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Clobetasol propionate, a Nrf-2 inhibitor, sensitizes human lung cancer cells to radiation-induced killing via mitochondrial ROS-dependent ferroptosis

Acta Pharmacologica Sinica (2024)Cite this article

Abstract

Combining radiotherapy with Nrf-2 inhibitor holds promise as a potential therapeutic strategy for radioresistant lung cancer. Here, the radiosensitizing efficacy of a synthetic glucocorticoid clobetasol propionate (CP) in A549 human lung cancer cells was evaluated. CP exhibited potent radiosensitization in lung cancer cells via inhibition of Nrf-2 pathway, leading to elevation of oxidative stress. Transcriptomic studies revealed significant modulation of pathways related to ferroptosis, fatty acid and glutathione metabolism. Consistent with these findings, CP treatment followed by radiation exposure showed characteristic features of ferroptosis in terms of mitochondrial swelling, rupture and loss of cristae. Ferroptosis is a form of regulated cell death triggered by iron-dependent ROS accumulation and lipid peroxidation. In combination with radiation, CP showed enhanced iron release, mitochondrial ROS, and lipid peroxidation, indicating ferroptosis induction. Further, iron chelation, inhibition of lipid peroxidation or scavenging mitochondrial ROS prevented CP-mediated radiosensitization. Nrf-2 negatively regulates ferroptosis through upregulation of antioxidant defense and iron homeostasis. Interestingly, Nrf-2 overexpressing A549 cells were refractory to CP-mediated ferroptosis induction and radiosensitization. Thus, this study identified anti-psoriatic drug clobetasol propionate can be repurposed as a promising radiosensitizer for Keap-1 mutant lung cancers.

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Fig. 1: Clobetasol propionate enhanced radiosensitivity of human lung cancer cells.
Fig. 2: Clobetasol propionate induced oxidative stress via inhibition of Nrf-2.
Fig. 3: CP treatment resulted in increased DNA damage when combined with radiation.
Fig. 4: Clobetasol propionate impaired mitochondrial health and function when combined with radiation.
Fig. 5: Clobetasol propionate induced ferroptosis in lung cancer cells exposed to radiation.
Fig. 6: Radiosensitization by clobetasol propionate is dependent on mitochondrial ROS.
Fig. 7: Role of Nrf-2 in ferroptosis mediated radiosensitization.
Scheme 1: Clobetasol propionate induces radiosensitization of human lung cancer cells via ferroptosis.

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Data will be made available upon reasonable request.

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Acknowledgements

Authors acknowledge the scientific inputs provided by Dr. Deepak Sharma, SO/G, RB&HSD, Dr. Dharmendra K. Maurya, SO/G, RB&HSD and Dr.Dibakar Goswami, SO/G, BOD. Authors also acknowledge the technical help provided by Ms. Binita Kislay Kumar for flow cytometry and Mr. B. A. Naidu & Mr. Deepak Kathole for help during irradiation of cells. Authors would like to thank ACTREC’s TEM facility and animal house facility. The authors acknowledge the funding provided by DAE, Government of India to conduct research as outlined in this article.

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Authors and Affiliations

  1. Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre, Trombay, Mumbai, 400085, India

    Archita Rai, Raghavendra S. Patwardhan, Sundarraj Jayakumar & Santosh K. Sandur

  2. Homi Bhabha National Institute, Training School Complex, Anushaktinagar, Mumbai, 400094, India

    Archita Rai, Sundarraj Jayakumar, Pradnya Pachpatil, Dhruv Das, Sejal Patwardhan & Santosh K. Sandur

  3. Bio Organic Division, Bhabha Atomic Research Centre, Trombay, Mumbai, 400085, India

    Pradnya Pachpatil

  4. Applied Genomics Section, Bhabha Atomic Research Centre, Trombay, Mumbai, 400085, India

    Dhruv Das

  5. Advanced Centre for Treatment Research & Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Kharghar, Navi Mumbai, 410210, India

    Girish Ch. Panigrahi, Vikram Gota & Sejal Patwardhan

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Contributions

Conceptualization: SKS; Methodology: AR, PP, SJ, GCP; Investigation: AR, SJ, SP, DD, GCP; Visualization: AR, RSP, SJ, SP, DD; Funding acquisition: SKS; Resources: SKS, SJ, VG; Project administration: SKS; Supervision: SKS; Writing – original draft: AR; Writing – review & editing: RSP, SJ, SKS.

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Correspondence to Santosh K. Sandur.

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Rai, A., Patwardhan, R.S., Jayakumar, S. et al. Clobetasol propionate, a Nrf-2 inhibitor, sensitizes human lung cancer cells to radiation-induced killing via mitochondrial ROS-dependent ferroptosis. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01233-8

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