Abstract
Hormonally insensitive prostate cancer is a relatively slow-growing, but usually fatal, disease with no long-term treatment options. Transformation of normal prostate cells to a malignant phenotype often involves corruption of the apoptotic machineries. Bcl-2 protein is one of the key inhibitors of apoptosis and is often unregulated in advanced prostate cancer. The prostate cancer cell line DU-145 was used as a model of a hormonally insensitive, advanced prostate cancer. Cell growth in liquid culture was significantly inhibited by antisense Bcl-2 oligonucleotides compared with control sense oligonucleotides; inhibition by these oligonucleotides was significantly enhanced on combination with the synthetic retinoid N-(2-hydroxyphenyl)all-trans-retinamide (2-HPR). Interestingly, growth inhibition occurred in the absence of apoptosis as measured using two assay techniques. We hypothesize that in these recalcitrant cells the apoptotic pathway is compromised at several levels, and Bcl-2 may play another role in promoting cell growth. The use of Bcl-2 antisense oligonucleotides plus 2-HPR may provide a novel approach to therapy of hormone-resistant prostate cancer.
Highlights
Prostate cancer has become the most frequently diagnosed nonskin cancer among American men and the second leading cause of cancer mortality in this group, with similar mortality rates in many western European countries (Parker et al, 1997)
We investigated whether growth inhibition was additively enhanced by the combination of the optimum AS oligonucleotide concentration (2,UM) with various retinoids (ATRA, 9-cis retinoic acid (9cRA) and 2HPR)
We used a dose for further experiments that had a noticeable but submaximal inhibitory effect; this effect was obtained by all three retinoids at 0.1,IM and was equal to approximately 30% growth inhibition
Summary
Prostate cancer has become the most frequently diagnosed nonskin cancer among American men and the second leading cause of cancer mortality in this group, with similar mortality rates in many western European countries (Parker et al, 1997). The rapid rise in the incidence of prostate cancer may be, in part, due to the increasing use of the prostate-specific antigen (PSA) blood test by physicians (Jacobsen et al, 1995), the underlying increase in this disease is probably real. Despite the increase in the incidence of the disease and its large-scale effects, no successful long-term therapies exist once the cancer progresses beyond the prostate capsule
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