Significant activity of ecdysteroids on the resistance to doxorubicin in mammalian cancer cells expressing the human ABCB1 transporter
Abstract
Multidrug resistance (MDR) is a major cause of failure of cancer chemotherapy. Fifty-eight ecdysteroids, herbal analogues of the insect molting hormone and their semisynthetic derivatives, were tested for their activity against L5178 mouse T-cell lymphoma cells (non-MDR) and their subcell line transfected with pHa MDR1/A retrovirus overexpressing the human ABCB1 efflux pump (MDR cell line). The compounds showed very low antiproliferative activities but modulated the efflux of rhodamine 123 mediated by the ABCB1 transporter. Roughly depending on the polarity, mild to strong synergism or antagonism was observed by combining ecdysteroids with doxorubicin, and specific structure-activity relationships were also found. Our results show the effect of ecdysteroids on MDR cancer cells for the first time. Less polar derivatives may serve as valuable leads toward a potent and safe resistance modulator. Biological significance of the resistance-increasing activity of the most abundant phytoecdysteroids including 20-hydroxyecdysone is yet to be clarified.
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Ecdysterone made both drug-resistant and non-drug-resistant cancer cells more susceptible to doxorubicin treatment.
“Our results are in accordance with other studies (Konovalova et al., 2002; Martins et al., 2012; Martins et al., 2015) that have shown that ecdysterone made both drug-resistant and non-drug-resistant cancer cells more susceptible to doxorubicin treatment.”
From An Arthropod Hormone, Ecdysterone, Inhibits the Growth of Breast Cancer Cells via Different Mechanisms (2020) · cites this paper as Martins et al., 2012
Screened phytoecdysteroids showed mild to strong synergism or antagonism when tested in combination with doxorubicin.
“Screened PEs showed mild to strong synergism or antagonism when tested in combination with doxorubicin, which suggests that ecdysteroids could be potentially used for enhancing the specific structure‒activity relationships for cancer chemotherapeutics.”
From The Phytochemical, Biological, and Medicinal Attributes of Phytoecdysteroids: An Updated Review (2021) · cites this paper as [173]
Fifty-eight ecdysteroids showed slight inhibition of L5178 mouse T-cell lymphoma cell proliferation but notable modulation of rhodamine 123 efflux mediated by the ABCB1 transporter.
“The tested PEs showed slight inhibition of cell proliferation, but notable modulation of the efflux of rhodamine 123 mediated by the ABCB1 transporter173.”
From The Phytochemical, Biological, and Medicinal Attributes of Phytoecdysteroids: An Updated Review (2021) · cites this paper as [173]
PEs exhibit toxicity against mouse T-cell lymphoma cells and their subcell line transfected with retrovirus overexpressing the ABCB1 efflux pump.
“PEs exhibit their toxicity against mouse T-cell lymphoma cells and their subcell line transfected with retrovirus overexpressing the ABCB1 efflux pump.”
From Phytoecdysteroids: Distribution, Structural Diversity, Biosynthesis, Activity, and Crosstalk with Phytohormones (2022) · cites this paper as [160]
PEs inhibit cell proliferation and rhodomine efflux associated with the ABCB1 transporter.
“PEs inhibit cell proliferation and rhodomine efflux associated with the ABCB1 transporter [121,160].”
From Phytoecdysteroids: Distribution, Structural Diversity, Biosynthesis, Activity, and Crosstalk with Phytohormones (2022) · cites this paper as [160]
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 [13]
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 [13]
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 [13]
20-hydroxyecdysone 2,3;20,22-diacetonide (1) is a promising anticancer lead compound.
“our group revealed that relatively apolar ecdysteroids can strongly sensitize cancer cells to chemotherapeutics”
From Nitrogen-containing ecdysteroid derivatives vs. multi-drug resistance in cancer: Preparation and antitumor activity of oximes, oxime ethers and a lactam (2018) · cites this paper as [17]
Ecdysteroid derivatives with low polarity have chemo-sensitizing activity on drug-susceptible and multi-drug resistant cancer cells.
“We had previously described the chemo-sensitizing activity of ecdysteroid derivatives with low polarity on drug susceptible and multi-drug resistant (MDR) cancer cells.”
From Nitrogen-containing ecdysteroid derivatives vs. multi-drug resistance in cancer: Preparation and antitumor activity of oximes, oxime ethers and a lactam (2018) · cites this paper as [17]
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Self-citation
- Authors
- Martins, A., Tóth, N., Ványolós, A., Béni, Z., Zupkó, I., Molnár, J., Báthori, M., & Hunyadi, A.
- Affiliations
- University of Szeged (HU)
- Gedeon Richter (Hungary) (HU)
- Corresponding author
- Hunyadi, Attila
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2012-05-30
- Volume
- 55
- Issue
- 11
- Pages
- 5034-5043
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W1969764664
- Cited by
- 59
- References
- 35
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 2 · 2023: 1 · 2022: 7 · 2021: 5 · 2020: 8 · 2019: 3 · 2018: 5 · 2017: 6 · 2016: 5 · 2015: 4 · 2014: 4 · 2013: 2 · 2012: 1
- FWCI
- 1.74
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- SZTE Publicatio Repozitórium (University of Szeged) (acceptedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Phytochemical Studies and Bioactivities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Natural product bioactivities and synthesis
- Keywords
- ecdysteroids, phytoecdysteroids, doxorubicin resistance, multidrug resistance, P-glycoprotein, rhodamine 123 efflux, structure-activity relationship, synergistic and antagonistic effects, 20-hydroxyecdysone
- MeSH terms
- Animals, Antibiotics, Antineoplastic, Antineoplastic Agents, Phytogenic, Doxorubicin, Drug Antagonism, Drug Screening Assays, Antitumor, Drug Synergism, Humans, Structure-Activity Relationship, Drug Resistance, Multiple, ATP Binding Cassette Transporter, Subfamily B, Drug Resistance, Neoplasm, ATP Binding Cassette Transporter, Subfamily B, Member 1, Ecdysteroids, Cell Line, Tumor, Mice
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