Chemosensitization of carmustine with maitake beta-glucan on androgen-independent prostatic cancer cells: involvement of glyoxalase I.
OBJECTIVE
To improve the poor efficacy (< 10%) of chemotherapy for patients with hormone-refractory prostate cancer, we investigated a possible cytotoxic effect of carmustine/beta-glucan combination on prostatic cancer PC-3 cells, focusing on a glutathione-dependent detoxifying enzyme, glyoxalase I (Gly-I).


METHODS
Carmustine (BCNU) is an anticancer agent and a putative inhibitor of Gly-I, while beta-glucan is a unique, nontoxic polysaccharide extracted from maitake mushrooms. The cytotoxic effects of BCNU or other anticancer agents with beta-glucan on PC-3 cells were assessed by cell-viability testing and Gly-I activity was measured using the spectrophotometric method.


RESULTS
BCNU, 5-fluorouracil (5-FU), and methotrexate (MTX) were capable of inducing approximately a 50% reduction in cell viability at 72 hours, while etoposide, cisplatin, and mitomycin C were all ineffective. Only the combination of BCNU (50 micro ;mol) and beta-glucan (60 micro g/mL) exhibited an enhanced cytotoxicity with an approximate 90% cell viability reduction, but little improvement was seen with any combinations of 5-FU, MTX, or beta-glucon. Gly-I assays revealed that such a profound (approximately 90%) cell death was accompanied by an approximate 80% reduction in Gly-I activity by 6 hours.


CONCLUSIONS
This study demonstrates a sensitized cytotoxic effect of BCNU with beta-glucan in PC-3 cells, which was associated with a drastic (approximately 80%) inactivation of Gly-I. Therefore, the BCNU/beta-glucan combination may help to improve current treatment efficacy by targeting Gly-I, which appears to be critically involved in prostate cancer viability.
Finkelstein
Michael P
MP
Department of Urology, New York Medical College, Valhalla, NY 10595, USA.
Aynehchi
Shahrad
S
Samadi
Albert A
AA
Drinis
Sophia
S
Choudhury
Muhammad S
MS
Tazaki
Hiroshi
H
Konno
Sensuke
S
D000363:Agaricales; D000728:Androgens / Q000378:metabolism; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D002330:Carmustine / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005472:Fluorouracil / Q000494:pharmacology; D005936:Glucans / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007791:Lactoylglutathione Lyase / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008727:Methotrexate / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects; D047071:beta-Glucans
D000728:Androgens; D018906:Antineoplastic Agents, Alkylating; D005936:Glucans; D047071:beta-Glucans; C064197:beta-1,6-glucan; D007791:Lactoylglutathione Lyase; D005472:Fluorouracil; D002330:Carmustine; D008727:Methotrexate