Synergistic effect of 17-allylamino-17-demethoxygeldanamycin with dehydroxymethylepoxyquinomicin on the human anaplastic thyroid carcinoma cell line KTC2
Keywords:NF-κB inhibitor, Hsp90 inhibitor, synergy, targeted inhibitor, combined treatment
- A treatment modality that combines two or more therapeutic agents is the cornerstone of cancer therapy.
- Using combination-index/isobologram and Western analyses, the effect of the combined treatment of Hsp90 and NF-κB inhibitors, 17-allylamino-17-demethoxygeldanamycin and dehydroxymethylepoxyquinomicin respectively, on cancer cell growth and apoptosis in the anaplastic thyroid carcinoma cell line KTC2 was investigated.
- Compared to single agent treatment, the combined treatment enhanced the growth-inhibitory effects in a synergistic manner and strongly potentiated apoptosis.
- The combination of Hsp90 and NF-κB inhibitors is a more effective modality for inhibiting the proliferation/survival of KTC2 cells compared to either agent alone.
Abstract: The use of targeted inhibitors has shown promise as an effective approach in cancer therapy. However, targeted therapies based only on one drug, such as 17-allylamino-17-demethoxygeldanamycin (17-AAG), have limited success, partly because cancer cells engage alternate pathways for survival and proliferation. In the present study, we evaluated whether dehydroxymethylepoxyquinomicin (DHMEQ), a nuclear factor κB (NF-κB) inhibitor, can enhance the antitumor activities of 17-AAG, a 90 kDa heat shock protein (Hsp90) inhibitor, in the anaplastic thyroid cancer cell line KTC2. We examined the effect of combined drug treatment vs single drug treatment on cell survival. Isobologram analysis was performed to distinguish the additive vs synergistic effects of the drug combination. Western blotting was performed to investigate apoptosis markers: caspase 3, poly(ADP-ribose) polymerase-one (PARP-1), B-cell lymphoma-extra large (Bcl-XL), X-linked inhibitor of apoptosis (XIAP) and cellular inhibitor of apoptosis 2 (cIAP-2). Compared to monotherapy, the combined treatment enhanced growth-inhibitory effects in a synergistic manner and strongly potentiated apoptosis. These results demonstrate the first in vitro evidence that a combination of Hsp90 and NF-κB inhibitors is a more effective modality for inhibiting cell proliferation and survival in anaplastic thyroid carcinoma cells than either agent alone, warranting further investigations.
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