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


METHODS
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.
Ding
Z
Z
Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Prentis Building, 110 East Warren, Detroit, MI 48201, USA.
Parchment
R E
RE
LoRusso
P M
PM
Zhou
J Y
JY
Li
J
J
Lawrence
T S
TS
Sun
Y
Y
Wu
G S
GS
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects* / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D016195:G2 Phase / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008938:Mitosis / Q000187:drug effects; D009154:Mutation; D009369:Neoplasms / Q000473:pathology / Q000517:prevention & control; D011810:Quinoxalines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D011810:Quinoxalines; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; C118180:XK 469