Suberoylanilide hydroxamic acid (SAHA) is a promising
histone deacetylase (
HDAC) inhibitor approved by the US Food and Drug Administration (FDA) and whose clinical application for solid tumours is partially limited by decreased susceptibility in
cancer cells due to nuclear factor (NF)-κB activation. As an NF-κB inhibitor,
celastrol exhibits potent anticancer effects but has failed to enter clinical trials due to its toxicity. In this report, we demonstrated that the combination of
celastrol and SAHA exerted substantial synergistic efficacy against human
cancer cells in vitro and in vivo accompanied by enhanced
caspase-mediated apoptosis. This
drug combination inhibited the activation of NF-κB caused by SAHA monotherapy and consequently led to increased apoptosis in
cancer cells. Interestingly,
E-cadherin was dramatically downregulated in
celastrol-resistant
cancer cells, and
E-cadherin expression was closely related to decreased sensitivity to
celastrol. However, our combination treatment significantly augmented the expression of
E-cadherin, suggesting that mutual mechanisms contributed to the synergistic anticancer activity. Furthermore, the enhanced anticancer efficacy of
celastrol combined with SAHA was validated in a human
lung cancer 95-D xenograft model without increased toxicity. Taken together, our data demonstrated the synergistic anticancer effects of
celastrol and SAHA due to their reciprocal sensitisation, which was simultaneously regulated by NF-κB and
E-cadherin; thus, the combination of
celastrol and SAHA was superior to other combination regimens that rely on a single mechanism. Our findings not only open new opportunities for the clinical development of SAHA but should also motivate the clinical investigation of
celastrol, which has been hampered by its toxicity.