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.

• Authors: Anna Bianchi-Smiraglia, Archis Bagati, Emily E Fink, Hayley C Affronti, Brittany C Lipchick, Sudha Moparthy, Mark D Long, Spencer R Rosario, Shivana M Lightman, Kalyana Moparthy, David W Wolff, Dong Hyun Yun, Zhannan Han, Anthony Polechetti, Matthew V Roll, Ilya I Gitlin, Katerina I Leonova, Aryn M Rowsam, Eugene S Kandel, Andrei V Gudkov, P Leif Bergsagel, Kelvin P Lee, Dominic J Smiraglia, Mikhail A Nikiforov
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 128 Issue 10 Pg. 4682-4696 (10 01 2018) ISSN: 1558-8238 [Electronic] United States
• PMID: 30198908 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Biogenic Polyamines
• Neoplasm Proteins
• Receptors, Aryl Hydrocarbon
• Clofazimine

Topics

• Animals
• Biogenic Polyamines (biosynthesis)
• Cell Line, Tumor
• Clofazimine (pharmacology)
• HEK293 Cells
• Humans
• Mice
• Multiple Myeloma (drug therapy, genetics, metabolism, pathology)
• Neoplasm Proteins (antagonists & inhibitors, genetics, metabolism)
• Neoplasms, Experimental (drug therapy, genetics, metabolism, pathology)
• Receptors, Aryl Hydrocarbon (antagonists & inhibitors, genetics, metabolism)