PXD101 consistently repressed p-AKT and p-ERK in the prior study. One potential explanation of this inconsistency between two studies is the very high dose of PXD101 that was applied in previous study as compared with our current study. Such high doses of PXD101 are more likely to repress p-AKT and p-ERK. Our study additionally demonstrates that multiple molecular events induced by PXD101 may cause cytotoxicity, and shows the efficacy of combination therapy using PXD101 with conventional chemotherapy currently in use for anaplastic thyroid cancer. Importantly, we demonstrate synergistic effects of combination PXD101 with doxorubicin and paclitaxel, suggesting likely clinical significance in treating patients with ATC. In conclusion, PXD101 imposed significant cytotoxicity in four major histologic types of thyroid cancer. Nude mice bearing 8505C xenograft tumors demonstrated the therapeutic efficacy and safety profiles of PXD101. Importantly, PXD101 synergistically improves the therapeutic effect of doxorubicin and paclitaxel against four ATC cell lines. These favorable data support the design of future clinical trials studying the utility of PXD101 as an agent to treat patients with advanced thyroid cancer. The anthracycline antibiotic doxorubicin is used to treat a wide variety of cancers, but reports of its cardiotoxic properties compromises its clinical utility. The cardiotoxic effects of doxorubicin are thought to be mediated via disruption of the mitochondrial function. Previous studies have also shown doxorubicin to cause cardiotoxicity through the generation of free radicals, stimulation of lipid peroxidation and alteration and disruption of cellular membrane integrity. Arrhythmias, hypotension and depression of the contractile function are some of the acute effects of doxorubicin-induced cardiotoxicity, while chronic heart failure and dilative cardiomyopathy are more common and severe in patients who are on long term anthracyclines treatment. Large scale clinical trials have shown that doxorubicin induced cardiotoxicity is 28643-80-3 irreversible and dose dependent. Due to advances in basic and clinical cancer research, cancer and malignancies are becoming more manageable, unfortunately the adverse Torin 2 cardiovascular effects of systemic anticancer agents are still a serious concern. Thus it is imperative to unders
