Recently, Chan et al. also reported that PXD101 retards the growth of PTC xenograft tumors. PXD101 therefore has an ability to inhibit the growth of both well-differentiated and undifferentiated thyroid cancer in vivo. These data strengthen the possibility that PXD101 can be used to treat patients with this fatal disease. In contrast to our findings, 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 SB431542 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 Y-27632 dihydrochloride anthracyclines treatment. Large scale clinical trials have shown that doxorubicin induced cardiotoxicity is irreversible and dose dependent. Due to advances in basic and clinical cancer research, cancer and malignancies are becoming more manageable, unfortunately the adverse cardiovascular effects of systemic anticancer agents are still a serious concern. Thus it is imperative to understand the cellular and molecular basis of doxorubicin-induced cardiotoxicity with the view to finding therapies that would offer cardioprotection without affecting its anti-tumour effects. Interventions using �� blockers, free radical scavengers, antioxidants and renin-angiotensin system inhibitors have met with limited success due, not only, to side effects but also because of their negative interactions with doxorubicin. While aiming to reduce the cardiotoxic effects of anthracyclines using adjunct therapies, it is imperative to assess the effects in cancer cell line to ascertain the clinical utility of such treatments. Interestingly, recent studies using the phosphodiesterase-5 inhibitors sildenafil or tadalafil have shown promise by showing a reduction in the cardiotoxic effects of doxorubicin without affecting its anti-cancer activity. Cell death pathways activated by doxorubicin treatment usually involve the mitochondria to initiate apoptosis or necrosis. Mitochondrial dynamics are found to play an essential role in cellular function and apoptosis. In order to maintain mitochondrial integrity and efficiency, a constant interplay between mitochondrial fission and fusion is important. Previous studies have demonstrated that upon induction of oxidative stress or ischaemia, dynamin related protein 1, a protein involved in mitochondrial fission, translocates from the cytosol to the mitochondria to execute the mitochondrial division process. This involves hydrolysing GTP, which dysregulates the balance between mitochondrial fusion and fission. Mitochondrial fission leads to cytochrome c release and activation of caspases, which can ultimately lead to cell death. Studies also reported that the dominant negative form of Drp1, DrpK38A, had the ability to inhibit mitochondrial division suggesting a regulatory role for Drp1 in mitochondria-mediated apoptosis.