males worldwide. Overexpression of 15-lipoxygenase-1 (15-LOX-1) enzyme and high activity of its metabolic pathway is reported to be a driver for prostate cancer malignancy. Farnesyloxycoumarin derivatives (3f, 4f and 7f) inhibit lipoxygenase enzyme. We hypothesized that farnesyloxycoumarins may exert an anti-cancer effect on prostate cancer cells due to their 15-LOX-1 inhibitory potential.
The enzyme inhibitory activity of 3f, 4f and 7f was initially evaluated on PC-3 and DU145 prostate cancer cell lines. MTT assay was performed on cancer cell lines and HFF3 cell line to assess cytotoxicity of the compounds. The apoptotic morphology of cells after treatments was assessed by DAPI staining and single cell gel electrophoresis. Propidium iodide staining was also performed to detect cell cycle variations after treatment.
7f inhibited 15-LOX-1 at IC50=4.3 µg/mL, while 3f and 4f did not show high inhibitory activity. 7f reduced cell viability in PC-3 cells at IC50=22-31 µg/mL, however, no significant cytotoxicity was revealed on normal cells. DAPI staining and comet assay confirmed apoptosis and DNA damage in PC-3 cells after 7f treatment, while flow cytometry results revealed G1 arrest in PC-3 cells.
The results are indicative of a distinctive cytotoxic mechanism for 7f compared to other coumarins, possibly due to its 15-LOX-1 inhibitory potential. Thus, this compound is valued for further assessments with the aim of developing a promising targeted therapy for prostate cancer patients.
前列腺癌是全球男性癌症相关死亡的主要原因之一。据报道，15-脂氧合酶-1（15-LOX-1）酶的过表达及其代谢途径的高活性是前列腺癌恶性肿瘤的驱动因素。法呢酰氧基香豆素衍生物（3f、4f 和 7f）抑制脂氧合酶。我们假设由于其 15-LOX-1 抑制潜力，法呢酰氧基香豆素可能对前列腺癌细胞发挥抗癌作用。
首先在 PC-3 和 DU145 前列腺癌细胞系上评估 3f、4f 和 7f 的酶抑制活性。在癌细胞系和 HFF3 细胞系上进行 MTT 测定，以评估化合物的细胞毒性。用 DAPI 染色和单细胞凝胶电泳评估处理后细胞的凋亡形态。处理后还进行碘化丙啶染色以检测细胞周期变化。
7f 在 IC50=4.3 µg/mL 时抑制 15-LOX-1，而 3f 和 4f 没有显示出高抑制活性。7f 在 IC50=22-31 µg/mL 时降低 PC-3 细胞的细胞活力，但对正常细胞没有显示出显著的细胞毒性。DAPI 染色和彗星试验证实 7f 处理后 PC-3 细胞发生凋亡和 DNA 损伤，而流式细胞术结果显示 PC-3 细胞发生 G1 期阻滞。
与其他香豆素相比，7f 的结果表明其具有独特的细胞毒性机制，可能是由于其 15-LOX-1 抑制潜力。因此，该化合物值得进一步评估，以期为前列腺癌患者开发有前途的靶向治疗方法。
