Cell death induction in resting lymphocytes by pan

Authors: Makiko Kobayashi Ikuko TakahashiSuzuki Toshiyasu Shimomura Yoshikazu Iwasawa Hiroshi Hirai

Publish Date: 2010/06/04

Volume: 29, Issue: 5, Pages: 921-931

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Abstract

Immunosuppression is one of the common side effects of many antitumor agents targeting proliferating cells We previously reported the development of a new class of pancyclindependent kinase Cdk inhibitor compounds that induce immunosuppression in rodents Here we demonstrated that a panCdk inhibitor Compound 1 very rapidly reduced white blood cells in mice only 8 h after administration Compound 1 induced death of peripheral blood cells or purified resting nonstimulated lymphocytes ex vivo Cell death was induced very rapidly after 4 h of incubation suggesting that acute immunosuppression observed in rodents might be at least in part due to direct cytotoxic effects of Compound 1 on resting lymphocytes While cell cyclerelated Cdks were not activated the carboxyl terminal domain CTD of the largest subunit of RNA polymerase II was phosphorylated indicating activation of Cdk7 or Cdk9 which phosphorylates this domain in resting lymphocytes Indeed the panCdk inhibitor suppressed CTD phosphorylation in resting cells at the dose required for cell death induction Inhibition of Cdk7 or Cdk9 by Compound 1 was also confirmed by suppression of nuclear factorkappa B NFκBdependent transcription activity in the human cancer cell line U2OS Interestingly a Cdk4/6 inhibitor with selectivity against Cdk7 and Cdk9 did not induce cell death in resting lymphocytes These results suggest that CTD phosphorylation possibly by Cdk7 or Cdk9 might be important for survival of resting lymphocytes and that Cdk inhibitors without inhibitory activity on these kinases might be an attractive agent for cancer chemotherapy

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