Demethylating agent 5-aza-2'-deoxycytidine enhances susceptibility of renal cell carcinoma to paclitaxel.
OBJECTIVE
To examine the effect of 5-aza-2'-deoxycytidine (DAC), a DNA methyltransferase inhibitor, on the growth of renal cell carcinoma (RCC) and examine the synergistic growth suppression by DAC and chemotherapeutic agents.


METHODS
The synergy of DAC and chemotherapeutic agents against RCC cell lines was analyzed by isobolographic analysis. The induction of apoptosis and cell cycle arrest by each single agent or the combination of agents was examined by flow cytometric analysis. Caspase activity assays and proliferating cell nuclear antigen protein expression were also examined to clarify the mechanism of the synergism of DAC and chemotherapeutic agents against RCC.


RESULTS
We demonstrated that DAC combined with paclitaxel (PTX) synergistically inhibited the growth of all the RCC cell lines tested, but DAC did not show such synergism with 5-fluorouracil, vinblastine, or Adriamycin. DAC suppressed RCC cell proliferation by inducing G2/M cell cycle arrest without inducing apoptosis, and PTX induced both apoptosis and G2/M cell cycle arrest in a dosage-dependent manner. DAC could enhance the PTX-induced upregulation of caspase activity and antiproliferative effect to increase the fraction of cells in the sub-G1 and G2/M phase.


CONCLUSIONS
DAC and PTX caused synergistic growth suppression of RCC, suggesting that DAC could strikingly increase the susceptibility of RCC to PTX and that combination chemotherapy with DAC and PTX might be a novel strategy to improve the clinical response rate of RCC.
Shang
Donghao
D
Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Ito
Noriyuki
N
Kamoto
Toshiyuki
T
Ogawa
Osamu
O
D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000473:pathology; D020169:Caspases / Q000187:drug effects* / Q000378:metabolism; D003841:Deoxycytidine / Q000494:pharmacology*; D004357:Drug Synergism; D005434:Flow Cytometry; D005472:Fluorouracil / Q000494:pharmacology; D049690:History, Ancient; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology*; D012680:Sensitivity and Specificity; D014407:Tumor Cells, Cultured; D014747:Vinblastine / Q000494:pharmacology
D003841:Deoxycytidine; D014747:Vinblastine; D020169:Caspases; D017239:Paclitaxel; D005472:Fluorouracil