{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T01:11:02Z","timestamp":1774487462716,"version":"3.50.1"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,8,8]],"date-time":"2024-08-08T00:00:00Z","timestamp":1723075200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>Multiple myeloma (MM) remains a challenging condition to cure, with persistent drug resistance negating the benefits of treatment advancements. The unraveling complexities in programmed cell death (PCD), inclusive of apoptosis, autophagy, and ferroptosis, have highlighted novel therapeutic avenues. Our study focuses on deciphering how adapalene (ADA), a small molecule compound, accelerates the demise of MM cells via targeting their compensatory survival mechanisms.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To assess the impact of ADA on MM, we employed flow cytometry and trypan blue exclusion assays to determine cell viabilities across MM cell lines and primary patient samples post-treatment. To delineate ADA\u2019s therapeutic targets and mechanisms, we conducted RNA sequencing (RNA-seq), gene set enrichment analysis (GSEA), molecular docking, and molecular dynamics simulations. We further designed pre-clinical trials emphasizing MM, exploring the efficacy of ADA as a standalone and in combination with bortezomib (BTZ).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>ADA elicited a dose-responsive induction of MM cell death. Building upon ADA\u2019s anti-MM capabilities as a single agent, we proposed that ADA-BTZ co-treatment might amplify this lethality. Indeed, ADA and BTZ together greatly potentiated MM cell death. ADA proved beneficial in restoring BTZ susceptibility in BTZ-resistant relapsed or refractory MM (RRMM) patient cells. Molecular simulations highlighted ADA\u2019s high affinity (\u22129.17\u00a0kcal\/mol) for CD138, with MM-GBSA revealing a binding free energy of \u221227.39\u00a0kcal\/mol. Detailed interaction analyses indicated hydrogen-bonding of ADA with CD138 at the Asp35 and Gln34 residues. Additionally, ADA emerged as a versatile instigator of both ferroptosis and apoptosis in MM cells. Furthermore, ADA disrupted activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-\u03baB) pathway triggered by BTZ, fostering cell death in BTZ-resistant MM subsets.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>ADA demonstrates a comprehensive capability to orchestrate MM cell death, exerting pronounced anti-MM activity while disrupting NF-\u03baB-related drug resistance. ADA sensitization of MM cells to BTZ unravels its potential as a novel therapeutic drug for MM management.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2024.1415224","type":"journal-article","created":{"date-parts":[[2024,8,8]],"date-time":"2024-08-08T04:26:35Z","timestamp":1723091195000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Multidimensional role of adapalene in regulating cell death in multiple myeloma"],"prefix":"10.3389","volume":"15","author":[{"given":"Xinya","family":"Cao","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jie","family":"Xiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinwen","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dongming","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yong","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peipei","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bing","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hua","family":"Bai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2024,8,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"153371","DOI":"10.1016\/j.phymed.2020.153371","article-title":"Cytotoxicity of apigenin toward multiple myeloma cell lines and suppression of iNOS and COX-2 expression in STAT1-transfected HEK293 cells","volume":"80","author":"Adham","year":"","journal-title":"Phytomedicine Int. J. phytotherapy Phytopharm."},{"key":"B2","doi-asserted-by":"publisher","first-page":"113458","DOI":"10.1016\/j.jep.2020.113458","article-title":"Cytotoxicity and apoptosis induction by Fumaria officinalis extracts in leukemia and multiple myeloma cell lines","volume":"266","author":"Adham","year":"","journal-title":"J. Ethnopharmacol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"4136","DOI":"10.3390\/cancers15164136","article-title":"In silico, in vitro, and in vivo investigations on adapalene as repurposed third generation retinoid against multiple myeloma and leukemia","volume":"15","author":"Boulos","year":"2023","journal-title":"Cancers."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1285","DOI":"10.1016\/j.addr.2010.07.003","article-title":"Retinoid pathway and cancer therapeutics","volume":"62","author":"Bushue","year":"2010","journal-title":"Adv. drug Deliv. Rev."},{"key":"B5","doi-asserted-by":"publisher","first-page":"953","DOI":"10.1080\/14740338.2018.1513487","article-title":"The safety of bortezomib for the treatment of multiple myeloma","volume":"17","author":"Cengiz Seval","year":"2018","journal-title":"Expert Opin. drug Saf."},{"key":"B6","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1023\/a:1024164700094","article-title":"Mechanisms of cell death and survival in multiple myeloma (MM): therapeutic implications","volume":"8","author":"Chauhan","year":"2003","journal-title":"Int. J. Program. Cell. death"},{"key":"B7","doi-asserted-by":"publisher","first-page":"22129","DOI":"10.1039\/c6cp03670h","article-title":"Assessing the performance of the MM\/PBSA and MM\/GBSA methods. 6. Capability to predict protein-protein binding free energies and re-rank binding poses generated by protein-protein docking","volume":"18","author":"Chen","year":"2016","journal-title":"Phys. Chem. Chem. Phys. PCCP"},{"key":"B8","doi-asserted-by":"publisher","first-page":"2287","DOI":"10.3390\/cells10092287","article-title":"Omega-3 fatty acids DHA and EPA reduce bortezomib resistance in multiple myeloma cells by promoting glutathione degradation","volume":"10","author":"Chen","year":"2021","journal-title":"Cells"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1425","DOI":"10.7534\/j.issn.1009-2137.2018.05.028","article-title":"Effects of luteolin on proliferation and programmed cell death of human multiple myeloma cell RPMI-8226","volume":"26","author":"Chen","year":"2018","journal-title":"Zhongguo shi yan xue ye xue za zhi"},{"key":"B10","doi-asserted-by":"publisher","first-page":"2866","DOI":"10.1093\/bioinformatics\/btw230","article-title":"Combenefit: an interactive platform for the analysis and visualization of drug combinations","volume":"32","author":"Di Veroli","year":"2016","journal-title":"Bioinformatics"},{"key":"B11","doi-asserted-by":"publisher","first-page":"472","DOI":"10.4081\/oncol.2020.472","article-title":"Apoptosis and genes involved in oral cancer - a comprehensive review","volume":"14","author":"Dwivedi","year":"2020","journal-title":"Oncol. Rev."},{"key":"B12","doi-asserted-by":"publisher","first-page":"342","DOI":"10.1038\/35077213","article-title":"Proliferation, cell cycle and apoptosis in cancer","volume":"411","author":"Evan","year":"2001","journal-title":"Nature"},{"key":"B13","doi-asserted-by":"publisher","first-page":"784983","DOI":"10.3389\/fcell.2021.784983","article-title":"The role and therapeutic value of syndecan-1 in cancer metastasis and drug resistance","volume":"9","author":"Guo","year":"2021","journal-title":"Front. Cell. Dev. Biol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"674","DOI":"10.1111\/1440-1681.13643","article-title":"Solamargine induces autophagy-mediated apoptosis and enhances bortezomib activity in multiple myeloma","volume":"49","author":"Han","year":"2022","journal-title":"Clin. Exp. Pharmacol. physiology"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1046","DOI":"10.1182\/blood-2009-01-199604","article-title":"Bortezomib induces canonical nuclear factor-kappaB activation in multiple myeloma cells","volume":"114","author":"Hideshima","year":"2009","journal-title":"Blood"},{"key":"B16","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1007\/s10495-022-01721-4","article-title":"Nobiletin as an inducer of programmed cell death in cancer: a review","volume":"27","author":"Huang","year":"2022","journal-title":"Int. J. Program. Cell. death"},{"key":"B17","doi-asserted-by":"publisher","first-page":"2452","DOI":"10.1074\/jbc.RA117.000667","article-title":"Hyaluronan and proteoglycan link protein 1 (HAPLN1) activates bortezomib-resistant NF-\u03baB activity and increases drug resistance in multiple myeloma","volume":"293","author":"Huynh","year":"2018","journal-title":"J. Biol. Chem."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1145","DOI":"10.1111\/jphp.13273","article-title":"Drug repositioning: a brief overview","volume":"72","author":"Jourdan","year":"2020","journal-title":"J. Pharm. Pharmacol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"4968","DOI":"10.3390\/ijms20194968","article-title":"Programmed cell-death by ferroptosis: antioxidants as mitigators","volume":"20","author":"Kajarabille","year":"2019","journal-title":"Int. J. Mol. Sci."},{"key":"B20","doi-asserted-by":"publisher","first-page":"26085","DOI":"10.1074\/jbc.M109.018473","article-title":"Syndecan-1 is required for robust growth, vascularization, and metastasis of myeloma tumors in vivo","volume":"284","author":"Khotskaya","year":"2009","journal-title":"J. Biol. Chem."},{"key":"B21","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/j.freeradbiomed.2017.02.039","article-title":"Regulation of STAT3 and NF-\u03baB activations by S-nitrosylation in multiple myeloma","volume":"106","author":"Kim","year":"2017","journal-title":"Free Radic. Biol. Med."},{"key":"B22","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1007\/s12272-022-01384-4","article-title":"Adapalene induces adipose browning through the RAR\u03b2-p38 MAPK-ATF2 pathway","volume":"45","author":"Lee","year":"2022","journal-title":"Archives pharmacal Res."},{"key":"B23","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1016\/j.ejphar.2019.03.004","article-title":"Adapalene suppressed the proliferation of melanoma cells by S-phase arrest and subsequent apoptosis via induction of DNA damage","volume":"851","author":"Li","year":"2019","journal-title":"Eur. J. Pharmacol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1025067","DOI":"10.3389\/fonc.2022.1025067","article-title":"Shikonin induces ferroptosis in multiple myeloma via GOT1-mediated ferritinophagy","volume":"12","author":"Li","year":"2022","journal-title":"Front. Oncol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"e0158760","DOI":"10.1371\/journal.pone.0158760","article-title":"All-trans retinoic acid plus arsenic trioxide versus all-trans retinoic acid plus chemotherapy for newly diagnosed acute promyelocytic leukemia: a meta-analysis","volume":"11","author":"Ma","year":"2016","journal-title":"PloS one"},{"key":"B26","doi-asserted-by":"publisher","first-page":"1356","DOI":"10.1158\/1541-7786.MCR-08-0108","article-title":"Bortezomib-resistant nuclear factor-kappaB activity in multiple myeloma cells","volume":"6","author":"Markovina","year":"2008","journal-title":"Mol. Cancer Res."},{"key":"B27","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1016\/j.bioorg.2011.07.003","article-title":"New synthesis of 6[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid and evaluation of the influence of adamantyl group on the DNA binding of a naphthoic retinoid","volume":"39","author":"Milanese","year":"2011","journal-title":"Bioorg. Chem."},{"key":"B28","doi-asserted-by":"publisher","first-page":"17187","DOI":"10.1002\/jcp.28504","article-title":"NF-\u03baB targeting for overcoming tumor resistance and normal tissues toxicity","volume":"234","author":"Mortezaee","year":"2019","journal-title":"J. Cell. physiology"},{"key":"B29","doi-asserted-by":"publisher","first-page":"801624","DOI":"10.3389\/fphar.2022.801624","article-title":"Adapalene inhibits prostate cancer cell proliferation in vitro and in vivo by inducing DNA damage, S-phase cell cycle arrest, and apoptosis","volume":"13","author":"Nong","year":"2022","journal-title":"Front. Pharmacol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1002\/ijc.11410","article-title":"The synthetic retinoid adapalene inhibits proliferation and induces apoptosis in colorectal cancer cells in vitro","volume":"107","author":"Ocker","year":"2003","journal-title":"Int. J. cancer"},{"key":"B31","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/j.canlet.2003.12.026","article-title":"Potentiated anticancer effects on hepatoma cells by the retinoid adapalene","volume":"208","author":"Ocker","year":"2004","journal-title":"Cancer Lett."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1123","DOI":"10.1038\/leu.2016.325","article-title":"Epigenetic silencing of miR-137 induces drug resistance and chromosomal instability by targeting AURKA in multiple myeloma","volume":"31","author":"Qin","year":"2017","journal-title":"Leukemia"},{"key":"B33","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1002\/bmb.20966","article-title":"Using the PyMOL application to reinforce visual understanding of protein structure","volume":"44","author":"Rigsby","year":"2016","journal-title":"Biochem. Mol. Biol. Educ. a Bimon. Publ. Int. Union Biochem. Mol. Biol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"2197","DOI":"10.1016\/S0140-6736(14)60493-1","article-title":"Multiple myeloma","volume":"385","author":"R\u00f6llig","year":"2015","journal-title":"Lancet"},{"key":"B35","doi-asserted-by":"publisher","first-page":"217","DOI":"10.3390\/ph13090217","article-title":"Recent advances regarding the therapeutic potential of adapalene","volume":"13","author":"Rusu","year":"2020","journal-title":"Pharm. (Basel, Switz.)"},{"key":"B36","doi-asserted-by":"publisher","first-page":"S96","DOI":"10.1016\/s0190-9622(97)70050-1","article-title":"Pharmacology and chemistry of adapalene","volume":"36","author":"Shroot","year":"1997","journal-title":"J. Am. Acad. Dermatology"},{"key":"B37","first-page":"253","article-title":"Effects of all-trans retinoic acid and antireceptor antibodies on growth and programmed cell death of human myeloma cells","volume":"2","author":"Taetle","year":"1996","journal-title":"Clin. Cancer Res."},{"key":"B38","volume-title":"Disclosure: heidi Dearborn declares no relevant financial relationships with ineligible companies. Disclosure: patrick Zito declares no relevant financial relationships with ineligible companies.: \u00a9 2024","author":"Tolaymat","year":"2024"},{"key":"B39","doi-asserted-by":"publisher","first-page":"1386","DOI":"10.1080\/19420862.2016.1207030","article-title":"Targeted immunotherapy using anti-CD138-interferon \u03b1 fusion proteins and bortezomib results in synergistic protection against multiple myeloma","volume":"8","author":"Vasuthasawat","year":"2016","journal-title":"mAbs"},{"key":"B40","doi-asserted-by":"publisher","first-page":"723","DOI":"10.1007\/s00228-023-03486-4","article-title":"Drug repositioning in the COVID-19 pandemic: fundamentals, synthetic routes, and overview of clinical studies","volume":"79","author":"Vaz","year":"2023","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"103315","DOI":"10.1016\/j.bioorg.2019.103315","article-title":"Adapalene inhibits ovarian cancer ES-2 cells growth by targeting glutamic-oxaloacetic transaminase 1","volume":"93","author":"Wang","year":"2019","journal-title":"Bioorg. Chem."},{"key":"B42","doi-asserted-by":"publisher","first-page":"110557","DOI":"10.1016\/j.mehy.2021.110557","article-title":"Etoricoxib may inhibit cytokine storm to treat COVID-19","volume":"150","author":"Wang","year":"2021","journal-title":"Med. hypotheses"},{"key":"B43","doi-asserted-by":"publisher","first-page":"600","DOI":"10.1182\/blood-2008-12-194126","article-title":"RARalpha2 expression is associated with disease progression and plays a crucial role in efficacy of ATRA treatment in myeloma","volume":"114","author":"Wang","year":"2009","journal-title":"Blood"},{"key":"B44","doi-asserted-by":"publisher","first-page":"W296","DOI":"10.1093\/nar\/gky427","article-title":"SWISS-MODEL: homology modelling of protein structures and complexes","volume":"46","author":"Waterhouse","year":"2018","journal-title":"Nucleic acids Res."},{"key":"B45","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1089\/jir.2014.0125","article-title":"Anti-CD138-targeted interferon is a potent therapeutic against multiple myeloma","volume":"35","author":"Yoo","year":"2015","journal-title":"J. Interferon Cytokine Res."},{"key":"B46","doi-asserted-by":"publisher","first-page":"1692","DOI":"10.1182\/blood-2006-07-037077","article-title":"Gene-expression signature of benign monoclonal gammopathy evident in multiple myeloma is linked to good prognosis","volume":"109","author":"Zhan","year":"2007","journal-title":"Blood"},{"key":"B47","doi-asserted-by":"publisher","first-page":"2020","DOI":"10.1182\/blood-2005-11-013458","article-title":"The molecular classification of multiple myeloma","volume":"108","author":"Zhan","year":"2006","journal-title":"Blood"},{"key":"B48","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1186\/s12943-022-01530-y","article-title":"Ferroptosis in cancer therapy: a novel approach to reversing drug resistance","volume":"21","author":"Zhang","year":"2022","journal-title":"Mol. cancer"},{"key":"B49","doi-asserted-by":"publisher","first-page":"118077","DOI":"10.1016\/j.lfs.2020.118077","article-title":"FTY720 induces ferroptosis and autophagy via PP2A\/AMPK pathway in multiple myeloma cells","volume":"260","author":"Zhong","year":"2020","journal-title":"Life Sci."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2024.1415224\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,8]],"date-time":"2024-08-08T04:26:44Z","timestamp":1723091204000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2024.1415224\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,8]]},"references-count":49,"alternative-id":["10.3389\/fphar.2024.1415224"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2024.1415224","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,8]]},"article-number":"1415224"}}