Extended Exposure Topotecan Significantly Improves Long-Term Drug Sensitivity by Decreasing Malignant Cell Heterogeneity and by Preventing Epithelial–Mesenchymal Transition
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 im...
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MDPI AG
2023-05-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/10/8490 |
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| author | Joshua T. Davis Taraswi Mitra Ghosh Suman Mazumder Amit Mitra Richard Curtis Bird Robert D. Arnold |
| author_facet | Joshua T. Davis Taraswi Mitra Ghosh Suman Mazumder Amit Mitra Richard Curtis Bird Robert D. Arnold |
| author_sort | Joshua T. Davis |
| collection | DOAJ |
| description | 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. |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T03:40:49Z |
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| spelling | doaj.art-a9f317b15c6940f0a9c2ade39db84a492023-11-18T01:36:43ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-05-012410849010.3390/ijms24108490Extended Exposure Topotecan Significantly Improves Long-Term Drug Sensitivity by Decreasing Malignant Cell Heterogeneity and by Preventing Epithelial–Mesenchymal TransitionJoshua T. Davis0Taraswi Mitra Ghosh1Suman Mazumder2Amit Mitra3Richard Curtis Bird4Robert D. Arnold5Department of Drug Discovery and Development, Auburn University, Auburn, AL 36849, USADepartment of Drug Discovery and Development, Auburn University, Auburn, AL 36849, USADepartment of Drug Discovery and Development, Auburn University, Auburn, AL 36849, USADepartment of Drug Discovery and Development, Auburn University, Auburn, AL 36849, USADepartment of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USADepartment of Drug Discovery and Development, Auburn University, Auburn, AL 36849, USAMaximum 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.https://www.mdpi.com/1422-0067/24/10/8490oncologyalternative dosingresistanceheterogeneitytranscriptomicsspheroid model |
| spellingShingle | Joshua T. Davis Taraswi Mitra Ghosh Suman Mazumder Amit Mitra Richard Curtis Bird Robert D. Arnold 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 oncology alternative dosing resistance heterogeneity transcriptomics spheroid model |
| title | Extended Exposure Topotecan Significantly Improves Long-Term Drug Sensitivity by Decreasing Malignant Cell Heterogeneity and by Preventing Epithelial–Mesenchymal Transition |
| title_full | Extended Exposure Topotecan Significantly Improves Long-Term Drug Sensitivity by Decreasing Malignant Cell Heterogeneity and by Preventing Epithelial–Mesenchymal Transition |
| title_fullStr | Extended Exposure Topotecan Significantly Improves Long-Term Drug Sensitivity by Decreasing Malignant Cell Heterogeneity and by Preventing Epithelial–Mesenchymal Transition |
| title_full_unstemmed | Extended Exposure Topotecan Significantly Improves Long-Term Drug Sensitivity by Decreasing Malignant Cell Heterogeneity and by Preventing Epithelial–Mesenchymal Transition |
| title_short | Extended Exposure Topotecan Significantly Improves Long-Term Drug Sensitivity by Decreasing Malignant Cell Heterogeneity and by Preventing Epithelial–Mesenchymal Transition |
| title_sort | extended exposure topotecan significantly improves long term drug sensitivity by decreasing malignant cell heterogeneity and by preventing epithelial mesenchymal transition |
| topic | oncology alternative dosing resistance heterogeneity transcriptomics spheroid model |
| url | https://www.mdpi.com/1422-0067/24/10/8490 |
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