Cellular drug action profile paradigm applied to XK469.
The cellular paradigm presented here defines the cellular action profile of new anticancer agents that complements our discovery and development paradigm. The main elements of this profile include a concentration clonogenicity response relationship on proliferating and plateau phase cells, flow cytometry studies assessing progression delay and apoptosis, macromolecular synthesis inhibition, and DNA damage assessment by the comet assay; other specific assessments then derive from these findings such as topoisomerase assays. XK469 is a new anticancer agent derived from the herbicide Assure that is the inactive parent compound of a family of quinoxaline analogs found to have anticancer activity in vivo. We have applied the described cellular action profile paradigm to XK469 to define a novel action at the cellular level. XK469 is a G2M phase-specific, antiproliferative agent whose activity is related to the 7-position of the chlorine ion in the benzene ring and expressed through a unique cellular action profile resulting in the irreversible increase in cyclin B1 (possibly by specific inhibition of its ubiquitination) and leading, in the absence of apoptosis, to the final mitotic arrest of HCT-116 cells in prophase with subsequent loss of clonogenicity.
Subramanian
Balanehru
B
Drug Discovery and Development Program, Josephine Ford Cancer Center, Henry Ford Health System, Detroit, MI, USA. bsubram1@hfhs.org
Nakeff
Alexander
A
Media
Joseph
J
Wentland
Mark
M
Valeriote
Frederick
F
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000096:biosynthesis; D006801:Humans; D008940:Mitotic Index; D011810:Quinoxalines / Q000493:pharmacokinetics / Q000494:pharmacology*; D059004:Topoisomerase I Inhibitors; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D011810:Quinoxalines; D059004:Topoisomerase I Inhibitors; C118180:XK 469