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Effects of the herbal extract PC-SPES on microtubule dynamics and paclitaxel-mediated prostate tumor growth inhibition.

AbstractBACKGROUND:
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 alpha-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 mm(3), 95% confidence interval [CI] = 2380 to 3586 mm(3)), tumors were statistically significantly smaller in mice that received PC-SPES (mean tumor volume = 2018 mm(3), 95% CI = 1450 to 2568 mm(3); P =.028), paclitaxel (mean tumor volume = 1340 mm(3), 95% CI = 697 to 1983 mm(3); P<.001), or the combination of PC-SPES and paclitaxel (mean tumor volume = 1955 mm(3), 95% CI = 1260 to 2650 mm(3); 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.
AuthorsMichael J Bonham, Anna Galkin, Bruce Montgomery, William L Stahl, David Agus, Peter S Nelson
JournalJournal of the National Cancer Institute (J Natl Cancer Inst) Vol. 94 Issue 21 Pg. 1641-7 (Nov 06 2002) ISSN: 0027-8874 [Print] United States
PMID12419791 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Antineoplastic Agents, Phytogenic
  • Drugs, Chinese Herbal
  • Plant Extracts
  • Tubulin
  • herbal preparation PC-SPES
  • Paclitaxel
Topics
  • Animals
  • Antineoplastic Agents, Phytogenic (therapeutic use)
  • Cell Division (drug effects)
  • Drugs, Chinese Herbal
  • Gene Expression Regulation, Neoplastic (drug effects)
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Microtubules (drug effects, ultrastructure)
  • Oligonucleotide Array Sequence Analysis
  • Paclitaxel (therapeutic use)
  • Phytotherapy
  • Plant Extracts (therapeutic use)
  • Prostatic Neoplasms (drug therapy, genetics, pathology)
  • Transplantation, Heterologous
  • Tubulin (genetics, metabolism)
  • Tumor Cells, Cultured

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