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A novel hydroxamic acid compound, BMD188, demonstrates anti-prostate cancer effects by inducing apoptosis. I: In
Background:
Prostate cancer is the most frequently diagnosed malignancy in the Western countries. Apoptosis-targeted drug development could represent a specific and effective weapon against the disease (Tang and Porter, 32: 284-293, 1997). We previously demonstrated that the arachidonate 12-lipoxygenase and its metabolic products could function as survival factors for many solid tumors (Tang et al., Proc. Natl. Acad. Sci. USA 93: 5241-5246, 1996; Tang and Honn, J. Cell. Physiol. 172: 155-170, 1997).
Materials And Methods:
In this study, we synthesized a series of novel cyclic hydroxamic acid compounds that demonstrated varying degrees of inhibitory effects on the arachidonate 12-lipoxygenase. Subsequently we studied the effects of these novel compounds on human prostate cancer cells. First, all these compounds were screened on androgen-independent PC3 adenocarcinoma cells. Second, based on the results (i.e., the LD50 values) of the primary, secondary and tertiary screening, lead compounds were determined. Third, the lead compounds were utilized to study their cytotoxic effects on various prostate cancer cells as well as several types of normal cells. Finally, the molecular nature of the cell death was thoroughly characterized and the potential mechanisms of cell death were determined.
Results:
About 30% of the compounds screened induced a strong apoptotic death of androgen-independent prostate cancer cells, PC3, with an LD50 mostly at 10-20 microM. A lead compound, BMD188 [cis-1-hydroxy-4-(1-naphthyl)-6-octylpiperidine-2-one], was subsequently identified which inhibited the growth of PC3 cells with an LD50 at approximately 10 microM. Comparative studies indicated that BMD188 induced a more potent apoptotic response in PC3 cells than several conventional chemotherapeutic drugs. Furthermore, unlike the above drugs, BMD188 could induce 100% apoptosis in tumor cells. BMD188 also caused apoptosis of other types of prostate cancer cells including cells with multidrug resistance phenotype, independent of the androgen-dependence and p53 status. By contrast, BMD188 generally demonstrated 2-5 fold lower cytotoxicity towards several normal cell types including normal prostate epithelial cells. The growth inhibition by BMD188 was due to apoptosis induction as evidenced by DNA ladder formation, PARP [poly(ADP-ribose)polymerase] cleavage, and typical apoptotic morphology. BMD188-induced apoptosis does not depend on its inhibitory effects on lipoxygenase since target cells (i.e., PC3 and Du145) did not express the lipoxygenase mRNA and protein. In contrast, the apoptosis-inducing effect of BMD188 in PC3 cells could be significantly inhibited by serine protease inhibitors TPCK and TLCK as well as by caspase inhibitors DEVD and zVAD. The involvement of caspases in the apoptotic effects of BMD188 was further confirmed by the activation of caspase-3 (CPP32). In the accompanying paper, we show that BMD188 also inhibits the primary growth and local invasion of Du145 prostate cancer cells orthotopically implanted into the SCID or athymic nude mice.
Conclusion:
The data presented here suggest that these novel cyclic hydroxamic acid compounds, via induction of apoptotic death, may find potential clinical applications in the treatment of human prostate cancers.
Insights
Novel cyclic hydroxamic acid compounds effectively induce apoptosis in prostate cancer cells, with BMD188 showing potent anti-cancer activity. This discovery offers a promising new avenue for prostate cancer treatment by targeting programmed cell death.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- Prostate cancer is a leading malignancy in Western countries.
- Targeting apoptosis presents a promising strategy for effective cancer therapy.
- Arachidonate 12-lipoxygenase metabolites can promote solid tumor survival.
Purpose of the Study:
- To synthesize and evaluate novel cyclic hydroxamic acid compounds for their inhibitory effects on arachidonate 12-lipoxygenase.
- To investigate the efficacy of these compounds in inducing apoptosis in human prostate cancer cells.
- To identify lead compounds and characterize their mechanisms of action.
Main Methods:
- Synthesis of novel cyclic hydroxamic acid compounds.
- Screening of compounds for inhibitory activity against arachidonate 12-lipoxygenase and cytotoxicity in PC3 cells.
- Determination of LD50 values and selection of lead compounds.
- Detailed characterization of cell death mechanisms, including DNA laddering, PARP cleavage, and caspase activation.
Main Results:
- Approximately 30% of screened compounds induced significant apoptosis in PC3 cells (LD50 10-20 microM).
- BMD188, a lead compound, demonstrated potent apoptosis induction in PC3 cells (LD50 ~10 microM), surpassing conventional chemotherapeutics and achieving 100% tumor cell apoptosis.
- BMD188 exhibited broad efficacy against various prostate cancer cells, including multidrug-resistant and androgen-independent types, with lower toxicity to normal cells.
- Apoptosis induction by BMD188 was independent of lipoxygenase inhibition and mediated through caspase activation.
Conclusions:
- Novel cyclic hydroxamic acid compounds, particularly BMD188, effectively induce apoptosis in prostate cancer cells.
- BMD188 demonstrates significant potential for clinical application in treating human prostate cancers.
- The findings highlight a promising new class of apoptosis-inducing agents for prostate cancer therapy.