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


CONCLUSIONS
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.
Bonham
Michael J
MJ
Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA.
Galkin
Anna
A
Montgomery
Bruce
B
Stahl
William L
WL
Agus
David
D
Nelson
Peter S
PS
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D002455:Cell Division / Q000187:drug effects*; D004365:Drugs, Chinese Herbal; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008870:Microtubules / Q000187:drug effects* / Q000648:ultrastructure; D020411:Oligonucleotide Array Sequence Analysis; D017239:Paclitaxel / Q000627:therapeutic use*; D008517:Phytotherapy; D010936:Plant Extracts / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D014183:Transplantation, Heterologous; D014404:Tubulin / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D004365:Drugs, Chinese Herbal; D010936:Plant Extracts; D014404:Tubulin; C114209:herbal preparation PC-SPES; D017239:Paclitaxel