Antisense bcl-2 treatment increases programmed cell death in non-small cell lung cancer cell lines

Programmed cell death (PCD) is a genetically regulated pathway that is alte red in many cancers. This process is, in part, regulated by the ratio of PC D inducers (Bax) or inhibitors (Bcl-2). An abnormally high ratio of Bcl-2 t o Pax prevents PCD, thus contributing to resistance to chemotherapeutic age nts, many of which are capable of inducing PCD. Non-small cell lung cancer (NSCLC) cells demonstrate resistance to these PCD-inducing agents. If Bcl-2 prevents NSCLC cells from entering the PCD pathway, then reducing the amou nt of endogenous Bcl-2 product may allow these cells to spontaneously enter the PCD pathway. Our purpose was to determine the effects of bcl-2 antisen se treatment on the levels of programmed cell death in NSCLC cells. First, we determined whether bcl-2 and bar mRNA were expressed in three morphologi cally distinct NSCLC cell lines: NCI-H226 (squamous), NCI-H358 (adenocarcin oma), and NCI-H596 (adenosquamous). Cells were then exposed to synthetic an tisense bcl-2 oligonucleotide treatment, after which programmed cell death was determined, as evidenced by DNA fragmentation. Bcl-2 protein expression was detected immunohistochemically. All three NSCLC cell lines expressed b oth bcl-2 and bar mRNA and had functional PCD pathways. Synthetic antisense bcl-2 oligonucleotide treatment resulted in decreased Bcl-2 levels, reduce d cell proliferation, decreased cell viability, and increased levels of spo ntaneous PCD. This represents the first evidence that decreasing Bcl-2 in t hree morphologically distinct NSCLC cell lines allows the cells to spontane ously enter a PCD pathway. It also indicates the potential therapeutic use of antisense bcl-2 in the treatment of NSCLC. (C) 1999 Elsevier Science Ire land Ltd. All rights reserved.