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- Title
Extended Exposure Topotecan Significantly Improves Long-Term Drug Sensitivity by Decreasing Malignant Cell Heterogeneity and by Preventing Epithelial–Mesenchymal Transition.
- Authors
Davis, Joshua T.; Ghosh, Taraswi Mitra; Mazumder, Suman; Mitra, Amit; Bird, Richard Curtis; Arnold, Robert D.
- 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.
- Subjects
EPITHELIAL-mesenchymal transition; ANDROGEN receptors; TOPOTECAN; CANCER cells; ABIRATERONE acetate; CASTRATION-resistant prostate cancer; PHENOTYPIC plasticity
- Publication
International Journal of Molecular Sciences, 2023, Vol 24, Issue 10, p8490
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms24108490