Castasterone, a Plant Steroid Hormone, Affects Human Small-Cell Lung Cancer Cells and Reverses Multi-Drug Resistance
Small-cell lung cancer (SCLC) has a dismal prognosis, in part because of the development of multi-drug resistance. Castasterone (CAS) is the metabolic precursor of the plant steroid hormone epibrassinolide (EB). In some plants, EB accounts for the total hormone activity, whereas in other plants, CAS...
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MDPI AG
2023-01-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/16/2/170 |
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| author | David Sadava Shiuan Chen |
| author_facet | David Sadava Shiuan Chen |
| author_sort | David Sadava |
| collection | DOAJ |
| description | Small-cell lung cancer (SCLC) has a dismal prognosis, in part because of the development of multi-drug resistance. Castasterone (CAS) is the metabolic precursor of the plant steroid hormone epibrassinolide (EB). In some plants, EB accounts for the total hormone activity, whereas in other plants, CAS is the active form. The effects of CAS, a BR present in most plants, on animal cells in general and cancer cells in particular have not been described. Here, we report the effects of CAS on drug-sensitive (H69) and drug-resistant (VPA17) SCLC cells. CAS was equally cytotoxic to both cell lines (IC<sub>50</sub> = 1 μM), indicating a lack of cross-resistance. Pre-incubation of VPA17 cells with CAS for 96 h reversed drug resistance to etoposide and doxorubicin. Synergism between CAS and EB, as well as with chemotherapy drugs, was investigated by exposure of VPA17 cells to 1:1 ratios of CAS and the other drugs at the respective IC<sub>50</sub> values, with dilutions at 0.25 to 2.0 × IC<sub>50</sub> and determination of the combination index (CI). CAS and EB were additive, indicating that the two drugs act on the same pathway, whereas CAS–etoposide (CI = 0.77) and CAS–doxorubicin were synergistic, indicating that CAS and the two chemotherapeutic drugs act on different pathways. Apoptosis in SCLC cells was measured by immuno-detection of single-strand DNA breaks. Following 96 h incubation of SCLC H69 cells in CAS, the level of DNA breaks was similar to measurements made after incubation in EB and etoposide, indicating that CAS is pro-apoptotic. Incubation of SCLC cells in CAS led to a time-dependent reduction (by 80%) in the transcriptional activator β-catenin. These data indicate that CAS may act via <i>Wnt</i> signaling. Taken together, our study reveals that CAS is pharmacologically active in both drug-sensitive and drug-resistant SCLC cells. |
| first_indexed | 2024-03-11T08:17:55Z |
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| institution | Directory Open Access Journal |
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| language | English |
| last_indexed | 2024-03-11T08:17:55Z |
| publishDate | 2023-01-01 |
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| series | Pharmaceuticals |
| spelling | doaj.art-6b706f3770cd42aeac4961799b8a9dba2023-11-16T22:35:59ZengMDPI AGPharmaceuticals1424-82472023-01-0116217010.3390/ph16020170Castasterone, a Plant Steroid Hormone, Affects Human Small-Cell Lung Cancer Cells and Reverses Multi-Drug ResistanceDavid Sadava0Shiuan Chen1Department of Cancer Biology and Molecular Medicine, Beckman Research Institute, City of Hope, 1500 E. Duarte Rd., Duarte, CA 91010, USADepartment of Cancer Biology and Molecular Medicine, Beckman Research Institute, City of Hope, 1500 E. Duarte Rd., Duarte, CA 91010, USASmall-cell lung cancer (SCLC) has a dismal prognosis, in part because of the development of multi-drug resistance. Castasterone (CAS) is the metabolic precursor of the plant steroid hormone epibrassinolide (EB). In some plants, EB accounts for the total hormone activity, whereas in other plants, CAS is the active form. The effects of CAS, a BR present in most plants, on animal cells in general and cancer cells in particular have not been described. Here, we report the effects of CAS on drug-sensitive (H69) and drug-resistant (VPA17) SCLC cells. CAS was equally cytotoxic to both cell lines (IC<sub>50</sub> = 1 μM), indicating a lack of cross-resistance. Pre-incubation of VPA17 cells with CAS for 96 h reversed drug resistance to etoposide and doxorubicin. Synergism between CAS and EB, as well as with chemotherapy drugs, was investigated by exposure of VPA17 cells to 1:1 ratios of CAS and the other drugs at the respective IC<sub>50</sub> values, with dilutions at 0.25 to 2.0 × IC<sub>50</sub> and determination of the combination index (CI). CAS and EB were additive, indicating that the two drugs act on the same pathway, whereas CAS–etoposide (CI = 0.77) and CAS–doxorubicin were synergistic, indicating that CAS and the two chemotherapeutic drugs act on different pathways. Apoptosis in SCLC cells was measured by immuno-detection of single-strand DNA breaks. Following 96 h incubation of SCLC H69 cells in CAS, the level of DNA breaks was similar to measurements made after incubation in EB and etoposide, indicating that CAS is pro-apoptotic. Incubation of SCLC cells in CAS led to a time-dependent reduction (by 80%) in the transcriptional activator β-catenin. These data indicate that CAS may act via <i>Wnt</i> signaling. Taken together, our study reveals that CAS is pharmacologically active in both drug-sensitive and drug-resistant SCLC cells.https://www.mdpi.com/1424-8247/16/2/170small-celllung cancercastasteroneplant hormonemulti-drug resistance |
| spellingShingle | David Sadava Shiuan Chen Castasterone, a Plant Steroid Hormone, Affects Human Small-Cell Lung Cancer Cells and Reverses Multi-Drug Resistance Pharmaceuticals small-cell lung cancer castasterone plant hormone multi-drug resistance |
| title | Castasterone, a Plant Steroid Hormone, Affects Human Small-Cell Lung Cancer Cells and Reverses Multi-Drug Resistance |
| title_full | Castasterone, a Plant Steroid Hormone, Affects Human Small-Cell Lung Cancer Cells and Reverses Multi-Drug Resistance |
| title_fullStr | Castasterone, a Plant Steroid Hormone, Affects Human Small-Cell Lung Cancer Cells and Reverses Multi-Drug Resistance |
| title_full_unstemmed | Castasterone, a Plant Steroid Hormone, Affects Human Small-Cell Lung Cancer Cells and Reverses Multi-Drug Resistance |
| title_short | Castasterone, a Plant Steroid Hormone, Affects Human Small-Cell Lung Cancer Cells and Reverses Multi-Drug Resistance |
| title_sort | castasterone a plant steroid hormone affects human small cell lung cancer cells and reverses multi drug resistance |
| topic | small-cell lung cancer castasterone plant hormone multi-drug resistance |
| url | https://www.mdpi.com/1424-8247/16/2/170 |
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