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Factors Affecting Topotecan-induced Programmed Cell Death: Adhesion Protects Cells from Apoptosis and Impairs Cleavage of Poly(ADP-Ribose)Polymerase¹

Department of Medicine and Cancer Center, Case Western Reserve University, School of Medicine, Cleveland, Ohio 44106-4937

We have evaluated the influence of anchorage status together with endogenous levels of bcl-2 family members on the ability of the topoisomerase I inhibitor, topotecan (TPT), to induce programmed cell death (PCD) in human colon, breast, lymphoid, and cervical cancer cell lines. As part of this study, we assessed the use of measuring poly(ADP-ribose) polymerase (PARP) cleavage by Western blot, as an index of apoptosis, relative to measuring chromatin condensation by acridine orange analysis. Our results show a strong correlation between both assays, indicating that PARP cleavage is an accurate method to examine PCD. We have encountered a strong association between cell attachment and sensitivity to TPT-induced PCD. Cells growing attached to flasks appear to be relatively more resistant than suspension-growing cells in spite of endogenous bcl-2, bax, or bcl-x levels. Furthermore, we demonstrate that interference with attachment status alters the sensitivity of cells to TPT-induced PCD. Although cell attachment to ProNectin F confers protection against TPT-induced chromatin condensation and cleavage of PARP, cell detachment by poly(2-hydroxyethyl methacrylate) stimulates TPT-induced PCD and PARP cleavage.

¹ These studies were supported by Grants PO1 CA51183, P30 CA43703, and U01 CA63200 from the National Cancer Institute.

² To whom requests for reprints should be addressed, at Department of Medicine, School of Medicine BRB 301A, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106-4937. Phone: (216) 368-2825; Fax: (216) 368-116.

Received 6/20/96. Accepted 4/ 4/97.

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