Open Accessp53‐independent anti‐tumor effects of the nitrogen‐containing bisphosphonate zoledronic acid
Author(s) -
Kuroda Junya,
Kimura Shinya,
Segawa Hidekazu,
Sato Kiyoshi,
Matsumoto Seiji,
Nogawa Masaki,
Yuasa Takeshi,
Kobayashi Yutaka,
Yoshikawa Toshikazu,
Ottmann Oliver G.,
Maekawa Taira
Publication year - 2004
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2004.tb03202.x
Subject(s) - apoptosis , cell cycle , cyclin , cyclin dependent kinase , cancer research , zoledronic acid , chemistry , kinase , bisphosphonate , cell cycle checkpoint , cell growth , biology , biochemistry , medicine , endocrinology , osteoporosis
Zoledronic acid (ZOL), a nitrogen‐containing bisphosphonate, exerts anti‐tumor effects by inhibiting the prenylation of small GT‐Pases. We have also reported that ZOL shows an anti‐leukemic effect by inducing apoptosis throughout the S phase to the G 2 /M boundary. Here, we studied the effects of ZOL on various cell cycle regulators, including p53, cyclin‐dependent kinases (CDKs), CDK inhibitors and cyclins, using BV173 leukemia and HCT116 colorectal carcinoma cell lines, harboring wild‐type (wt‐) p53. ZOL induced the accumulation of neither p53 nor p21 WAF1/CIP1 during the execution of apoptosis in BV173 cells. Therefore, we investigated the dependence of ZOL‐induced apoptosis on intact p53 by using wt‐p53 HCT116 and a p53‐degraded HCT116 subline, and observed no significant difference. p57 KIP2 was upregulated by ZOL in BV173 cells, but not in HCT116 cells. Flow cytometric analyses showed that ZOL also impaired the cell cycle‐dependent expression patterns of cyclins A, B and D3 in BV173. In conclusion, the p53‐independent anti‐tumor activities of ZOL suggest that it may be an attractive agent for treating cancers, including those with chemoresistance resulting from the loss of p53 function. ZOL also affected the coordinate expression patterns of several cell cycle regulators during the execution of anti‐tumor activity.