An Integrative Proteome-Based Pharmacologic Characterization and Therapeutic Strategy Exploration of SAHA in Solid Malignancies

Targeting
histone epigenetic modification is an important strategy
for anticancer therapy. Histone deacetylase inhibitors (HDACis) have
been clinically approved in the treatment of diverse hematological
cancers, but mechanisms of drug resistance and poor therapeutic efficacy
in solid malignancies remain largely unknown. In this study, we applied
a mass spectrometry-based quantitative proteomic strategy to investigate
the molecular differences in HDACi vorinostat (SAHA) sensitive and
resistant cell lines. The proteomic results revealed that the glycolysis
pathway was highly enriched after vorinostat treatment in the resistant
cell line, leading to the prediction of a new drug combination, SAHA
and hexokinase inhibitor (2-deoxyglucose). The efficacy of this combination
was further verified in several solid tumor cell lines. Quantitative
proteomics revealed that alterations in the transcription process
and protein homeostasis could play roles in the synergetic utilization
of these two compounds. Our study showed the application of proteomics
in elucidating the drug mechanism and predicting drug combination
and the potential of expanding the utilization of HDACi.