Ecdysteroid derivatives that reverse P-glycoprotein-mediated drug resistance
Open accessAbstract
High Resolution Image Download MS PowerPoint Slide The expression of multidrug resistance P-glycoprotein (P-gp) by cancer cells represents one of the major drawbacks to successful cancer therapy. Accordingly, the development of drugs that inhibit the activity of this transporter remains a major challenge in cancer drug discovery. In this context, several new ecdysteroid derivatives have been synthesized and evaluated as P-gp inhibitors. Two of them (compounds 9 and 14 ) were able to resensitize CEM Vbl100 and LoVo Doxo resistant cell lines to vinblastine and doxorubicin, respectively. Indeed, both compounds 9 and 14 increased the cellular accumulation of rhodamine 123 in cells expressing P-gp and stimulated basal P-glycoprotein-ATPase activity at a 1 μM concentration, demonstrating their interference with the transport of other substrates in a competitive mode. Moreover, in a medulloblastoma cell line (DAOY), compounds 9 and 14 reduced the side population representing cancer stem cells, which are characterized by a high expression of ABC drug transporters. Further, in DAOY cells, the same two compounds synergized with cisplatin and vincristine, two drugs used commonly in the therapy of medulloblastoma. Molecular docking studies on the homology-modeled structure of the human P-glycoprotein provided a rationale for the biological results, validating the binding mode within the receptor site, in accordance with lipophilicity data and observed structure–activity relationship information. Altogether, the present results endorse these derivatives as promising P-gp inhibitors, and they may serve as candidates to reverse drug resistance in cancer cells.
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20E may possess antineoplastic activity.
“Recent studies have shown that 20E may also possess antineoplastic activity.”
From 20-Hydroxyecdysone Confers Antioxidant and Antineoplastic Properties in Human Non-Small Cell Lung Cancer Cells (2023) · cites this paper as [18]
20E and its derivatives sensitize breast cancer cells to genotoxic stress, induce autophagy, and attenuate multiple drug resistance.
“We and others have shown that 20E and its derivates sensibilize breast cancer cells to genotoxic stress, induce autophagy, and attenuate multiple drug resistance [12,13,14,15,16,17,18,19].”
From 20-Hydroxyecdysone Confers Antioxidant and Antineoplastic Properties in Human Non-Small Cell Lung Cancer Cells (2023) · cites this paper as [18]
20E and its derivatives modulate the resistance of cancer cells to genotoxic drugs and mitigate multidrug resistance.
“Furthermore, it has been shown previously that 20E and its derivates modulate the resistance of cancer cells to genotoxic drugs and mitigate multidrug resistance [12,13,14,15,16,17,18,19].”
From 20-Hydroxyecdysone Confers Antioxidant and Antineoplastic Properties in Human Non-Small Cell Lung Cancer Cells (2023) · cites this paper as [18]
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- Authors
- Bortolozzi, R., Luraghi, A., Mattiuzzo, E., Sacchetti, A., Silvani, A., & Viola, G.
- Affiliations
- University of Padua (IT)
- University of Milan (IT)
- Politecnico di Milano (IT)
- Corresponding author
- Bortolozzi, Roberta
- Silvani, Alessandra
- ORCID
- Venue
- Journal of Natural Products
- Publisher
- American Chemical Society (ACS)
- Published
- 2020-08-13
- Volume
- 83
- Issue
- 8
- Pages
- 2434-2446
- ISSN
- 0163-3864 (ISSN-L)
- 1520-6025
- PMC
- PMC8009596
- OpenAlex
- W3048494033
- Cited by
- 21
- References
- 42
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 2 · 2023: 3 · 2022: 8 · 2021: 4 · 2020: 1
- FWCI
- 1.44
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Journal of Natural Products (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Virtual Community of Pathological Anatomy (University of Castilla La Mancha) (submittedVersion, other-oa)
- Padua Research Archive (University of Padova) (submittedVersion, cc-by)
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Antibiotic Resistance in Bacteria
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Keywords
- P-glycoprotein inhibitors, multidrug resistance reversal, P-glycoprotein, doxorubicin resistance, vinblastine resistance, medulloblastoma, cancer stem cells, drug efflux, structure-activity relationship, molecular docking, CCRF-CEM cells, LoVo cells, cisplatin, vincristine
- MeSH terms
- Antineoplastic Agents, Humans, Structure-Activity Relationship, ATP Binding Cassette Transporter, Subfamily B, ATP-Binding Cassette Transporters, Drug Resistance, Neoplasm, Rhodamine 123, Ecdysteroids, Cell Line, Tumor
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