Dexamethasone and OLT1177 Cooperate in the Reduction of Melanoma Growth by Inhibiting STAT3 Functions

Abstract

The NLRP3 inflammasome is a multimolecular complex that processes inactive IL-1β and IL-18 into proinflammatory cytokines. OLT1177 is an orally active small compound that specifically inhibits NLRP3. Here, B16F10 melanoma were implanted in mice and treated with OLT1177 as well as combined with the glucocorticoid dexamethasone. At sacrifice, OLT1177 treated mice had significantly smaller tumors compared to tumor-bearing mice treated with vehicle. However, the combined treatment of OLT1177 plus dexamethasone revealed a greater suppression of tumor growth. This reduction was accompanied by a downregulation of nuclear and mitochondrial STAT3-dependent gene transcription and by a significant reduction of STAT3 Y705 and S727 phosphorylations in the tumors. In vitro, the human melanoma cell line 1205Lu, stimulated with IL-1α, exhibited significantly lower levels of STAT3 Y705 phosphorylation by the combination treatment, thus affecting the nuclear functions of STAT3. In the same cells, STAT3 serine 727 phosphorylation was also lower, affecting the mitochondrial functions of STAT3. In addition, metabolic analyses revealed a marked reduction of ATP production rate and glycolytic reserve in cells treated with the combination of OLT1177 plus dexamethasone. These findings demonstrate that the combination of OLT1177 and dexamethasone reduces tumor growth by targeting nuclear as well as mitochondrial functions of STAT3.

The ‘speck’-tacular oversight of the NLRP3-pyroptosis pathway on gastrointestinal inflammatory diseases and tumorigenesis

“…Currently, OLT1177 and Tranilast inhibitors represent two promising pharmacological candidates in this setting. The combination of OLT1177 and dexamethasone affects the nuclear and mitochondrial isoforms of the signal transducer and activator of transcription 3 (STAT3), capable to shrink tumor growth [ 180 ]; alternatively, Tranilast, although though indirect links with NLRP3 inflammasome, has been proposed to inhibit melanoma cell proliferation by activating CD8 + T cells [ 181 ]. Ovarian cancer (OC) is the seventh most commonly diagnosed cancer among women [ 182 ].…”

Dapansutrile OLT1177 suppresses foreign body response inflammation while preserving vascularisation of implanted materials

“…11 OLT1177 is an orally available drug, currently in Phase 2 trials for gout, 12 with demonstrated Phase 1 safety in patients with cardiovascular disease. 13 Preclinical data also shows efficacy in treating multiple sclerosis, 14 Alzheimer's disease, 15 melanoma, 16 reperfusion injury, 17 intracerebral hemorrhage 18 and osteoarthritis. 19 As the evidence of its safety continues to grow, OLT1177 is emerging as an exciting new candidate.…”