Antiproliferative mechanisms of the flavonoids 2,2'-dihydroxychalcone and fisetin in human prostate cancer cells.
We have previously demonstrated the antiproliferative effect of two flavonoids-2,2'-dihydroxychalcone (DHC), a novel synthetic flavonoid, and fisetin, a naturally occurring flavonol-in prostate cancer cells. In this study, we further examine the mechanisms of these compounds on survival and proliferation pathways. DHC and fisetin (1-50 microM) caused a dose-dependent reduction in viability, a concomitant increase in apoptosis in PC3 cells at 72 h, and a decrease in clonogenic survival at 24 h treatment. DHC was considerably more potent than fisetin in these cytotoxicity assays. The mechanism of accelerated cellular senescence was not activated by either compound in PC3 or lymph node carcinoma of the prostate (LNCaP) cells. Gene expression alterations in PC3 and LNCaP cells treated with 15 muM DHC and 25 microM fisetin for 6 to 24 h were determined by oligonucleotide array. Amongst the most highly represented functional categories of genes altered by both compounds was the cell cycle category. In total, 100 cell cycle genes were altered by DHC and fisetin including 27 genes with key functions in G2/M phase that were downregulated by both compounds. Other functional categories altered included chromosome organization, apoptosis, and stress response. These results demonstrate the multiple mechanisms of antitumor activity of DHC and fisetin in prostate cancer cells in vitro.
Haddad
Ahmed Q
AQ
Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
Fleshner
Neil
N
Nelson
Colleen
C
Saour
Basil
B
Musquera
Mireia
M
Venkateswaran
Vasundara
V
Klotz
Laurence
L
D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D047188:Chalcones / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology*; D044948:Flavonols; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D008938:Mitosis / Q000187:drug effects; D020411:Oligonucleotide Array Sequence Analysis; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology
C552398:2,2'-dihydroxychalcone; D047188:Chalcones; D005419:Flavonoids; D044948:Flavonols; C017875:fisetin