Ancistrocladinium A Induces Apoptosis in Proteasome Inhibitor-Resistant Multiple Myeloma Cells: A Promising Therapeutic Agent Candidate

Author:

Brünnert Daniela1ORCID,Seupel Raina2,Goyal Pankaj3,Bach Matthias4,Schraud Heike1,Kirner Stefanie1,Köster Eva2,Feineis Doris2,Bargou Ralf C.1,Schlosser Andreas4,Bringmann Gerhard2ORCID,Chatterjee Manik1

Affiliation:

1. University Hospital of Würzburg, Comprehensive Cancer Center Mainfranken, Translational Oncology, 97080 Würzburg, Germany

2. Institute of Organic Chemistry, University of Würzburg, 97074 Würzburg, Germany

3. Department of Biotechnology, School of Life Sciences, Central University of Rajasthan, Bandar Sindri, Kishangarh 305817, India

4. Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, 97080 Würzburg, Germany

Abstract

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.

Funder

Deutsche Forschungsgemeinschaft

Department of Biotechnology

Indian Council of Medical Research

Publisher

MDPI AG

Subject

Drug Discovery,Pharmaceutical Science,Molecular Medicine

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