Ancistrocladinium A induces apoptosis in proteasome inhibitor-resistant multiple myeloma cells: a promising therapeutic agent candidate
Please always quote using this URN: urn:nbn:de:bvb:20-opus-362887
- The N,C-coupled naphthylisoquinoline alkaloid ancistrocladinium A belongs to a novel class of natural products with potent antiprotozoal activity. Its effects on tumor cells, however, have not yet been explored. We demonstrate the antitumor activity of ancistrocladinium A in multiple myeloma (MM), a yet incurable blood cancer that represents a model disease for adaptation to proteotoxic stress. Viability assays showed a potent apoptosis-inducing effect of ancistrocladinium A in MM cell lines, including those with proteasome inhibitor (PI)The N,C-coupled naphthylisoquinoline alkaloid ancistrocladinium A belongs to a novel class of natural products with potent antiprotozoal activity. Its effects on tumor cells, however, have not yet been explored. We demonstrate the antitumor activity of ancistrocladinium A in multiple myeloma (MM), a yet incurable blood cancer that represents a model disease for adaptation to proteotoxic stress. Viability assays showed a potent apoptosis-inducing effect of ancistrocladinium A in MM cell lines, including those with proteasome inhibitor (PI) resistance, and in primary MM cells, but not in non-malignant blood cells. Concomitant treatment with the PI carfilzomib or the histone deacetylase inhibitor panobinostat strongly enhanced the ancistrocladinium A-induced apoptosis. Mass spectrometry with biotinylated ancistrocladinium A revealed significant enrichment of RNA-splicing-associated proteins. Affected RNA-splicing-associated pathways included genes involved in proteotoxic stress response, such as PSMB5-associated genes and the heat shock proteins HSP90 and HSP70. Furthermore, we found strong induction of ATF4 and the ATM/H2AX pathway, both of which are critically involved in the integrated cellular response following proteotoxic and oxidative stress. Taken together, our data indicate that ancistrocladinium A targets cellular stress regulation in MM and improves the therapeutic response to PIs or overcomes PI resistance, and thus may represent a promising potential therapeutic agent.…
Author: | Daniela BrünnertORCiD, Raina Seupel, Pankaj Goyal, Matthias Bach, Heike Schraud, Stefanie Kirner, Eva Köster, Doris Feineis, Ralf C. Bargou, Andreas Schlosser, Gerhard BringmannORCiD, Manik Chatterjee |
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URN: | urn:nbn:de:bvb:20-opus-362887 |
Document Type: | Journal article |
Faculties: | Fakultät für Biologie / Rudolf-Virchow-Zentrum |
Fakultät für Chemie und Pharmazie / Institut für Organische Chemie | |
Medizinische Fakultät / Comprehensive Cancer Center Mainfranken | |
Language: | English |
Parent Title (English): | Pharmaceuticals |
ISSN: | 1424-8247 |
Year of Completion: | 2023 |
Volume: | 16 |
Issue: | 8 |
Article Number: | 1181 |
Source: | Pharmaceuticals (2023) 16:8, 1181. https://doi.org/10.3390/ph16081181 |
DOI: | https://doi.org/10.3390/ph16081181 |
Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
Tag: | H2A histone family member X (H2AX); RNA splicing; activating transcription factor 4 (ATF4); ancistrocladinium A; ataxia teleagiectasia mutated (ATM); cellular stress response; multiple myeloma; naphthylisoquinoline alkaloids; proteasome inhibitor resistance; proteasome subunit beta type-5 (PSMB5) |
Release Date: | 2024/06/12 |
Licence (German): | CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International |