KML001Displays Vascular Disrupting Properties and Irinotecan Combined Antitumor Activities in a Murine Tumor Model
Abstract
KML001 is sodium metaarsenite, and has shown cytotoxic activity in humantumor cell lines. The anti-cancer mechanism of KML001 involves
cancer celldestruction due to DNA damage at the telomeres of cancer cell chromosomes. Inthis study, we assessed the vascular disrupting
properties of KML001 andinvestigated whether KML001 as VDA is able to increase anti-tumor activity in irinotecan combined treatment.
We used a murine model of the CT26colon carcinoma cell line. CT26 isograftmice treated intraperitoneally with 10 mg/kg KML001displayed
extensive central necrosis of tumor by 24 h. The vascular disruptingeffects of KML001 were assessed by dynamic contrast enhanced magnetic
resonanceimaging. Gadopentetic acid-diethylene triaminepentaacetic acid contrastenhancement was markedly decreased in KML001-treated
mice one day aftertreatment, whereas persistently high signal enhancement was observed in miceinjected with saline. Rate constant Kep
valuerepresenting capillary permeability was significantly decreased (p<0.05) inmice treated with KML001. Cytoskeletal changes of human
umbilical vein endothelial cells (HUVECs)treated with 10 uM KML001 were assessedby immune blotting and confocal imaging.
KML001degraded tubulin protein in HUVECs,which may be related to vascular disrupting properties of KML001. Finally, inthe mouse CT26
isograft model, KML001combined with irinotecan significantlydelayed tumor growth as compared to control and irinotecan alone. These results
suggest that KML001 is a novel vasculardisrupting agent, which exhibits significant vascular shut-down activity andenhances anti-tumor activity
in combination with chemotherapy. These datafurther suggest an avenue for effective combination therapy in treating solidtumors.
'>Propidiumiodide (PI) staining also showed that NAC restored membrane integrity, damagedby sodium meta-arsenite.Therefore, these results
suggestthat sodium meta-arsenite induces apoptotic, necrotic, and autophagiccell death through intracellular ROS accumulation in both
androgen-sensitiveand androgen-insensitive prostate cancer cells and may be used as a newanticancer drug for the treatment of prostate cancer.
