Human malignant mesothelioma (MM) is an aggressive and highly lethal cancer that has been linked to asbestos and erionite exposure. MM causes about 3,200 deaths per year in the US and more than 100,000 deaths per year worldwide. We previously found that high-mobility group box-1 protein (HMGB1), a prototypic damage-associated molecular pattern (DAMP), plays a critical role in the early events of HM malignant transformation and MM development. More recently we showed that MM cells are “addicted” to HMGB1 that supports the malignant phenotype by promoting proliferation and invasiveness of MM cells. We demonstrated that MM growth is inhibited by targeting HMGB1 using HMGB1 neutralizing antibody or BoxA, a HMGB1 antagonist. Ethyl pyruvate (EP) is the ethyl ester of pyruvic acid, known to suppress oxygen radical formation and HMGB1 secretion. Here we show that EP impaired motility, survival and proliferation of MM cells in vitro. Both BoxA and EP inhibited the activity of the pro-inflammatory transcription factor NF-kappaB, as well as reduced HMGB1 serum levels and the growth of MM xenografts in SCID mice. Taken together, our results provide a preclinical proof-of-principle that inhibition of HMGB1 activity using either HMGB1 antibody, BoxA or EP offers novel therapeutic approaches for MM treatment.
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