Inhibition of the aryl hydrocarbon receptor/polyamine biosynthesis axis suppresses multiple myeloma

Abstract

Polyamine inhibition for cancer therapy is, conceptually, an attractive approach but has yet to meet success in the clinical setting. The aryl hydrocarbon receptor (AHR) is the central transcriptional regulator of the xenobiotic response. Our study revealed that AHR also positively regulates intracellular polyamine production via direct transcriptional activation of 2 genes, ODC1 and AZIN1, which are involved in polyamine biosynthesis and control, respectively. In patients with multiple myeloma (MM), AHR levels were inversely correlated with survival, suggesting that AHR inhibition may be beneficial for the treatment of this disease. We identified clofazimine (CLF), an FDA-approved anti-leprosy drug, as a potent AHR antagonist and a suppressor of polyamine biosynthesis. Experiments in a transgenic model of MM (Vk*Myc mice) and in immunocompromised mice bearing MM cell xenografts revealed high efficacy of CLF comparable to that of bortezomib, a first-in-class proteasome inhibitor used for the treatment of MM. This study identifies a previously unrecognized regulatory axis between AHR and polyamine metabolism and reveals CLF as an inhibitor of AHR and a potentially clinically relevant anti-MM agent.

Blockade of the AHR restricts a Treg-macrophage suppressive axis induced by L-Kynurenine

“…4a). Similar results were observed using clofazimine, a recently described antagonist of the AHR 31 , and KYN-101, an optimized, selective synthetic antagonist of AHR (Supplementary Fig. 6a).…”

“…Clofazimine was prepared in a solution of 5% DMSO in PBS and mice were treated with daily i.p. injections at 10 mg/kg as described 31 . Epacadostat was dissolved in a 0.5% MC vehicle solution and 680C91 in a 5% DMSO + 5% Solutol solution in water and administered daily by oral gavage at 300 mg/kg and 20 mg/kg, respectively.…”

Antimigraine Drug Avitriptan Is a Ligand and Agonist of Human Aryl Hydrocarbon Receptor that Induces CYP1A1 in Hepatic and Intestinal Cells

“…Indeed, the AhR active drugs, such as tranilast, flutamide or omeprazole, might be effective chemotherapeutics for the treatment of breast and pancreatic cancers [7]. An anti-leprosy Food and Drug Administration (FDA)-approved drug and AhR antagonist clofazimine suppressed multiple myeloma in transgenic mice [8]. Targeting of AhR with antagonists was suggested as a strategy for delaying the relapse during the treatment of melanoma with vemurafenib [9] or for inhibiting constitutive AhR activity in prostate cancer [10].…”

Dietary natural flavonoids treating cancer by targeting aryl hydrocarbon receptor

“…Traces of environmental pollutants can be discovered throughout the world in a variety of sources, including the air, water, soil. Clinical studies have shown that these environmental carcinogens are toxic to the body by binding to AhR and cause cancer in many tissue types, especially the prostate and breast (Bianchi-Smiraglia et al 2018;Yu et al 2018).…”