Combination treatment of prostate cancer cell lines with bioactive soy isoflavones and perifosine causes increased growth arrest and/or apoptosis.

Abstract

PURPOSE:

To determine whether targeting the androgen receptor (AR) and Akt pathways using a combination of genistein combined polysaccharide (GCP) and perifosine is more effective at inducing growth arrest/apoptosis in prostate cancer cells compared with treatment with GCP or perifosine as single agents.

EXPERIMENTAL DESIGN:

The effect of GCP and perifosine treatment was assessed in five prostate cancer cell lines: LNCaP (androgen sensitive), LNCaP-R273H, C4-2, Cds1, and PC3 (androgen insensitive). A clonogenic assay assessed the long-term effects on cell growth and survival. Flow cytometry and Western blot analysis of poly(ADP)ribose polymerase cleavage were used to assess short-term effects. Preliminary studies to investigate mechanism of action included Western blot for P-Akt, Akt, P-p70S6K, p70S6K, p53, and p21; prostate-specific antigen analysis; and the use of myristoylated Akt and AR-specific small interfering RNA.

RESULTS:

Combination treatment with GCP and perifosine caused a decrease in clonogenic potential in all cell lines. In short-term assays, growth arrest was observed in the majority of cell lines, as well as increased inhibition of Akt activity and induction of p21 expression. Increased apoptosis was only observed in LNCaP. Knockdown of AR caused a further increase in apoptosis.

CONCLUSION:

Combination treatment with GCP and perifosine targets the Akt pathway in the majority of the prostate cancer cell lines and causes increased inhibition of cell growth and clonogenicity. In LNCaP, combination treatment targets both the Akt and AR pathways and causes increased apoptosis. These data warrant clinical validation in prostate cancer patients.

• Authors: Ruth L Vinall, Kimberley Hwa, Paramita Ghosh, Chong-Xian Pan, Primo N Lara Jr, Ralph W de Vere White
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 13 Issue 20 Pg. 6204-16 (Oct 15 2007) ISSN: 1078-0432 [Print] United States
• PMID: 17947488 (Publication Type: Journal Article)

Chemical References

• Isoflavones
• Polysaccharides
• RNA, Small Interfering
• Receptors, Androgen
• Phosphorylcholine
• perifosine
• Poly(ADP-ribose) Polymerases
• Proto-Oncogene Proteins c-akt

Topics

• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Apoptosis
• Cell Line, Tumor
• Cell Proliferation
• Dose-Response Relationship, Drug
• Humans
• Inhibitory Concentration 50
• Isoflavones (pharmacology)
• Male
• Phosphorylation
• Phosphorylcholine (administration & dosage, analogs & derivatives, pharmacology)
• Poly(ADP-ribose) Polymerases (metabolism)
• Polysaccharides (metabolism)
• Prostatic Neoplasms (drug therapy, metabolism, pathology)
• Proto-Oncogene Proteins c-akt (metabolism)
• RNA, Small Interfering (metabolism)
• Receptors, Androgen (metabolism)
• Soybeans (metabolism)
• Transfection