The investigational new drug XK469 induces G(2)-M cell cycle arrest by p53-dependent and -independent pathways.

PURPOSE XK469 (2-[4-(7-chloro-2-quinoxalinyloxy) phenoxy]propionic acid), a synthetic quinoxaline phenoxypropionic acid derivative, has broad activity against murine tumors and is entering Phase I clinical development as a topoisomerase IIbeta inhibitor. This study investigated the underlying molecular mechanism of XK469's effects on the cell cycle. EXPERIMENTAL DESIGN Growth inhibition, cell cycle arrest, induction of p53 and p21 mRNA and protein, and cdc2 phosphorylation and kinase activity were studied in treated cells from the H460 lung cancer line and p21 and p53 knockout cells of the HCT 116 colon cancer line. RESULTS XK469 arrested H460 cells at G(2)-M, which was associated with cdc2 phosphorylation and decreased cdc2 kinase activity. Moreover, XK469 stabilized p53 and subsequently increased p21(WAF1/CIP1). Furthermore, HCT116 p21(-/-) cells were less sensitive than wild-type cells to XK469-induced growth inhibition, but p53(+/+) and p53(-/-) cells were equally sensitive despite the absence of p21 induction in the p53(-/-) cells. CONCLUSIONS When considered with published data, our study suggests a complex mechanism of XK469-mediated anticancer activity involving multiple pathways, including p53-dependent and -independent G(2)-M arrest via inactivation of cdc2-cyclin B1 kinase activity.

[1]  G. Li,et al.  Cytotoxic mechanism of XK469: resistance of topoisomerase IIbeta knockout cells and inhibition of topoisomerase I. , 2001, Biochemical and biophysical research communications.

[2]  N. Walworth,et al.  The G2-phase DNA-damage checkpoint. , 2000, Trends in cell biology.

[3]  W. El-Deiry,et al.  Cell cycle control as a basis for cancer drug development (Review). , 2000, International journal of oncology.

[4]  Hanlin Gao,et al.  XK469, a selective topoisomerase IIbeta poison. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[5]  K. Kinzler,et al.  Disruption of p53 in human cancer cells alters the responses to therapeutic agents. , 1999, The Journal of clinical investigation.

[6]  C. Prives,et al.  The p53 pathway , 1999, The Journal of pathology.

[7]  N. J. Wells,et al.  Physiological regulation of eukaryotic topoisomerase II. , 1998, Biochimica et biophysica acta.

[8]  C. Peters,et al.  Potential role for Cathepsin D in p53-dependent tumor suppression and chemosensitivity , 1998, Oncogene.

[9]  T. Fojo,et al.  Like p53, the proliferation-associated protein p120 accumulates in human cancer cells following exposure to anticancer drugs. , 1998, Biochemical and biophysical research communications.

[10]  M. Blagosklonny.  Loss of function and p53 protein stabilization , 1997, Oncogene.

[11]  H. Piwnica-Worms,et al.  The human Myt1 kinase preferentially phosphorylates Cdc2 on threonine 14 and localizes to the endoplasmic reticulum and Golgi complex , 1997, Molecular and cellular biology.

[12]  C. Sherr.  Cancer Cell Cycles , 1996, Science.

[13]  K Nasmyth,et al.  Viewpoint: Putting the Cell Cycle in Order , 1996, Science.

[14]  W. El-Deiry,et al.  Regulation of p21WAF1/CIP1 expression by p53-independent pathways. , 1996, Oncogene.

[15]  W. El-Deiry,et al.  Apoptotic death of tumor cells correlates with chemosensitivity, independent of p53 or bcl-2. , 1996, Clinical cancer research : an official journal of the American Association for Cancer Research.

[16]  W. El-Deiry,et al.  p53 and chemosensitivity , 1996, Nature Medicine.

[17]  K. Kinzler,et al.  p21 is necessary for the p53-mediated G1 arrest in human cancer cells. , 1995, Cancer research.

[18]  P. Sylvestre,et al.  Identification of a 95-kDa WEE1-like tyrosine kinase in HeLa cells. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[19]  T. Coleman,et al.  Myt1: A Membrane-Associated Inhibitory Kinase That Phosphorylates Cdc2 on Both Threonine-14 and Tyrosine-15 , 1995, Science.

[20]  N Watanabe,et al.  Regulation of the human WEE1Hu CDK tyrosine 15‐kinase during the cell cycle. , 1995, The EMBO journal.

[21]  J. Trent,et al.  WAF1, a potential mediator of p53 tumor suppression , 1993, Cell.

[22]  K. Sadhu,et al.  p55CDC25 is a nuclear protein required for the initiation of mitosis in human cells. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[23]  B. Vogelstein,et al.  Participation of p53 protein in the cellular response to DNA damage. , 1991, Cancer research.

[24]  Marc W. Kirschner,et al.  cdc25 is a specific tyrosine phosphatase that directly activates p34cdc2 , 1991, Cell.

[25]  J. Bigger,et al.  NEW DRUGS. , 1979, Canadian Medical Association journal.

[26]  W. El-Deiry,et al.  Regulation of p53 downstream genes. , 1998, Seminars in cancer biology.

[27]  L. Hartwell,et al.  The DNA Damage Checkpoint , 1997 .

[28]  F. Valeriote,et al.  New in vitro screening model for the discovery of antileukemic anticancer agents. , 1996, Cancer investigation.