Fontana J A, Sun R J, Rishi A K, Dawson M I, Ordónez J V, Zhang Y, Tschang S H, Bhalla K, Han Z, Wyche J, Poirer G, Sheikh M S, Shroot B, Reichert U
Department of Medicine, Marlene and Stewart Greenebaum Cancer Center, University of Maryland at Baltimore, USA.
Oncol Res. 1998;10(6):313-24.
Overexpression of bcl-2 or bcl-XL has been found to inhibit the induction of apoptosis in malignant cells by a large number of agents including a wide variety of chemotherapeutic drugs. CD437 ¿6-[3-(1-adamantyl)-4 hydroxyphenyl]-2-naphthalene carboxylic acid¿ is a novel retinoid that induces apoptosis in a number of malignant cells through a unique mechanism of action. The addition of 1 microM CD437 to HL-60/NEO cells resulted in capase 3 (CPP32) activation and poly(ADP-ribose) polymerase (PARP) cleavage in 3 h whereas in bcl-2- or bcl-XL-overexpressing HL-60 cells CD437 induced CPP32 activation and PARP cleavage in 6 h. Although 50 and 300 nM CD437 were required to induce PARP cleavage in HL-60/NEO and HL-60/bcl-2, HL-60/bcl-XL cells, respectively, maximal apoptosis in both cell lines was achieved utilizing 300 nM CD437. All three cell lines, however, share identical dose-response curves in terms of their growth inhibition, suggesting that CD437-mediated inhibition of growth and induction of apoptosis represent two distinct and separable processes. In addition, CD437 induces GI arrest as well as p21WAFI/CIPI mRNA expression in these cells despite the overexpression of bcl-2 or bcl-XL. CD437 induced mitochondrial instability as indicated by cytochrome c leakage into the cytoplasm in all three cell lines. CD437 also induced growth inhibition and apoptosis of an apoptosis-resistant variant of the HL-60 cell line (HCW-2), which switched expression from bcl-2 to bcl-XL. CD437-mediated apoptosis is not accompanied by downregulation of bcl-2 or bcl-XL or upregulation of bax. The reason for the inability of bcl-2 or bcl-XL overexpression to inhibit CD437-mediated apoptosis is unclear. The ability of CD437 to initiate apoptosis in a spectrum of malignant cells without interference from bcl-2 or bcl-XL overexpression suggests that CD437 may possess significant therapeutic potential in the treatment of malignancy.
已发现bcl-2或bcl-XL的过表达可抑制包括多种化疗药物在内的大量药物诱导恶性细胞凋亡。CD437（6-[3-(1-金刚烷基)-4-羟基苯基]-2-萘甲酸）是一种新型视黄酸，它通过独特的作用机制在多种恶性细胞中诱导凋亡。向HL-60/NEO细胞中添加1μM CD437会在3小时内导致半胱天冬酶3（CPP32）激活和聚（ADP-核糖）聚合酶（PARP）裂解，而在过表达bcl-2或bcl-XL的HL-60细胞中，CD437在6小时内诱导CPP32激活和PARP裂解。虽然分别需要50 nM和300 nM CD437才能在HL-60/NEO和HL-60/bcl-2、HL-60/bcl-XL细胞中诱导PARP裂解，但使用300 nM CD437可使两种细胞系都达到最大凋亡。然而，所有这三种细胞系在生长抑制方面具有相同的剂量反应曲线，这表明CD437介导的生长抑制和凋亡诱导代表两个不同且可分离的过程。此外，尽管bcl-2或bcl-XL过表达，CD437仍能在这些细胞中诱导G1期停滞以及p21WAF1/CIP1 mRNA表达。如所有三种细胞系中细胞色素c泄漏到细胞质所表明的，CD437诱导线粒体不稳定。CD437还诱导了HL-60细胞系的凋亡抗性变体（HCW-2）的生长抑制和凋亡，该变体的表达从bcl-2转换为bcl-XL。CD437介导的凋亡并不伴随着bcl-2或bcl-XL的下调或bax的上调。bcl-2或bcl-XL过表达无法抑制CD437介导的凋亡的原因尚不清楚。CD437能够在一系列恶性细胞中启动凋亡而不受bcl-2或bcl-XL过表达的干扰，这表明CD437在恶性肿瘤治疗中可能具有显著的治疗潜力。
