MIF Antagonist (CPSI-1306) Protects against UVB-Induced Squamous Cell Carcinoma

Abstract

Macrophage migration inhibitory factor (MIF) is a homotrimeric proinflammatory cytokine implicated in chronic inflammatory diseases and malignancies, including cutaneous squamous cell carcinomas (SCC). To determine whether MIF inhibition could reduce UVB light–induced inflammation and squamous carcinogenesis, a small-molecule MIF inhibitor (CPSI-1306) was utilized that disrupts homotrimerization. To examine the effect of CPSI-1306 on acute UVB-induced skin changes, Skh-1 hairless mice were systemically treated with CPSI-1306 for 5 days before UVB exposure. In addition to decreasing skin thickness and myeloperoxidase (MPO) activity, CPSI-1306 pretreatment increased keratinocyte apoptosis and p53 expression, decreased proliferation and phosphohistone variant H2AX (γ-H2AX), and enhanced repair of cyclobutane pyrimidine dimers. To examine the effect of CPSI-1306 on squamous carcinogenesis, mice were exposed to UVB for 10 weeks, followed by CPSI-1306 treatment for 8 weeks. CPSI-1306 dramatically decreased the density of UVB-associated p53 foci in non–tumor-bearing skin while simultaneously decreasing the epidermal Ki67 proliferation index. In addition to slowing the rate of tumor development, CPSI-1306 decreased the average tumor burden per mouse. Although CPSI-1306–treated mice developed only papillomas, nearly a third of papillomas in vehicle-treated mice progressed to microinvasive SCC. Thus, MIF inhibition is a promising strategy for prevention of the deleterious cutaneous effects of acute and chronic UVB exposure.

Sex differences in skin carotenoid deposition and acute UVB-induced skin damage in SKH-1 hairless mice after consumption oftangerinetomatoes

“…Dorsal skin samples for p53 analysis were fixed in 10% neutral buffered formalin for immunohistochemical analysis as previously described . Dorsal skin samples for the myeloperoxidase and cyclobutane pyrimidine dimer assays were snap frozen in liquid nitrogen and analyzed following previously developed methods .…”

Macrophage migration inhibitory factor inhibition as a novel therapeutic approach against triple-negative breast cancer

“…Further analysis revealed that CPSI-1306 treatment regulates cell-cycle progression and promotes apoptosis. MIF has been reported to induce apoptosis by inhibiting p53 activation and stabilization 26,41 . In our study, it is plausible that CPSI-1306 mediates its antitumor effects by impeding MIF-dependent negative regulation of apoptosis.…”

“…Since we observed that MIF is overexpressed in TNBC and enhance breast cancer growth and migration in vitro and in vivo, we evaluated the anticancer potency of a small-molecule chemical inhibitor of MIF to inhibit the proliferation and progression of TNBC. We used CPSI-1306, which has been reported to inhibit MIF activity 26 . A panel of human (MDA-MB-231, MDA-MB-468, SCP-2) and mouse (MVT-1) TNBC cells were treated with CPSI-1306 and cell viability was estimated by MTT assay.…”

Deletion of macrophage migration inhibitory factor inhibits murine oral carcinogenesis: Potential role for chronic pro‐inflammatory immune mediators

“…Numerous studies demonstrate that MIF contributes to tumorigenesis in colon, breast and melanoma and bladder cancer. 14,38 Although the mechanisms behind the observed MIF-mediated contribution to tumorigenesis in the above mentioned cancers are multiple, there exists some similarities and differences between these mechanisms and those of MIF mediated oral carcinogenesis. For example, in bladder cancer, MIF promotes cellular proliferation and angiogenesis, 39 mechanisms which are also important in oral carcinogenesis.…”