© 2002 by Oxford University Press
Journal of the National Cancer Institute, Vol. 94, No. 21, 1641-1647,
November 6, 2002
© 2002 Oxford University Press
ARTICLE |
Effects of the Herbal Extract PC-SPES on Microtubule Dynamics and Paclitaxel-Mediated Prostate Tumor Growth Inhibition
Affiliations of authors: M. J. Bonham, Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA; A. Galkin, D. Agus, Cedars-Sinai Prostate Cancer Center, Los Angeles, CA; B. Montgomery, W. L. Stahl, Division of Medical Oncology, Veterans Administration Hospital, Seattle; P. S. Nelson, Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center.
Correspondence to: Peter S. Nelson, M.D., Division of Human Biology, Fred Hutchinson Cancer Research Center, Mailstop D4–100, 1100 Fairview Ave. North, Seattle, WA 98109–1024 (e-mail: pnelson{at}fhcrc.org).
Background: PC-SPES is a botanical preparation shown to have efficacy in patients with androgen-dependent and androgen-independent prostate carcinoma. Several herbal constituents in PC-SPES inhibit tumor growth through cell cycle arrest and apoptosis, although the mechanisms of these activities are poorly defined. We sought to identify PC-SPES-induced changes in gene expression, specifically in those genes encoding cytoskeletal proteins that could be associated with PC-SPES-induced cytoxicity. Methods: LNCaP prostate carcinoma cells were treated with PC-SPES, and changes in gene expression were determined by complementary DNA (cDNA) microarray hybridization and northern blot analyses. PC-SPES and paclitaxel, a microtubule-stabilizing drug, effects on microtubules were assessed by immunofluorescence of treated cells and by in vitro tubulin polymerization assays. In vivo effects of PC-SPES and paclitaxel were assessed using CWR22R androgen-independent prostate cancer xenografts. All statistical tests were two-sided. Results: PC-SPES treatment of LNCaP cells for 24 hours altered the expression of 17 cytoskeletal genes. mRNA levels of 
-tubulin decreased sevenfold. Although paclitaxel stabilized and PC-SPES treatment disrupted microtubule architecture in LNCaP cells, the combination of both agents had an intermediate effect. PC-SPES inhibited tubulin polymerization in vitro, even in the presence of paclitaxel. Compared with tumors in control mice (mean tumor volume = 2983 mm3, 95% confidence interval [CI] = 2380 to 3586 mm3), tumors were statistically significantly smaller in mice that received PC-SPES (mean tumor volume = 2018 mm3, 95% CI = 1450 to 2568 mm3; P = .028), paclitaxel (mean tumor volume = 1340 mm3, 95% CI = 697 to 1983 mm3; P<.001), or the combination of PC-SPES and paclitaxel (mean tumor volume = 1955 mm3, 95% CI = 1260 to 2650 mm3; P = .034). Conclusion: PC-SPES may interfere with microtubule polymerization. This activity has implications for the clinical management of patients with advanced prostate cancer who may be taking PC-SPES concurrently with microtubule-modulating chemotherapeutic agents, such as paclitaxel.
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