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Experimental Therapeutics |
Departments of Medicine [I. L., C. A. S.] and Pharmacology [C. A. S.], Columbia University, New York, New York 10032, and Aronex Pharmaceuticals, The Woodlands, Texas 77381-1191 [R. R., J. O., P. C.]
Both Bcl-xL and Bcl-2, antiapoptotic members of the Bcl family, are found in prostate cancer cell lines. Although these proteins may have similar antiapoptotic functions, it is not clear to what extent each serves as an antiapoptotic effector in prostate cancer cells. We engineered LNCaP and PC-3 cells to overexpress Bcl-xL protein and demonstrated that this desensitized them to the effects of cytotoxic chemotherapy. We then used two "antisense" strategies to down-regulate Bcl-xL protein expression in the parental lines. The first strategy used C5-propynylated phosphorothioate-phosphodiester oligonucleotides and co-down-regulated both Bcl-xL and Bcl-2; the second strategy used isosequential "gap-mer" phosphorothioate oligonucleotides containing 2'-O-methyl oligoribonucleotides at the 3' and 5' termini. In this case, only Bcl-xL protein expression was affected. The most active oligonucleotides of both types decreased the level of Bcl-xL protein expression to 5–30% of the control level. Multiple controls were inactive. Experiments combining oligonucleotide treatment with cytotoxic chemotherapeutic agents (paclitaxel, docetaxel, etoposide, vinblastine, carboplatin, and mitoxantrone) demonstrated a marked increase in the sensitivity of these prostate cancer cells. However, the increase in chemosensitivity in PC-3 cells was statistically identical (except mitoxantrone) for both "antisense" strategies, indicating that basal expression of Bcl-2, in contrast to that of Bcl-xL, may play little cytoprotective role in these cells.
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