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Inhibition of the aryl hydrocarbon receptor/polyamine biosynthesis axis suppresses multiple myeloma
Anna Bianchi-Smiraglia, … , Dominic J. Smiraglia, Mikhail A. Nikiforov
Anna Bianchi-Smiraglia, … , Dominic J. Smiraglia, Mikhail A. Nikiforov
Published September 10, 2018
Citation Information: J Clin Invest. 2018;128(10):4682-4696. https://doi.org/10.1172/JCI70712.
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Research Article Cell biology Oncology Article has an altmetric score of 5

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

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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

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Figure 5

CLF inhibits MM xenograft growth.

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CLF inhibits MM xenograft growth.
(A) MM.1S cells were inoculated s.c. i...
(A) MM.1S cells were inoculated s.c. into both flanks of 4- to 6-week-old female SCID mice. The animals were randomized into 2 groups (6 animals/group) and treated with daily i.p. injections of vehicle in PBS or CLF (10 mg/kg). Tumor volumes were recorded every 5 days. *P < 0.05, by 2-tailed Student’s t test. (B) Protein extracts from 6 tumors/group from A were resolved by immunoblotting and probed for CYP1a1, AZIN1, or ODC1. Growth of MM.1S (C) or RPMI-8226 (D) cell xenografts was monitored as in A. Animals were randomized into 3 treatment groups: PBS, CLF, or BTZ (1 mg/kg, biweekly i.p. injections). Tumor measurement distributions were tested for normality by Shapiro-Wilk test, and the significance of individual comparisons (treated/untreated) were determined by Student’s t test with Bonferroni’s correction.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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