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Depsipeptide (FK228) inhibits growth of human prostate cancer cells
Ming-Tsung Lai1, Chuan-Ching Yang, Tsai-Yun Lin
1Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan.
Abstract:
FK228 (depsipeptide) is a natural prodrug that inhibits class I histone deacetylases. We aimed to investigate the effects FK228 has on prostate cancer cells in vivo. In non-obese diabetic-severe combined immunodeficient mice implanted with human prostate cancer cells, 50 mg/kg FK228 given orally 3 times a week inhibited tumor growth and metastasis. The median time to the experimental end point (tumor volume 2 cm(3) or death) in the untreated group was 52 days, and average tumor volume was 0.8 +/- 0.18 cm(3). At the same time, 94.4% of FK228-treated mice survived and had average tumor volumes of 0.37 +/- 0.1 cm(3). All untreated animals died at 98 days, whereas, 61% of treated animal remained alive. Sizeable metastatic tumors positively stained for prostate-specific antigen (PSA), and limited air gaps were found in the lungs of untreated mice. In animals treated with FK228, lung morphology appeared normal. Primary tumors of treated animals were highly positive for PSA, and had an increased level of p21 and the proapoptotic protein Bax. Sections taken from FK228-treated animals and examined under an electron microscope showed condensed chromatin and apoptotic bodies. PSA serum levels were higher in untreated than in treated animals and correlated with tumor volume. Because prolonged oral administration of 50 mg/kg or a single oral dose of 1.2 g/kg FK228 did not cause adverse effects and inhibited proliferation of human prostate cancer cells in vivo, FK228 likely has a potential anticancer effect for prostate cancer.
Insights
FK228, a histone deacetylase inhibitor, effectively suppressed prostate cancer growth and metastasis in mice. This natural prodrug demonstrated significant survival benefits and reduced tumor volume with no observed adverse effects.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- FK228 (depsipeptide) is a natural prodrug targeting class I histone deacetylases.
- Prostate cancer remains a significant health concern with a need for effective treatments.
Purpose of the Study:
- To investigate the in vivo effects of FK228 on human prostate cancer cells.
- To evaluate FK228's efficacy in inhibiting tumor growth and metastasis.
Main Methods:
- Utilized non-obese diabetic-severe combined immunodeficient (NOD-SCID) mice xenograft models implanted with human prostate cancer cells.
- Administered FK228 orally at 50 mg/kg, three times weekly.
- Assessed tumor volume, metastasis, survival rates, prostate-specific antigen (PSA) levels, and performed histological and electron microscopy analyses.
Main Results:
- FK228 treatment significantly inhibited tumor growth and metastasis, with treated mice showing smaller tumor volumes and improved survival rates compared to controls.
- Histological examination revealed normal lung morphology in FK228-treated mice, contrasting with metastatic tumors in untreated animals.
- Electron microscopy confirmed condensed chromatin and apoptotic bodies in tumors from FK228-treated mice, indicating apoptosis induction.
Conclusions:
- FK228 demonstrates potent anticancer effects against human prostate cancer in vivo.
- The drug effectively inhibits tumor proliferation, growth, and metastasis.
- FK228 shows a favorable safety profile, suggesting its potential as a therapeutic agent for prostate cancer.
