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Article

Ferroptosis Inducers Erastin and RSL3 Enhance Adriamycin and Topotecan Sensitivity in ABCB1/ABCG2-Expressing Tumor Cells

1
Laboratory of Genome Integrity and Structural Biology, National Institutes of Environmental Health Sciences (NIH), Research Triangle Park, North Carolina, NC 27709, USA
2
Mechanistic Toxicology Branch, Division of Translational Toxicology, National Institutes of Environmental Health Sciences (NIH), Research Triangle Park, Durham, NC 27709, USA
3
Boonshoft School of Medicine, Wright State University, Dayton, OH 45435, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2025, 26(2), 635; https://doi.org/10.3390/ijms26020635
Submission received: 4 December 2024 / Revised: 31 December 2024 / Accepted: 3 January 2025 / Published: 14 January 2025

Abstract

Acquired resistance to chemotherapeutic drugs is the primary cause of treatment failure in the clinic. While multiple factors contribute to this resistance, increased expression of ABC transporters—such as P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance proteins—play significant roles in the development of resistance to various chemotherapeutics. We found that Erastin, a ferroptosis inducer, was significantly cytotoxic to NCI/ADR-RES, a P-gp-expressing human ovarian cancer cell line. Here, we examined the effects of both Erastin and RSL3 (Ras-Selected Ligand 3) on reversing Adriamycin resistance in these cell lines. Our results show that Erastin significantly enhanced Adriamycin uptake in NCI/ADR-RES cells without affecting sensitive cells. Furthermore, we observed that Erastin enhanced Adriamycin cytotoxicity in a time-dependent manner. The selective iNOS inhibitor, 1400W, reduced both uptake and cytotoxicity of Adriamycin in P-gp-expressing NCI/ADR-RES cells only. These findings were also confirmed in a BCRP-expressing human breast cancer cell line (MCF-7/MXR), which was selected for resistance to Mitoxantrone. Both Erastin and RSL3 were found to be cytotoxic to MCF-7/MXR cells. Erastin significantly enhanced the uptake of Hoechst dye, a well-characterized BCRP substrate, sensitizing MCF-7/MXR cells to Topotecan. The effect of Erastin was inhibited by 1400W, indicating that iNOS is involved in Erastin-mediated enhancement of Topotecan cytotoxicity. RSL3 also significantly increased Topotecan cytotoxicity. Our findings—demonstrating increased cytotoxicity of Adriamycin and Topotecan in P-gp- and BCRP-expressing cells—suggest that ferroptosis inducers may be highly valuable in combination with other chemotherapeutics to manage patients’ cancer burden in the clinical setting.
Keywords: P-gp protein; breast cancer resistance protein; Adriamycin; Topotecan; ferroptosis; Erastin; RSL3 P-gp protein; breast cancer resistance protein; Adriamycin; Topotecan; ferroptosis; Erastin; RSL3

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MDPI and ACS Style

Perera, L.; Brown, S.M.; Silver, B.B.; Tokar, E.J.; Sinha, B.K. Ferroptosis Inducers Erastin and RSL3 Enhance Adriamycin and Topotecan Sensitivity in ABCB1/ABCG2-Expressing Tumor Cells. Int. J. Mol. Sci. 2025, 26, 635. https://doi.org/10.3390/ijms26020635

AMA Style

Perera L, Brown SM, Silver BB, Tokar EJ, Sinha BK. Ferroptosis Inducers Erastin and RSL3 Enhance Adriamycin and Topotecan Sensitivity in ABCB1/ABCG2-Expressing Tumor Cells. International Journal of Molecular Sciences. 2025; 26(2):635. https://doi.org/10.3390/ijms26020635

Chicago/Turabian Style

Perera, Lalith, Shalyn M. Brown, Brian B. Silver, Erik J. Tokar, and Birandra K. Sinha. 2025. "Ferroptosis Inducers Erastin and RSL3 Enhance Adriamycin and Topotecan Sensitivity in ABCB1/ABCG2-Expressing Tumor Cells" International Journal of Molecular Sciences 26, no. 2: 635. https://doi.org/10.3390/ijms26020635

APA Style

Perera, L., Brown, S. M., Silver, B. B., Tokar, E. J., & Sinha, B. K. (2025). Ferroptosis Inducers Erastin and RSL3 Enhance Adriamycin and Topotecan Sensitivity in ABCB1/ABCG2-Expressing Tumor Cells. International Journal of Molecular Sciences, 26(2), 635. https://doi.org/10.3390/ijms26020635

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