Overexpression of bcl-2 or bcl-XL fails to inhibit apoptosis mediated by a novel retinoid

Joseph A. Fontana, Rong Juan Sun, Arun K. Rishi, Marcia I. Dawson, José V. Ordónez, Yuxiang Zhang, Sheng Hung Tschang, Kapil Bhalla, Zhiyong Han, James Wyche, Guy Poirer, M. Saeed Sheikh, Braham Shroot, Uve Reichert

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

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 μM CD437 to HL-60/NEO cells resulted in capase 3 (CPP32) activation and poly(ADP-ribose) polymcrase (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 G1 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.

Original languageEnglish (US)
Pages (from-to)313-324
Number of pages12
JournalOncology Research
Volume10
Issue number6
StatePublished - 1998
Externally publishedYes

Keywords

  • Apoptosis
  • Bcl-2
  • Bcl-x
  • Retinoids

ASJC Scopus subject areas

  • Cancer Research

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