Clofazimine inhibits small-cell lung cancer progression by modulating the kynurenine/aryl hydrocarbon receptor axis

Gunjan Sharma¹, K M Abdullah¹, Faizan Abul Qais², Parvez Khan³, Jesse L Cox⁴, Tarique Sarwar⁵, Mohd Wasim Nasser⁶, Surinder K Batra⁶, Jawed A Siddiqui⁷

Affiliations

¹ Department of Cell and Molecular Biology, University of Mississippi Medical Center, Jackson MS-39216, USA; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha NE-68198, USA; Cancer Center and Research Institute, University of Mississippi Medical Center, Jackson MS-39216, USA.
² Department of Agricultural Microbiology, Faculty of Agricultural Sciences, Aligarh Muslim University, Aligarh, UP 202002, India.
³ Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha NE-68198, USA.
⁴ Department of Pathology, Microbiology and Immunology, University of Nebraska Medical Center, Omaha NE-68198, USA.
⁵ Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia.
⁶ Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha NE-68198, USA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
⁷ Department of Cell and Molecular Biology, University of Mississippi Medical Center, Jackson MS-39216, USA; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha NE-68198, USA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA; Cancer Center and Research Institute, University of Mississippi Medical Center, Jackson MS-39216, USA. Electronic address: jsiddiqui@umc.edu.

PMID: 39490481
PMCID: PMC12060262 (available on 2025-12-01)
DOI: 10.1016/j.ijbiomac.2024.136921

Clofazimine inhibits small-cell lung cancer progression by modulating the kynurenine/aryl hydrocarbon receptor axis

Gunjan Sharma et al. Int J Biol Macromol. 2024 Dec.

. 2024 Dec;282(Pt 3):136921.

doi: 10.1016/j.ijbiomac.2024.136921. Epub 2024 Oct 28.

Authors

Gunjan Sharma¹, K M Abdullah¹, Faizan Abul Qais², Parvez Khan³, Jesse L Cox⁴, Tarique Sarwar⁵, Mohd Wasim Nasser⁶, Surinder K Batra⁶, Jawed A Siddiqui⁷

Affiliations

¹ Department of Cell and Molecular Biology, University of Mississippi Medical Center, Jackson MS-39216, USA; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha NE-68198, USA; Cancer Center and Research Institute, University of Mississippi Medical Center, Jackson MS-39216, USA.
² Department of Agricultural Microbiology, Faculty of Agricultural Sciences, Aligarh Muslim University, Aligarh, UP 202002, India.
³ Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha NE-68198, USA.
⁴ Department of Pathology, Microbiology and Immunology, University of Nebraska Medical Center, Omaha NE-68198, USA.
⁵ Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia.
⁶ Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha NE-68198, USA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
⁷ Department of Cell and Molecular Biology, University of Mississippi Medical Center, Jackson MS-39216, USA; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha NE-68198, USA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA; Cancer Center and Research Institute, University of Mississippi Medical Center, Jackson MS-39216, USA. Electronic address: jsiddiqui@umc.edu.

PMID: 39490481
PMCID: PMC12060262 (available on 2025-12-01)
DOI: 10.1016/j.ijbiomac.2024.136921

Abstract

Small cell lung cancer (SCLC) is one of the highly metastatic malignancies that contributes to ∼15 % of all lung cancers. Most SCLC patients (50-60 %) develop osteolytic bone metastases, significantly affecting their quality of life. Among several factors, environmental pollutant 2,3,7,8-Tetrachlorodibenzodioxin (TCDD) and kynurenine (Kyn), an endogenous ligand derived from tryptophan (Trp) metabolism, activate the aryl hydrocarbon receptor (AhR) and are responsible for SCLC progression and metastasis. Further, elevated AhR expression in bone cells intensifies bone resorption, making the Kyn/AhR axis a potential target for the bone metastatic propensity of SCLC. We first assessed the expression profile of AhR in human SCLC cell lines and found a significantly increased expression compared to normal lung cells. Additionally, we also evaluated the clinical significance of AhR expression in the patient samples of SCLC along with the relevance of the same in the Rb1^fl/fl; Trp53^fl/fl; Myc^LSL/LSL (RPM) mouse model using immunohistochemistry and found the higher AhR expression in the patient samples and RPM mouse tumor tissues. Using computational simulations, we found that clofazimine (CLF) binds at the activator (Kyn) binding site by forming a stable complex with AhR. The CLF binding with AhR was favored by Van der Waals and hydrophobic forces, and the proteins retained their secondary structure. Furthermore, we found that Kyn treatment potentiates the migration and clonogenic ability of SCLC cell lines by activating Erk/Akt oncogenic signaling. Treatment with CLF reduces AhR expression, which inhibits Kyn-mediated proliferation of SCLC cells, induces apoptosis, and cell cycle arrest in the G2/M phase. Further, our examination indicates that Kyn treatment also promotes osteoblast-mediated osteoclast differentiation through RANKL. The treatment with CLF impedes RANKL expression and osteoclastogenesis, suggesting that CLF has the potential to be used as the therapeutic for SCLC patients having bone metastasis.

Keywords: Aryl hydrocarbon receptor; Bone metastasis; Clofazimine; Kynurenin; Small cell lung cancer.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: SKB is one of the co-founders of Sanguine Diagnostics and Therapeutics, Inc. The other authors declare no potential conflicts of interest.

References

1. Siegel RL, Giaquinto AN, Jemal A, Cancer statistics, 2024, CA Cancer J Clin 74(1) (2024) 12–49. - PubMed
1. Rudin CM, Brambilla E, Faivre-Finn C, Sage J, Small-cell lung cancer, Nat Rev Dis Primers 7(1) (2021) 3. - PMC - PubMed
1. Chen J, Qi Y, Wampfler JA, Jatoi A, Garces YI, Busta AJ, Mandrekar SJ, Yang P, Effect of cigarette smoking on quality of life in small cell lung cancer patients, Eur J Cancer 48(11) (2012) 1593–601. - PMC - PubMed
1. Wu Z, Su J, Li FL, Chen T, Mayner J, Engler A, Ma S, Li Q, Guan KL, YAP silencing by RB1 mutation is essential for small-cell lung cancer metastasis, Nat Commun 14(1) (2023) 5916. - PMC - PubMed
1. Wu Y, Zhang J, Zhou W, Yuan Z, Wang H, Prognostic factors in extensive-stage small cell lung cancer patients with organ-specific metastasis: unveiling commonalities and disparities, J Cancer Res Clin Oncol 150(2) (2024) 74. - PMC - PubMed

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Clofazimine inhibits small-cell lung cancer progression by modulating the kynurenine/aryl hydrocarbon receptor axis

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Clofazimine inhibits small-cell lung cancer progression by modulating the kynurenine/aryl hydrocarbon receptor axis

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