Campbell M J, Dawson M, Koeffler H P
Division of Hematology/Oncology, Cedars-Sinai Medical Center/UCLA School of Medicine, Los Angeles, CA 90048, USA.
Br J Cancer. 1998 Mar;77(5):739-44. doi: 10.1038/bjc.1998.121.
Hormonally insensitive prostate cancer is a relatively slow-growing, but usually fatal, disease with no long-term treatment options. Transformation of normal prostate cells to a malignant phenotype often involves corruption of the apoptotic machineries. Bcl-2 protein is one of the key inhibitors of apoptosis and is often unregulated in advanced prostate cancer. The prostate cancer cell line DU-145 was used as a model of a hormonally insensitive, advanced prostate cancer. Cell growth in liquid culture was significantly inhibited by antisense Bcl-2 oligonucleotides compared with control sense oligonucleotides; inhibition by these oligonucleotides was significantly enhanced on combination with the synthetic retinoid N-(2-hydroxyphenyl)all-trans-retinamide (2-HPR). Interestingly, growth inhibition occurred in the absence of apoptosis as measured using two assay techniques. We hypothesize that in these recalcitrant cells the apoptotic pathway is compromised at several levels, and Bcl-2 may play another role in promoting cell growth. The use of Bcl-2 antisense oligonucleotides plus 2-HPR may provide a novel approach to therapy of hormone-resistant prostate cancer.
激素不敏感型前列腺癌是一种生长相对缓慢但通常致命的疾病，目前尚无长期治疗方案。正常前列腺细胞向恶性表型的转变通常涉及凋亡机制的破坏。Bcl-2蛋白是凋亡的关键抑制因子之一，在晚期前列腺癌中常出现失调。前列腺癌细胞系DU-145被用作激素不敏感型晚期前列腺癌的模型。与对照正义寡核苷酸相比，反义Bcl-2寡核苷酸显著抑制液体培养中的细胞生长；这些寡核苷酸与合成视黄酸N-(2-羟基苯基)全反式视黄酰胺(2-HPR)联合使用时，抑制作用显著增强。有趣的是，使用两种检测技术检测发现，在没有凋亡的情况下发生了生长抑制。我们推测，在这些顽固的细胞中，凋亡途径在多个水平上受到损害，Bcl-2可能在促进细胞生长中发挥另一种作用。使用Bcl-2反义寡核苷酸加2-HPR可能为激素抵抗型前列腺癌的治疗提供一种新方法。
