Abstract 1288: Blocking tumor-associated immune suppression with BAY-218, a novel, selective aryl hydrocarbon receptor (AhR) inhibitor

Influence of Bisphenol Compounds at Nanomolar Concentrations on Chromosome Damage Induced by Metabolically Activated Carcinogens in HepG2 Cells

“…While in HepG2 cells pretreated with BPA (100 nM), all carcinogens induced micronucleus formation, the incubation with receptor inhibitors additionally present in the pretreatment (or ABT during the treatment) modulated carcinogen-induced micronucleus formation in different manners. As shown in Figure , coexposure of the cells to ABT (60 μM), a potent suicide inhibitor of various CYP enzymes, blocked the micronucleus formation by all carcinogens; BAY-218, an inhibitor of AhR, in the pretreatment, however, selectively blocked the effect of BaP. When KET, an inhibitor of PXR and CYP3A, , was included, the effect of AFB1 was selectively reduced, and the presence of CINPA1, an inhibitor of CAR, in the pretreatment slightly reduced the effect of NNK.…”

“…At 24 h, cells were pretreated with each BP compound at varying concentrations for 48 h. Then, the medium was changed, and after 2 h, each carcinogen (other than benzene) was added for another 48 h. Alternatively, a regime of 6 h exposure/42 h recovery was applied to the treatment with benzene, as persistent exposure to benzene may lead to false-negative results . In some experiments, known inducers of NRs, that is, PCB 126 (40 nM) for AhR, RIF (10 μM) for PXR, and CITCO (1 μM) for CAR, were used for pretreating the cells; while in some other experiments, known inhibitors of each NR, that is, BAY-218 (700 nM) for AhR, KET (10 μM) for PXR and CYP3A enzymes, , and CINPA1 (5 μM) for CAR, were present during both the pretreatment and treatment (98 h in total); alternatively, the CYP inhibitor ABT (60 μM) was present in some cultures immediately after the removal of BPs until the end of treatment (50 h in total). Please see the scheme of the various regimes shown in Figure .…”

Impact of Extended and Combined Exposure of Bisphenol Compounds on Their Chromosome-Damaging Effect─Increased Potency and Shifted Mode of Action

“…Moreover, BPA (1 μM) pretreatment significantly potentiated micronucleus formation by subsequent BPA and BPAF exposure, and this effect was blocked by ABT (60 μM, inhibitor of CYPs), 35 7-HF (10 μM, selective inhibitor of CYP1A1), 41 and BAY-218 (700 nM, inhibitor of AhR). 34 The results suggest that the activity of AhR, not PXR or CAR, is associated with the potentiating effect of BPA (probably through enhancing CYP1A1 expression). 17 It seems that through extended/combined exposure the genotoxic effect of BPs may be amplified through AhR stimulation and CYP1A1 induction, as in accordance to our recent report on BPpotentiated effects of several promutagens.…”

“…To clarify a role of CYP activity in the effect of BPs under various exposure periods, cells were coexposed to ABT (60 μM, inhibitor of CYP enzymes) from 2 h ahead of BP exposure to the termination of each regime (coexposure for 50, 74, and 98 h in total, respectively). In another set of experiments, cells were pretreated with BPs individually at relatively low (nongenotoxic) concentrations, i.e., 0.01, 0.1, and 1 μM for 48 h. Then, the medium was changed, and after 2 h, cells were exposed to each BP at the concentrations of 0.625, 1.25, 2.5, 5, and 10 μM for another 48 h. To understand the influence of various nuclear receptors (NRs) in the effect of BPs, cells were pretreated with PCB 126 (40 nM, activator of AhR), RIF [10 μM, activator of pregnane X receptor (PXR)], and CITCO [1 μM, activator of constitutive androstane receptor (CAR)] for 48 h, while BAY-218 (700 nM, inhibitor of AhR) was present during both the pretreatment and the test compound exposure period (98 h in total). As a selective CYP1A1 inhibitor, 7-HF (10 μM) was present from 2 h ahead of test compound exposure to the termination of 48 h regime (50 h in total).…”

Not Only Immune Escape—The Confusing Role of the TRP Metabolic Pathway in Carcinogenesis

“…In a preclinical test on mice xenografts with oral, breast and skin cancer HP163 reduces both tumor growth and a number of immunosuppressive cells [222]. Another small molecule AhR inhibitor-BAY218, used in the murine model-reduced tumor growth and enhanced immune response by increasing the infiltration of CD8+ T and NK cells with simultaneous reduction with regard to suppressive GR1+ myeloid cells and M2 macrophages [223]. A significant activity toward M2 macrophages under AhR inhibitor treatment was also observed by Garcia et al [224].…”