科研之友
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摘要
Overexpression of bcl-2 or bcl-X-L 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 it unique mechanism of action. The addition of 1 mu M 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-X-L-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/bcI-X-L 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 G(1) arrest as well as p21(WAFL/CIPI) mRNA expression in these cells despite the overexpression of bcl-2 or bcl-X-L. 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 bci-X-L or upregulation of bar. The reason for the inability of bcl-2 or bcl-X-L 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-X-L overexpression suggests that CD437 may possess significant therapeutic potential in the treatment of malignancy.
- 出版日期1998
- 单位NIH
