Enhanced Efficacy of CKD-516 in Combination with Doxorubicin: Pre-clinical Evaluation Using a Hepatocellular Carcinoma Xenograft Model

Aim: To evaluate the anticancer efficacy of CKD- 516, a novel vascular-disrupting agent, alone and in combination with doxorubicin in the treatment of hepatocellular carcinoma (HCC). Materials and Methods: In mice bearing luciferized HCC cells, therapeutic efficacy was assessed for seven days after single administration of CKD- 516, doxorubicin, or combination of CKD-516 and doxorubicin. Results: Bioluminescence-imaging (BLI) signals in the CKD-516 group abruptly decreased initially, but recovered at seven days after treatment. BLI signals in the doxorubicin group gradually decreased over the 7-day period. In the combination group, BLI signals were abruptly reduced and remained suppressed for the 7-day period. On histopathological examination, CKD-516-treated tumors showed extensive central necrosis, whereas the peripheral layers remained viable. Doxorubicin-treated tumors showed mild and scattered necrosis. Tumors from the combination group showed more extensive central and peripheral necrosis, with smaller viable peripheral layers than the CKD-516 group. Conclusion: Combination therapy can have additive effects for treatment of HCC compared with CKD- 516 or doxorubicin monotherapy. Playing an essential role in cell division and cell function, microtubule, a major type of cytoskeletal filament, has been an attractive target for anticancer drug development (1). In the course of experiments to better-understand the complexity of tubulin function and the different mechanisms of tubulin-