Department of Biochemistry, Faculty of Medicine, Chiang Mai University.
Department of Surgery, Faculty of Medicine, Chiang Mai University.
Biol Pharm Bull. 2019 Jun 1;42(6):906-914. doi: 10.1248/bpb.b18-00860. Epub 2019 Mar 30.
Prostate cancer is the second most common cancer among men worldwide, and it is ranked first in the United States and Europe. Since prostate cancer is slow-growing, active surveillance for low-risk cancer has been increasingly supported by various guidelines. Most prostate cancers reactivate telomerase to circumvent the replicative senescence caused by the end replication problem; therefore, telomerase inhibition is potentially useful for the suppression of prostate cancer progression during this active surveillance or for the prevention of cancer recurrence after conventional therapies. In this study, we demonstrated that the perylene derivatives, PM2 and PIPER, could suppress human telomerase reverse transcriptase (hTERT) expression and telomerase activity in the short-term treatment of androgen-dependent prostate cancer cell line LNCaP and the androgen-independent prostate cancer cell line PC3 prostate cancer cells. Long-term treatment with subcytotoxic doses of these compounds in both prostate cancer cells showed telomere shortening and a significant increase in senescent cells. Although the acute cytotoxicity of PM2 was about 30 times higher than that of PIPER in both prostate cancer cells, the cellular uptake of both compounds was comparable as determined by flow cytometry and fluorescent microscopy.
前列腺癌是全球男性中第二常见的癌症，在美国和欧洲排名第一。由于前列腺癌生长缓慢，各种指南越来越支持对低危癌症进行积极监测。大多数前列腺癌重新激活端粒酶以规避端粒末端复制问题引起的复制性衰老；因此，端粒酶抑制在这种积极监测期间抑制前列腺癌进展或预防常规治疗后癌症复发可能是有用的。在这项研究中，我们证明了苝衍生物 PM2 和 PIPER 可以在短期治疗雄激素依赖性前列腺癌细胞系 LNCaP 和雄激素非依赖性前列腺癌细胞系 PC3 前列腺癌细胞中抑制人端粒酶逆转录酶（hTERT）表达和端粒酶活性。用这些化合物的亚细胞毒性剂量长期处理两种前列腺癌细胞均显示出端粒缩短和衰老细胞显著增加。尽管 PM2 在两种前列腺癌细胞中的急性细胞毒性约比 PIPER 高 30 倍，但通过流式细胞术和荧光显微镜确定，两种化合物的细胞摄取相当。
