XK469, a novel antitumor agent, inhibits signaling by the MEK/MAPK signaling pathway

Abstract

Our findings suggest that the antiproliferative effect of XK469 is mediated by inhibiting the MEK/MAPK signaling pathways in U-937 human leukemia cells.

The Chemotherapeutic Agents XK469 (2-{4-[(7-Chloro-2-quinoxalinyl)oxy]phenoxy}propionic acid) and SH80 (2-{4-[(7-Bromo-2-quinolinyl)oxy]phenoxy}propionic acid) Inhibit Cytokinesis and Promote Polyploidy and Induce Senescence

“…With the exception of a study reporting that XK469 arrests H116 human colon carcinoma cells in prophase (Lin et al, 2002b), nothing else has been published related to the identities of the tetraploid populations accumulating in XK469/SH80-treated cultures. The binuclear status of the tetraploid populations observed in the current study indicates that XK469/SH80-treated Melan-a cultures proceed through telophase but do not undergo cytokinesis.…”

Painting with a molecular brush: Genomic/proteomic interfacing to define the drug action profile of novel solid‐tumor selective anticancer agents

“…The cellular accumulation of cyclin B1 also could be a consequence of an XK469-induced inhibition of the ubiquitin-mediated breakdown of cyclin B1. Studies reported elsewhere have confirmed that the mitotic arrest induced by XK469 is correlated with the inhibition of cyclin B1 ubiquitination (17,18). Further, identification of XK469-induced proteins by database matching revealed significant alterations of two ubiquitin-associated proteins, ubiquitin carboxyl terminal hydrolase 6 and ubiquitin carboxyl terminal hydrolase 5, that may play a role in inhibition (Table 2).…”

“…cDNA synthesis was performed in a 50 l reaction volume at 42°C with Superscript II RT, 0.5 g of anchored oligo(dT) [12][13][14][15][16][17][18] primer and a minimum of 50 g total RNA per reaction. Reactions were performed in the presence of either dNTPCy3 (untreated RNA) or dNTP-Cy5 (drug-treated RNA).…”

The role of autophagy in the death of L1210 leukemia cells initiated by the new antitumor agents, XK469 and SH80

“…This effect was independent of XK469/ SH80-induced autophagy because it also occurred in cultures in which the development of autophagy was blocked due to either Atg7 deficiency or cotreatment with wortmannin. Indeed, the ability of XK469 to induce G 2 -M arrest may be a general property of the agent, as it also occurred in XK469-treated U-937, HCT-116, and H460 cultures (5,6,9,10). Analyses of HCT-116 cultures indicated that XK469 suppressed the ubiquitination of cyclin B, a process necessary for proteasome-mediated degradation and progression through metaphase (5).…”

“…We have also observed similar effects in a murine hepatoma cell line. 5 Because the death programs associated with apoptosis and autophagy differ, agents capable of inducing cytotoxicity via the autophagic pathway might be useful in the treatment of tumors that are refractory to inducers of apoptosis. There may also be an additional therapeutic benefit associated with the induction of autophagy.…”