{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T08:27:26Z","timestamp":1773736046592,"version":"3.50.1"},"reference-count":58,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2023,8,18]],"date-time":"2023-08-18T00:00:00Z","timestamp":1692316800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft (DFG)","doi-asserted-by":"publisher","award":["KFO216"],"award-info":[{"award-number":["KFO216"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft (DFG)","doi-asserted-by":"publisher","award":["BT\/INF\/22\/SP44383\/2021"],"award-info":[{"award-number":["BT\/INF\/22\/SP44383\/2021"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft (DFG)","doi-asserted-by":"publisher","award":["BT\/HRD\/01\/59\/2020"],"award-info":[{"award-number":["BT\/HRD\/01\/59\/2020"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft (DFG)","doi-asserted-by":"publisher","award":["6\/9-7(234)2020\/ECD-II"],"award-info":[{"award-number":["6\/9-7(234)2020\/ECD-II"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001407","name":"Department of Biotechnology","doi-asserted-by":"publisher","award":["KFO216"],"award-info":[{"award-number":["KFO216"]}],"id":[{"id":"10.13039\/501100001407","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001407","name":"Department of Biotechnology","doi-asserted-by":"publisher","award":["BT\/INF\/22\/SP44383\/2021"],"award-info":[{"award-number":["BT\/INF\/22\/SP44383\/2021"]}],"id":[{"id":"10.13039\/501100001407","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001407","name":"Department of Biotechnology","doi-asserted-by":"publisher","award":["BT\/HRD\/01\/59\/2020"],"award-info":[{"award-number":["BT\/HRD\/01\/59\/2020"]}],"id":[{"id":"10.13039\/501100001407","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001407","name":"Department of Biotechnology","doi-asserted-by":"publisher","award":["6\/9-7(234)2020\/ECD-II"],"award-info":[{"award-number":["6\/9-7(234)2020\/ECD-II"]}],"id":[{"id":"10.13039\/501100001407","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001411","name":"Indian Council of Medical Research","doi-asserted-by":"publisher","award":["KFO216"],"award-info":[{"award-number":["KFO216"]}],"id":[{"id":"10.13039\/501100001411","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001411","name":"Indian Council of Medical Research","doi-asserted-by":"publisher","award":["BT\/INF\/22\/SP44383\/2021"],"award-info":[{"award-number":["BT\/INF\/22\/SP44383\/2021"]}],"id":[{"id":"10.13039\/501100001411","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001411","name":"Indian Council of Medical Research","doi-asserted-by":"publisher","award":["BT\/HRD\/01\/59\/2020"],"award-info":[{"award-number":["BT\/HRD\/01\/59\/2020"]}],"id":[{"id":"10.13039\/501100001411","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001411","name":"Indian Council of Medical Research","doi-asserted-by":"publisher","award":["6\/9-7(234)2020\/ECD-II"],"award-info":[{"award-number":["6\/9-7(234)2020\/ECD-II"]}],"id":[{"id":"10.13039\/501100001411","id-type":"DOI","asserted-by":"publisher"}]},{"name":"University of Wuerzburg","award":["KFO216"],"award-info":[{"award-number":["KFO216"]}]},{"name":"University of Wuerzburg","award":["BT\/INF\/22\/SP44383\/2021"],"award-info":[{"award-number":["BT\/INF\/22\/SP44383\/2021"]}]},{"name":"University of Wuerzburg","award":["BT\/HRD\/01\/59\/2020"],"award-info":[{"award-number":["BT\/HRD\/01\/59\/2020"]}]},{"name":"University of Wuerzburg","award":["6\/9-7(234)2020\/ECD-II"],"award-info":[{"award-number":["6\/9-7(234)2020\/ECD-II"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/ph16081181","type":"journal-article","created":{"date-parts":[[2023,8,18]],"date-time":"2023-08-18T10:28:48Z","timestamp":1692354528000},"page":"1181","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Ancistrocladinium A Induces Apoptosis in Proteasome Inhibitor-Resistant Multiple Myeloma Cells: A Promising Therapeutic Agent Candidate"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0870-9578","authenticated-orcid":false,"given":"Daniela","family":"Br\u00fcnnert","sequence":"first","affiliation":[{"name":"University Hospital of W\u00fcrzburg, Comprehensive Cancer Center Mainfranken, Translational Oncology, 97080 W\u00fcrzburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raina","family":"Seupel","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry, University of W\u00fcrzburg, 97074 W\u00fcrzburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pankaj","family":"Goyal","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, School of Life Sciences, Central University of Rajasthan, Bandar Sindri, Kishangarh 305817, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthias","family":"Bach","sequence":"additional","affiliation":[{"name":"Rudolf Virchow Center for Experimental Biomedicine, University of W\u00fcrzburg, 97080 W\u00fcrzburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heike","family":"Schraud","sequence":"additional","affiliation":[{"name":"University Hospital of W\u00fcrzburg, Comprehensive Cancer Center Mainfranken, Translational Oncology, 97080 W\u00fcrzburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefanie","family":"Kirner","sequence":"additional","affiliation":[{"name":"University Hospital of W\u00fcrzburg, Comprehensive Cancer Center Mainfranken, Translational Oncology, 97080 W\u00fcrzburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eva","family":"K\u00f6ster","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry, University of W\u00fcrzburg, 97074 W\u00fcrzburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Doris","family":"Feineis","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry, University of W\u00fcrzburg, 97074 W\u00fcrzburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ralf C.","family":"Bargou","sequence":"additional","affiliation":[{"name":"University Hospital of W\u00fcrzburg, Comprehensive Cancer Center Mainfranken, Translational Oncology, 97080 W\u00fcrzburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas","family":"Schlosser","sequence":"additional","affiliation":[{"name":"Rudolf Virchow Center for Experimental Biomedicine, University of W\u00fcrzburg, 97080 W\u00fcrzburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3583-5935","authenticated-orcid":false,"given":"Gerhard","family":"Bringmann","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry, University of W\u00fcrzburg, 97074 W\u00fcrzburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manik","family":"Chatterjee","sequence":"additional","affiliation":[{"name":"University Hospital of W\u00fcrzburg, Comprehensive Cancer Center Mainfranken, Translational Oncology, 97080 W\u00fcrzburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21654","article-title":"Cancer Statistics, 2021","volume":"71","author":"Siegel","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1001\/jama.2022.0003","article-title":"Diagnosis and management of multiple myeloma: A review","volume":"327","author":"Cowan","year":"2022","journal-title":"JAMA"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Guang, M.H.Z., Kavanagh, E.L., Dunne, L.P., Dowling, P., Zhang, L., Lindsay, S., Bazou, D., Goh, C.Y., Hanley, C., and Bianchi, G. (2019). Targeting proteotoxic stress in cancer: A review of the role that protein quality control pathways play in oncogenesis. Cancers, 11.","DOI":"10.3390\/cancers11010066"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.3324\/haematol.2012.064923","article-title":"DangER: Protein ovERload. Targeting protein degradation to treat myeloma","volume":"97","author":"Aronson","year":"2012","journal-title":"Haematologica"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3954","DOI":"10.1158\/1078-0432.CCR-03-0781","article-title":"Approval summary for bortezomib for injection in the treatment of multiple myeloma","volume":"10","author":"Bross","year":"2004","journal-title":"Clin. Cancer Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1621","DOI":"10.1056\/NEJMoa1516282","article-title":"Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma","volume":"374","author":"Moreau","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2817","DOI":"10.1182\/blood-2012-05-425934","article-title":"A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma","volume":"120","author":"Siegel","year":"2012","journal-title":"Blood"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2331","DOI":"10.1182\/blood-2013-01-481325","article-title":"PANORAMA 2: Panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory myeloma","volume":"122","author":"Richardson","year":"2013","journal-title":"Blood"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1038\/leu.2017.212","article-title":"Carfilzomib resistance due to ABCB1\/MDR1 overexpression is overcome by nelfinavir and lopinavir in multiple myeloma","volume":"32","author":"Besse","year":"2018","journal-title":"Leukemia"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1038\/s41375-018-0216-8","article-title":"Spectrum and functional validation of PSMB5 mutations in multiple myeloma","volume":"33","author":"Barrio","year":"2019","journal-title":"Leukemia"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1666","DOI":"10.1016\/j.bbadis.2019.04.003","article-title":"Novel cell line models to study mechanisms and overcoming strategies of proteasome inhibitor resistance in multiple myeloma","volume":"1865","author":"Kraus","year":"2019","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1038\/nrm3525","article-title":"Alternative splicing: A pivotal step between eukaryotic transcription and translation","volume":"14","author":"Kornblihtt","year":"2013","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.tig.2007.10.001","article-title":"Insights into the connection between cancer and alternative splicing","volume":"24","author":"Kim","year":"2008","journal-title":"Trends Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e1468","DOI":"10.1002\/wrna.1468","article-title":"Mutually exclusive alternative splicing of pre-mRNAs","volume":"9","author":"Jin","year":"2018","journal-title":"Wiley Interdiscip. Rev. RNA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1038\/nchembio.2007.18","article-title":"Spliceostatin A targets SF3b and inhibits both splicing and nuclear retention of pre-mRNA","volume":"3","author":"Kaida","year":"2007","journal-title":"Nat. Chem. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"945","DOI":"10.3324\/haematol.2014.122069","article-title":"Targeting the spliceosome in chronic lymphocytic leukemia with the macrolides FD-895 and pladienolide-B","volume":"100","author":"Kashyap","year":"2015","journal-title":"Haematologica"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"736","DOI":"10.3324\/haematol.2019.235424","article-title":"Differential RNA splicing as a potentially important driver mechanism in multiple myeloma","volume":"106","author":"Bauer","year":"2021","journal-title":"Haematologica"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1038\/s41408-022-00759-6","article-title":"In-depth analysis of alternative splicing landscape in multiple myeloma and potential role of dysregulated splicing factors","volume":"12","author":"Fulciniti","year":"2022","journal-title":"Blood Cancer J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1038\/s41416-022-02124-7","article-title":"Dysregulation of alternative splicing contributes to multiple myeloma pathogenesis","volume":"128","author":"Song","year":"2023","journal-title":"Br. J. Cancer"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1931","DOI":"10.1038\/s41467-020-15521-4","article-title":"Proteasome inhibitor-induced modulation reveals the spliceosome as a specific therapeutic vulnerability in multiple myeloma","volume":"11","author":"Huang","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1021\/acs.jnatprod.6b00967","article-title":"Dioncophyllines C2, D2, and F and related naphthylisoquinoline alkaloids from the Congolese liana Ancistrocladus ileboensis with potent activities against Plasmodium falciparum and against multiple myeloma and leukemia cell lines","volume":"80","author":"Li","year":"2017","journal-title":"J. Nat. Prod."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"18","DOI":"10.2533\/chimia.1998.18","article-title":"The alkaloids of Triphyophyllum peltatum (Dioncophyllaceae)","volume":"52","author":"Bringmann","year":"1998","journal-title":"Chimia"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2154","DOI":"10.1039\/D1NP00020A","article-title":"N,C-Coupled naphthylisoquinoline alkaloids: A versatile new class of axially chiral natural products","volume":"38","author":"Tajuddeen","year":"2021","journal-title":"Nat. Prod. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"9348","DOI":"10.1021\/jo061626w","article-title":"Ancistrocladinium A and B, the first N,C-coupled naphthyldihydroisoquinoline alkaloids, from a Congolese Ancistrocladus species","volume":"71","author":"Bringmann","year":"2006","journal-title":"J. Org. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1158\/1535-7163.MCT-12-0782","article-title":"Endoplasmic reticulum stress and the unfolded protein response: Targeting the Achilles heel of multiple myeloma","volume":"12","author":"Vincenz","year":"2013","journal-title":"Mol. Cancer Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2165","DOI":"10.1016\/j.bbamcr.2013.05.002","article-title":"Internal ribosome entry site-mediated translational regulation of ATF4 splice variant in mammalian unfolded protein response","volume":"1833","author":"Chan","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2744","DOI":"10.1002\/anie.201208749","article-title":"Target identification for small bioactive molecules: Finding the needle in the haystack","volume":"52","author":"Ziegler","year":"2013","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1039\/b702942j","article-title":"Identification of the cellular targets of bioactive small organic molecules using affinity reagents","volume":"37","author":"Leslie","year":"2008","journal-title":"Chem. Soc. Rev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1038\/leu.2014.318","article-title":"The impact of SF3B1 mutations in CLL on the DNA-damage response","volume":"29","author":"Derks","year":"2015","journal-title":"Leukemia"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"587","DOI":"10.3389\/fonc.2019.00587","article-title":"Small nucleolar RNAs: Insight into their function in cancer","volume":"9","author":"Liang","year":"2019","journal-title":"Front. Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5068","DOI":"10.1093\/nar\/gkw386","article-title":"An updated human snoRNAome","volume":"44","author":"Jorjani","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.gene.2007.10.037","article-title":"snoTARGET shows that human orphan snoRNA targets locate close to alternative splice junctions","volume":"408","author":"Bazeley","year":"2008","journal-title":"Gene"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.tcm.2017.08.002","article-title":"Biology and clinical relevance of noncoding sno\/scaRNAs","volume":"28","author":"Cao","year":"2018","journal-title":"Trends Cardiovasc. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1851","DOI":"10.1093\/nsr\/nwaa066","article-title":"Heightened protein-translation activities in mammalian cells and the disease\/treatment implications","volume":"7","author":"Wu","year":"2020","journal-title":"Natl. Sci. Rev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"24246","DOI":"10.1074\/jbc.M314298200","article-title":"Manipulation of alternative splicing by a newly developed inhibitor of Clks","volume":"279","author":"Muraki","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"855","DOI":"10.7164\/antibiotics.55.855","article-title":"GEX1 compounds, novel antitumor antibiotics related to herboxidiene, produced by Streptomyces sp. I. Taxonomy, production, isolation, physicochemical properties and biological activities","volume":"55","author":"Sakai","year":"2002","journal-title":"J. Antibiot."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1021\/cb400695j","article-title":"Pre-mRNA splicing-modulatory pharmacophores: The total synthesis of herboxidiene, a pladienolide-herboxidiene hybrid analog and related derivatives","volume":"9","author":"Lagisetti","year":"2014","journal-title":"ACS Chem. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2648","DOI":"10.1021\/ja067870m","article-title":"Total syntheses, fragmentation studies, and antitumor\/antiproliferative activities of FR901464 and its low picomolar analogue","volume":"129","author":"Albert","year":"2007","journal-title":"J. Am. Chem. Soc."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1021\/cb100356k","article-title":"Sudemycins, novel small molecule analogues of FR901464, induce alternative gene splicing","volume":"6","author":"Fan","year":"2011","journal-title":"ACS Chem. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1038\/onc.2014.60","article-title":"Persistent STAT5 activation in myeloid neoplasms recruits p53 into gene regulation","volume":"34","author":"Girardot","year":"2015","journal-title":"Oncogene"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1186\/s12935-021-01878-z","article-title":"Knockdown of GTF2E2 inhibits the growth and progression of lung adenocarcinoma via RPS4X in vitro and in vivo","volume":"21","author":"Bi","year":"2021","journal-title":"Cancer Cell Int."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"D100","DOI":"10.1093\/nar\/gky1128","article-title":"GTRD: A database on gene transcription regulation-2019 update","volume":"47","author":"Yevshin","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1016\/j.tem.2017.07.003","article-title":"Surviving Stress: Modulation of ATF4-Mediated Stress Responses in Normal and Malignant Cells","volume":"28","author":"Wortel","year":"2017","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1016\/j.cell.2012.03.042","article-title":"Ferroptosis: An iron-dependent form of nonapoptotic cell death","volume":"149","author":"Dixon","year":"2012","journal-title":"Cell"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2027","DOI":"10.1083\/jcb.201702058","article-title":"Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals","volume":"216","author":"Prado","year":"2017","journal-title":"J. Cell Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1007\/s00441-014-1862-4","article-title":"Histone variants: Key players of chromatin","volume":"356","author":"Biterge","year":"2014","journal-title":"Cell Tissue Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"31","DOI":"10.3892\/wasj.2021.102","article-title":"Phosphorylation of histone H2A.X as a DNA-associated biomarker (Review)","volume":"3","author":"Stope","year":"2021","journal-title":"World Acad. Sci. J."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"5678","DOI":"10.1093\/nar\/gkn550","article-title":"Gamma-H2AX in recognition and signaling of DNA double-strand breaks in the context of chromatin","volume":"36","author":"Kinner","year":"2008","journal-title":"Nucleic Acids Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1038\/cdd.2017.169","article-title":"How does p53 induce apoptosis and how does this relate to p53-mediated tumour suppression?","volume":"25","author":"Aubrey","year":"2018","journal-title":"Cell Death Differ."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"17046","DOI":"10.1038\/nrdp.2017.46","article-title":"Multiple myeloma","volume":"3","author":"Kumar","year":"2017","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/2050-7771-1-13","article-title":"The resistance mechanisms of proteasome inhibitor bortezomib","volume":"1","author":"Wang","year":"2013","journal-title":"Biomak. Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"6508","DOI":"10.1021\/acs.orglett.6b03480","article-title":"Directed Synthesis of All Four Pure Stereoisomers of the N,C-coupled naphthylisoquinoline alkaloid ancistrocladinium A","volume":"18","author":"Seupel","year":"2016","journal-title":"Org. Lett."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1021\/ja9097687","article-title":"Total synthesis of the N,C-coupled naphthylisoquinoline alkaloids ancistrocladinium A and B and related analogues","volume":"132","author":"Bringmann","year":"2010","journal-title":"J. Am. Chem. Soc."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1038\/leu.2016.264","article-title":"Pan-Raf co-operates with PI3K-dependent signalling and critically contributes to myeloma cell survival independently of mutated RAS","volume":"31","author":"Bauer","year":"2017","journal-title":"Leukemia"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"4147","DOI":"10.1021\/acs.jmedchem.6b01613","article-title":"Ugi reaction-derived alpha-Acyl aminocarboxamides bind to Phosphatidylinositol 3-Kinase-Related Kinases, inhibit HSF1-dependent heat shock response, and induce apoptosis in multiple myeloma cells","volume":"60","author":"Bach","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1111\/j.1365-2141.2010.08126.x","article-title":"Preclinical anti-myeloma activity of the novel HDAC-inhibitor JNJ-26481585","volume":"149","author":"Arts","year":"2010","journal-title":"Br. J. Haematol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/ng1180","article-title":"PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes","volume":"34","author":"Mootha","year":"2003","journal-title":"Nat. Genet."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/16\/8\/1181\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:37:08Z","timestamp":1760128628000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/16\/8\/1181"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,18]]},"references-count":58,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2023,8]]}},"alternative-id":["ph16081181"],"URL":"https:\/\/doi.org\/10.3390\/ph16081181","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,18]]}}}