Extended Exposure Topotecan Significantly Improves Long-Term Drug Sensitivity by Decreasing Malignant Cell Heterogeneity and by Preventing Epithelial–Mesenchymal Transition

Davis, Joshua T.; Ghosh, Taraswi Mitra; Mazumder, Suman; Mitra, Amit; Bird, Richard Curtis; Arnold, Robert D.

doi:10.3390/ijms24108490

Open AccessArticle

Extended Exposure Topotecan Significantly Improves Long-Term Drug Sensitivity by Decreasing Malignant Cell Heterogeneity and by Preventing Epithelial–Mesenchymal Transition

by

Joshua T. Davis

^1,*

,

Taraswi Mitra Ghosh

^1,2,

Suman Mazumder

^1,3,

Amit Mitra

^1,3,4

,

Richard Curtis Bird

⁵ and

Robert D. Arnold

^1,3,5,*

¹

Department of Drug Discovery and Development, Auburn University, Auburn, AL 36849, USA

²

Department of Urology Research, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02215, USA

³

UAB O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35233, USA

⁴

Center for Pharmacogenomics and Single-Cell Omics (AUPharmGx), Harrison College of Pharmacy, Auburn University, Auburn, AL 36849, USA

⁵

Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA

^*

Authors to whom correspondence should be addressed.

Int. J. Mol. Sci. 2023, 24(10), 8490; https://doi.org/10.3390/ijms24108490

Submission received: 11 April 2023 / Revised: 2 May 2023 / Accepted: 4 May 2023 / Published: 9 May 2023

(This article belongs to the Collection Feature Papers in Molecular Pharmacology)

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Abstract

Maximum tolerable dosing (MTD) of chemotherapeutics has long been the gold standard for aggressive malignancies. Recently, alternative dosing strategies have gained traction for their improved toxicity profiles and unique mechanisms of action, such as inhibition of angiogenesis and stimulation of immunity. In this article, we investigated whether extended exposure (EE) topotecan could improve long-term drug sensitivity by preventing drug resistance. To achieve significantly longer exposure times, we used a spheroidal model system of castration-resistant prostate cancer. We also used state-of-the-art transcriptomic analysis to further elucidate any underlying phenotypic changes that occurred in the malignant population following each treatment. We determined that EE topotecan had a much higher barrier to resistance relative to MTD topotecan and was able to maintain consistent efficacy throughout the study period (EE IC50 of 54.4 nM (Week 6) vs. MTD IC50 of 2200 nM (Week 6) vs. 83.8 nM IC50 for control (Week 6) vs. 37.8 nM IC50 for control (Week 0)). As a possible explanation for these results, we determined that MTD topotecan stimulated epithelial–mesenchymal transition (EMT), upregulated efflux pumps, and produced altered topoisomerases relative to EE topotecan. Overall, EE topotecan resulted in a more sustained treatment response and maintained a less aggressive malignant phenotype relative to MTD topotecan.

Keywords: oncology; alternative dosing; resistance; heterogeneity; transcriptomics; spheroid model; long-term exposure

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MDPI and ACS Style

Davis, J.T.; Ghosh, T.M.; Mazumder, S.; Mitra, A.; Bird, R.C.; Arnold, R.D. Extended Exposure Topotecan Significantly Improves Long-Term Drug Sensitivity by Decreasing Malignant Cell Heterogeneity and by Preventing Epithelial–Mesenchymal Transition. Int. J. Mol. Sci. 2023, 24, 8490. https://doi.org/10.3390/ijms24108490

AMA Style

Davis JT, Ghosh TM, Mazumder S, Mitra A, Bird RC, Arnold RD. Extended Exposure Topotecan Significantly Improves Long-Term Drug Sensitivity by Decreasing Malignant Cell Heterogeneity and by Preventing Epithelial–Mesenchymal Transition. International Journal of Molecular Sciences. 2023; 24(10):8490. https://doi.org/10.3390/ijms24108490

Chicago/Turabian Style

Davis, Joshua T., Taraswi Mitra Ghosh, Suman Mazumder, Amit Mitra, Richard Curtis Bird, and Robert D. Arnold. 2023. "Extended Exposure Topotecan Significantly Improves Long-Term Drug Sensitivity by Decreasing Malignant Cell Heterogeneity and by Preventing Epithelial–Mesenchymal Transition" International Journal of Molecular Sciences 24, no. 10: 8490. https://doi.org/10.3390/ijms24108490

APA Style

Davis, J. T., Ghosh, T. M., Mazumder, S., Mitra, A., Bird, R. C., & Arnold, R. D. (2023). Extended Exposure Topotecan Significantly Improves Long-Term Drug Sensitivity by Decreasing Malignant Cell Heterogeneity and by Preventing Epithelial–Mesenchymal Transition. International Journal of Molecular Sciences, 24(10), 8490. https://doi.org/10.3390/ijms24108490

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Extended Exposure Topotecan Significantly Improves Long-Term Drug Sensitivity by Decreasing Malignant Cell Heterogeneity and by Preventing Epithelial–Mesenchymal Transition

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