{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:49:28Z","timestamp":1787028568789,"version":"build-2736575974"},"reference-count":133,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T00:00:00Z","timestamp":1754870400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Bryostatin 1, a natural macrolide isolated from Bugula neritina, is a potent modulator of protein kinase C (PKC) isoforms with promising anticancer properties. In numerous in vitro studies, bryostatin 1 has been shown to inhibit tumor cell proliferation and induce differentiation and apoptotic cell death in a wide range of cell lines, including leukemia, lymphoma, glioma, and solid tumors such as ovarian and breast cancer. Its antitumor activity, both as monotherapy and in combination with conventional chemotherapy, has been confirmed in in vivo models, where synergistic effects have been observed, including sensitization of tumor cells to cytostatic agents. Despite promising preclinical findings, phase I and II clinical trials have not yielded the expected results, suggesting limited efficacy of the macrolide as a single agent with a relatively favorable safety profile. Current research directions focus on optimizing dosing regimens, combining bryostatin 1 with other anticancer drugs and identifying predictive biomarkers of response. This article reviews the current state of knowledge on the anticancer effects of bryostatin 1, analyzing available data from in vitro, in vivo, and clinical trials and discussing potential directions for further translational research.<\/jats:p>","DOI":"10.3390\/ijms26167765","type":"journal-article","created":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T14:32:36Z","timestamp":1754922756000},"page":"7765","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Anticancer Activity of the Marine-Derived Compound Bryostatin 1: Preclinical and Clinical Evaluation"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4559-5015","authenticated-orcid":false,"given":"Tomasz","family":"Kowalczyk","sequence":"first","affiliation":[{"name":"Department of Molecular Biotechnology and Genetics, Faculty of Biology and Environmental Protection, University of Lodz, Banacha 12\/16, 90-237 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2783-522X","authenticated-orcid":false,"given":"Marek","family":"Staszewski","sequence":"additional","affiliation":[{"name":"Department of Synthesis and Technology of Drugs, Medical University of Lodz, Muszynskiego 1, 90-151 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1012-6550","authenticated-orcid":false,"given":"Magdalena","family":"Markowicz-Piasecka","sequence":"additional","affiliation":[{"name":"Department of Applied Pharmacy, Medical University of Lodz, Muszynskiego 1, 90-151 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7044-9696","authenticated-orcid":false,"given":"Joanna","family":"Sikora","sequence":"additional","affiliation":[{"name":"Department of Bioinorganic Chemistry, Medical University of Lodz, Muszynskiego 1, 90-151 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catarina","family":"Amaro","sequence":"additional","affiliation":[{"name":"Students Research Group (Erasmus Student), Department of Medical Biology, Medical University of Lodz, 90-151 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4656-3557","authenticated-orcid":false,"given":"Laurent","family":"Picot","sequence":"additional","affiliation":[{"name":"Littoral Environnement et Soci\u00e9t\u00e9s UMRi CNRS 7266 LIENSs, La Rochelle Universit\u00e9, 17042 La Rochelle, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5495-3550","authenticated-orcid":false,"given":"Przemys\u0142aw","family":"Sitarek","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Medical University of Lodz, Muszynskiego 1, 90-151 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,11]]},"reference":[{"key":"ref_1","unstructured":"(2025, March 31). World Health Organization (WHO) Cancer. Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/cancer."},{"key":"ref_2","unstructured":"(2025, March 31). Cancer TODAY DataViz. Available online: https:\/\/gco.iarc.fr\/today\/en\/dataviz\/pie?mode=population&group_populations=0."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Sharifi-Rad, J., Ozleyen, A., Boyunegmez Tumer, T., Oluwaseun Adetunji, C., El Omari, N., Balahbib, A., Taheri, Y., Bouyahya, A., Martorell, M., and Martins, N. (2019). Natural Products and Synthetic Analogs as a Source of Antitumor Drugs. Biomolecules, 9.","DOI":"10.3390\/biom9110679"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Naeem, A., Hu, P., Yang, M., Zhang, J., Liu, Y., Zhu, W., and Zheng, Q. (2022). Natural Products as Anticancer Agents: Current Status and Future Perspectives. Molecules, 27.","DOI":"10.3390\/molecules27238367"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Hashem, S., Ali, T.A., Akhtar, S., Nisar, S., Sageena, G., Ali, S., Al-Mannai, S., Therachiyil, L., Mir, R., and Elfaki, I. (2022). Targeting Cancer Signaling Pathways by Natural Products: Exploring Promising Anti-Cancer Agents. Biomed. Pharmacother., 150.","DOI":"10.1016\/j.biopha.2022.113054"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/B978-0-444-59603-1.00008-4","article-title":"Marine Resource: A Promising Future for Anticancer Drugs","volume":"40","author":"Gupta","year":"2013","journal-title":"Stud. Nat. Prod. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Khalifa, S.A.M., Elias, N., Farag, M.A., Chen, L., Saeed, A., Hegazy, M.-E.F., Moustafa, M.S., Abd El-Wahed, A., Al-Mousawi, S.M., and Musharraf, S.G. (2019). Marine Natural Products: A Source of Novel Anticancer Drugs. Mar. Drugs, 17.","DOI":"10.3390\/md17090491"},{"key":"ref_8","first-page":"740","article-title":"Recent Advances in Marine-Derived Bioactives towards Cancer Therapy","volume":"4","author":"Tamzi","year":"2024","journal-title":"Int. J. Transl. Med."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Barreca, M., Span\u00f2, V., Montalbano, A., Cueto, M., D\u00edaz Marrero, A.R., Deniz, I., Erdo\u011fan, A., Luki\u0107 Bilela, L., Moulin, C., and Taffin-de-Givenchy, E. (2020). Marine Anticancer Agents: An Overview with a Particular Focus on Their Chemical Classes. Mar. Drugs, 18.","DOI":"10.3390\/md18120619"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Wu, L., Ye, K., Jiang, S., and Zhou, G. (2021). Marine Power on Cancer: Drugs, Lead Compounds, and Mechanisms. Mar. Drugs, 19.","DOI":"10.3390\/md19090488"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1527-3458.2006.00001.x","article-title":"Bryostatin-1: Pharmacology and Therapeutic Potential as a CNS Drug","volume":"12","author":"Sun","year":"2006","journal-title":"CNS Drug Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1081\/CNV-120025095","article-title":"Bryostatin-1: A Novel PKC Inhibitor in Clinical Development","volume":"21","author":"Kortmansky","year":"2003","journal-title":"Cancer Investig."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1016\/j.copbio.2010.09.018","article-title":"Bryostatins: Biological Context and Biotechnological Prospects","volume":"21","author":"Sharp","year":"2010","journal-title":"Curr. Opin. Biotechnol."},{"key":"ref_14","unstructured":"(2025, April 02). Smithsonian Environmental Research Center Bugula Neritina. Available online: https:\/\/invasions.si.edu\/nemesis\/species_summary\/-95."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1038\/ismej.2007.78","article-title":"Localization of \u201cCandidatus Endobugula Sertula\u201d and the Bryostatins throughout the Life Cycle of the Bryozoan Bugula Neritina","volume":"1","author":"Sharp","year":"2007","journal-title":"ISME J."},{"key":"ref_16","unstructured":"(2025, April 01). National Library of Medicine (NIH) Bryostatin 1, Available online: https:\/\/pubchem.ncbi.nlm.nih.gov\/compound\/5280757."},{"key":"ref_17","unstructured":"(2025, April 01). Sigma Aldrich NMR Chemical Shifts of Impurities. Available online: https:\/\/www.sigmaaldrich.com\/MX\/en\/technical-documents\/technical-article\/genomics\/cloning-and-expression\/blue-white-screening."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Saeed, A.F.U.H., Su, J., and Ouyang, S. (2021). Marine-Derived Drugs: Recent Advances in Cancer Therapy and Immune Signaling. Biomed. Pharmacother., 134.","DOI":"10.1016\/j.biopha.2020.111091"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Quit\u00e9rio, E., Soares, C., Ferraz, R., Delerue-Matos, C., and Grosso, C. (2021). Marine Health-Promoting Compounds: Recent Trends for Their Characterization and Human Applications. Foods, 10.","DOI":"10.3390\/foods10123100"},{"key":"ref_20","unstructured":"(2025, April 01). DrugBank Trabectedin. Available online: https:\/\/go.drugbank.com\/drugs\/DB05109."},{"key":"ref_21","unstructured":"(2025, April 01). Smithsonian Environmental Research Center Ecteinascidia Turbinata. Available online: https:\/\/invasions.si.edu\/nemesis\/species_summary\/159142."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1007\/s00280-015-2918-1","article-title":"Unique Features of Trabectedin Mechanism of Action","volume":"77","author":"Larsen","year":"2015","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Gadducci, A., and Cosio, S. (2022). Trabectedin and Lurbinectedin: Mechanisms of Action, Clinical Impact, and Future Perspectives in Uterine and Soft Tissue Sarcoma, Ovarian Carcinoma, and Endometrial Carcinoma. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.914342"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1641","DOI":"10.2217\/fon-2018-0936","article-title":"Perspectives on the Mechanism of Action and Clinical Application of Eribulin for Metastatic Breast Cancer","volume":"15","author":"Kaklamani","year":"2019","journal-title":"Future Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"57","DOI":"10.4103\/2278-330X.126527","article-title":"Eribulin Drug Review","volume":"3","author":"Shetty","year":"2014","journal-title":"South Asian J. Cancer"},{"key":"ref_26","first-page":"227","article-title":"Case History: Discovery of Eribulin (HALAVENTM), a Halichondrin B Analogue That Prolongs Overall Survival in Patients with Metastatic Breast Cancer","volume":"46","author":"Yu","year":"2011","journal-title":"Annu. Rep. Med. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"157","DOI":"10.52586\/S559","article-title":"Multifarious Targets beyond Microtubules\u2014Role of Eribulin in Cancer Therapy","volume":"13","author":"Seshadri","year":"2021","journal-title":"Front. Biosci.-Sch."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"253","DOI":"10.2147\/DDDT.S94165","article-title":"Plitidepsin: Design, Development, and Potential Place in Therapy","volume":"11","author":"Pardal","year":"2017","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_29","unstructured":"(2025, April 01). Washington Invasive Species Council Tunicate, Available online: https:\/\/invasivespecies.wa.gov\/priorityspecies\/tunicate\/."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Losada, A., Mu\u00f1oz-Alonso, M.J., Garc\u00eda, C., S\u00e1nchez-Murcia, P.A., Mart\u00ednez-Leal, J.F., Dom\u00ednguez, J.M., Lillo, M.P., Gago, F., and Galmarini, C.M. (2016). Translation Elongation Factor EEF1A2 Is a Novel Anticancer Target for the Marine Natural Product Plitidepsin. Sci. Rep., 6.","DOI":"10.1038\/srep35100"},{"key":"ref_31","unstructured":"(2018). European Medicines Agency Annex Scientific Conclusions and Grounds for Refusal Presented by the European Medicines Agency."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1007\/s40199-019-00273-4","article-title":"Marine Anticancer Drugs and Their Relevant Targets: A Treasure from the Ocean","volume":"27","author":"Nigam","year":"2019","journal-title":"DARU J. Pharm. Sci."},{"key":"ref_33","unstructured":"(2025, July 26). DrugBank Cytarabine. Available online: https:\/\/go.drugbank.com\/drugs\/DB00987."},{"key":"ref_34","first-page":"239","article-title":"Lagoon sponges from carrie bow cay (Belize): Ecological benefits of selective sediment incorporation","volume":"68","author":"Cerrano","year":"2004","journal-title":"BMIB-Boll. Dei Musei E Degli Ist. Biol."},{"key":"ref_35","unstructured":"(2025, July 26). DrugBank Vidarabine. Available online: https:\/\/go.drugbank.com\/drugs\/DB00194."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2619","DOI":"10.3390\/md8102619","article-title":"Antiviral Lead Compounds from Marine Sponges","volume":"8","author":"Sagar","year":"2010","journal-title":"Mar. Drugs"},{"key":"ref_37","first-page":"435","article-title":"Analgesic and Antipyretic Natural Products","volume":"55","author":"Shilpi","year":"2020","journal-title":"Annu. Rep. Med. Chem."},{"key":"ref_38","first-page":"79","article-title":"Bioassays for Bioactivity Screening","volume":"65","author":"Singh","year":"2014","journal-title":"Compr. Anal. Chem."},{"key":"ref_39","unstructured":"(2025, July 26). DrugBank Ziconotide. Available online: https:\/\/go.drugbank.com\/drugs\/DB06283."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.2174\/1568026620666200325110444","article-title":"Preclinical and Clinical Studies on Bryostatins, a Class of Marine-Derived Protein Kinase c Modulators: A Mini-Review","volume":"20","author":"Raghuvanshi","year":"2020","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"273","DOI":"10.2307\/1542952","article-title":"Identification of Sibling Species of the Bryozoan Bugula Neritina That Produce Different Anticancer Bryostatins and Harbor Distinct Strains of the Bacterial Symbiont \u201cCandidatus Endobugula Sertula\u201d","volume":"196","author":"Davidson","year":"1999","journal-title":"Biol. Bull."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/bs.mie.2018.01.034","article-title":"Chemoenzymatic Dissection of Polyketide \u03b2-Branching in the Bryostatin Pathway","volume":"604","author":"Slocum","year":"2018","journal-title":"Methods Enzymol."},{"key":"ref_43","first-page":"135","article-title":"Nature as Source of Medicines; Novel Drugs from Nature; Screening for Antitumor Activity","volume":"3","author":"Cragg","year":"2010","journal-title":"Compr. Nat. Prod. II"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1021\/cb300671s","article-title":"Biological Profile of the Less Lipophilic and Synthetically More Accessible Bryostatin 7 Closely Resembles that of Bryostatin 1","volume":"8","author":"Kedei","year":"2013","journal-title":"ACS Chem. Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1126\/science.abb7271","article-title":"Total Synthesis of Bryostatin 3","volume":"368","author":"Trost","year":"2020","journal-title":"Science"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"7540","DOI":"10.1021\/ja990860j","article-title":"Total Synthesis of Bryostatin 2","volume":"121","author":"Evans","year":"1999","journal-title":"J. Am. Chem. Soc."},{"key":"ref_47","unstructured":"(2025, April 02). DrugBank Bryostatin 1: Uses, Interactions, Mechanism of Action|DrugBank Online. Available online: https:\/\/go.drugbank.com\/drugs\/DB11752."},{"key":"ref_48","unstructured":"(2025, April 02). National Library of Medicine (NIH) Antineoplastic Agents\u2014MeSH\u2014NCBI, Available online: https:\/\/www.ncbi.nlm.nih.gov\/mesh\/68000970."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"e202423465","DOI":"10.1002\/anie.202423465","article-title":"Total Syntheses of Bryostatins 1, 7, 9 and 9-N3","volume":"64","author":"Guo","year":"2025","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"6846","DOI":"10.1021\/ja00388a092","article-title":"Isolation and Structure of Bryostatin 1","volume":"104","author":"Pettit","year":"1982","journal-title":"J. Am. Chem. Soc."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1021\/np060361d","article-title":"Identification of the Putative Bryostatin Polyketide Synthase Gene Cluster from \u201cCandidatusEndobugula Sertula\u201d, the Uncultivated Microbial Symbiont of the Marine BryozoanBugula Neritina","volume":"70","author":"Sudek","year":"2007","journal-title":"J. Nat. Prod."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"6573","DOI":"10.1128\/AEM.01800-16","article-title":"Lack of Overt Genome Reduction in the Bryostatin-Producing Bryozoan Symbiont \u201cCandidatus Endobugula Sertula\u201d","volume":"82","author":"Miller","year":"2016","journal-title":"Appl. Environ. Microbiol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1021\/np50077a004","article-title":"The Large-Scale Isolation of Bryostatin 1 from Bugula Neritina Following Current Good Manufacturing Practices","volume":"54","author":"Schaufelberger","year":"1991","journal-title":"J. Nat. Prod."},{"key":"ref_54","unstructured":"Castor, T.P. (1998). Method and Apparatus for Isolating Therapeutic Compositions from Source Materials 1998. (5,750,709), U.S. Patent."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1021\/ja110198y","article-title":"Total Synthesis of Bryostatin 1","volume":"133","author":"Keck","year":"2010","journal-title":"J. Am. Chem. Soc."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2149","DOI":"10.1021\/ol050511w","article-title":"Synthetic Studies on the Bryostatins: Preparation of a Truncated BC-Ring Intermediate by Pyran Annulation","volume":"7","author":"Keck","year":"2005","journal-title":"Org. Lett."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"8267","DOI":"10.1016\/j.tetlet.2006.09.094","article-title":"Synthetic Studies toward Bryostatin 1: Preparation of a C1\u2013C16 Fragment by Pyran Annulation","volume":"47","author":"Keck","year":"2006","journal-title":"Tetrahedron Lett."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1126\/science.aan7969","article-title":"Scalable Synthesis of Bryostatin 1 and Analogs, Adjuvant Leads against Latent HIV","volume":"358","author":"Wender","year":"2017","journal-title":"Science"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"4374","DOI":"10.1021\/ja00767a075","article-title":"Selective Carbon-Carbon Bond Formation by Cross-Coupling of Grignard Reagents with Organic Halides. Catal. By Nickel-Phosphine Complexes","volume":"94","author":"Tamao","year":"1972","journal-title":"J. Am. Chem. Soc."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Corriu, R.J.P., and Masse, J.P. (1972). Activation of Grignard Reagents by Transition-Metal Complexes. A New and Simple Synthesis of Trans-Stilbenes and Polyphenyls. J. Chem. Soc. Chem. Commun., 144a.","DOI":"10.1039\/c3972000144a"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.cclet.2020.11.039","article-title":"Diverse Synthesis of the c Ring Fragment of Bryostatins via Zn\/Cu-Promoted Conjugate Addition of \u03b1-Hydroxy Iodide with Enone","volume":"32","author":"Chu","year":"2021","journal-title":"Chin. Chem. Lett."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1038\/nrm2847","article-title":"PKC and the Control of Localized Signal Dynamics","volume":"11","author":"Rosse","year":"2010","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1038\/308693a0","article-title":"The Role of Protein Kinase c in Cell Surface Signal Transduction and Tumour Promotion","volume":"308","author":"Nishizuka","year":"1984","journal-title":"Nature"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"117290","DOI":"10.1016\/j.ejmech.2025.117290","article-title":"Recent Advances in PKC Inhibitor Development: Structural Design Strategies and Therapeutic Applications","volume":"287","author":"Li","year":"2025","journal-title":"Eur. J. Med. Chem."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1161\/CIRCRESAHA.110.217117","article-title":"Activation of Protein Kinase c Isoforms and Its Impact on Diabetic Complications","volume":"106","author":"Geraldes","year":"2010","journal-title":"Circ. Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1124\/jpet.107.124669","article-title":"Neuroprotective Effect of Protein Kinase C\u03b4 Inhibitor Rottlerin in Cell Culture and Animal Models of Parkinson\u2019s Disease","volume":"322","author":"Zhang","year":"2007","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.semcancer.2017.04.012","article-title":"Protein Kinase c (PKC) Isoforms in Cancer, Tumor Promotion and Tumor Suppression","volume":"48","author":"Isakov","year":"2018","journal-title":"Semin. Cancer Biol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"531","DOI":"10.3390\/cancers3010531","article-title":"Protein Kinase C: An Attractive Target for Cancer Therapy","volume":"3","author":"Marengo","year":"2011","journal-title":"Cancers"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.tips.2009.10.006","article-title":"Protein Kinase C\u03b1: Disease Regulator and Therapeutic Target","volume":"31","author":"Konopatskaya","year":"2010","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1007\/s12311-017-0898-x","article-title":"Protein Kinase c in the Cerebellum: Its Significance and Remaining Conundrums","volume":"17","author":"Hirai","year":"2018","journal-title":"Cerebellum"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1038\/nrd3871","article-title":"Protein Kinase C, an Elusive Therapeutic Target?","volume":"11","author":"Das","year":"2012","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Tian, Z., Lu, X.-T., Jiang, X., and Tian, J. (2023). Bryostatin-1: A Promising Compound for Neurological Disorders. Front. Pharmacol., 14.","DOI":"10.3389\/fphar.2023.1187411"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1007\/s12031-012-9816-3","article-title":"Bryostatin-1 vs. TPPB: Dose-Dependent APP Processing and PKC-\u03b1, -\u03b4, and -\u03b5 Isoform Activation in SH-SY5Y Neuronal Cells","volume":"48","author":"Yi","year":"2012","journal-title":"J. Mol. Neurosci."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"34514","DOI":"10.1074\/jbc.M109.016683","article-title":"Reduction of \u03b2-Amyloid Levels by Novel Protein Kinase C\u03f5 Activators","volume":"284","author":"Nelson","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"13620","DOI":"10.1073\/pnas.0805952105","article-title":"Poststroke Neuronal Rescue and Synaptogenesis Mediated in Vivo by Protein Kinase c in Adult Brains","volume":"105","author":"Sun","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"555","DOI":"10.3233\/JAD-180759","article-title":"A Randomized, Double-Blind, Placebo-Controlled, Phase II Study Assessing Safety, Tolerability, and Efficacy of Bryostatin in the Treatment of Moderately Severe to Severe Alzheimer\u2019s Disease","volume":"67","author":"Farlow","year":"2019","journal-title":"J. Alzheimer\u2019s Dis. JAD"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1080\/10428190310001639470","article-title":"Bryostatin Induces Protein Kinase c Modulation, Mcl-1 Up-Regulation and Phosphorylation of Bcl-2 Resulting in Cellular Differentiation and Resistance to Drug-Induced Apoptosis in B-Cell Chronic Lymphocytic Leukemia Cells","volume":"45","author":"Thomas","year":"2004","journal-title":"Leuk. Lymphoma"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"34859","DOI":"10.1074\/jbc.274.49.34859","article-title":"P90RSK Blocks Bad-Mediated Cell Death via a Protein Kinase C-Dependent Pathway","volume":"274","author":"Tan","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"25436","DOI":"10.1074\/jbc.273.39.25436","article-title":"A Functional Role for Mitochondrial Protein Kinase C\u03b1 in Bcl2 Phosphorylation and Suppression of Apoptosis","volume":"273","author":"Ruvolo","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_80","first-page":"61","article-title":"Bryostatin 1-Induced Hairy Cell Features on Chronic Lymphocytic Leukemia Cells in Vitro","volume":"21","author":"Mohammad","year":"1993","journal-title":"Exp. Hematol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1515\/bchm.1998.379.10.1253","article-title":"Potentiation of 2-Chlorodeoxyadenosine Activity by Bryostatin 1 in the Resistant Chronic Lymphocytic Leukemia Cell Line (WSU-CLL): Association with Increased Ratios of DCK\/5\u2032-NT and Bax\/Bcl-2","volume":"379","author":"Mohammad","year":"1998","journal-title":"Biol. Chem."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1046\/j.1365-2141.1999.01642.x","article-title":"Bryostatin and CD40-Ligand Enhance Apoptosis Resistance and Induce Expression of Cell Survival Genes in B-Cell Chronic Lymphocytic Leukaemia","volume":"106","author":"Kitada","year":"1999","journal-title":"Br. J. Haematol."},{"key":"ref_83","first-page":"3716","article-title":"Inhibition of Leukemic Cell Growth by the Protein Kinase c Activator Bryostatin 1 Correlates with the Dephosphorylation of Cyclin-Dependent Kinase 2","volume":"55","author":"Asiedu","year":"1995","journal-title":"Cancer Res."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1046\/j.1432-0436.1998.6310033.x","article-title":"Divergent Effects of Bryostatin 1 and Phorbol Myristate Acetate on Cell Cycle Arrest and Maturation in Human Myelomonocytic Leukemia Cells (U937)","volume":"63","author":"Vrana","year":"1998","journal-title":"Differentiation"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/S0006-2952(99)00077-5","article-title":"Inhibition of Protein Kinase c Activator-Mediated Induction of P21CIP1 and P27KIP1 by Deoxycytidine Analogs in Human Leukemia Cells","volume":"58","author":"Vrana","year":"1999","journal-title":"Biochem. Pharmacol."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Rajabi, S., Maresca, M., Yumashev, A.V., Choopani, R., and Hajimehdipoor, H. (2021). The Most Competent Plant-Derived Natural Products for Targeting Apoptosis in Cancer Therapy. Biomolecules, 11.","DOI":"10.3390\/biom11040534"},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Dalisay, D.S., Tenebro, C.P., Sabido, E.M., Faith, A., June, M., Reyes-Salarda, R., and Saludes, J.P. (2024). Marine-Derived Anticancer Agents Targeting Apoptotic Pathways: Exploring the Depths for Novel Cancer Therapies. Mar. Drugs, 22.","DOI":"10.3390\/md22030114"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"100418","DOI":"10.1016\/j.phyplu.2023.100418","article-title":"Understanding Mechanistic Aspects and Therapeutic Potential of Natural Substances as Anticancer Agents","volume":"3","author":"Deep","year":"2023","journal-title":"Phytomed. Plus"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1124\/jpet.301.2.568","article-title":"Bryostatin 1 Increases 1-\u03b2-d-Arabinofuranosylcytosine-Induced Cytochrome c Release and Apoptosis in Human Leukemia Cells Ectopically Expressing Bcl-XL","volume":"301","author":"Wang","year":"2002","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_90","first-page":"165","article-title":"Bryostatin 1 Induces Ubiquitination and Proteasome Degradation of Bcl-2 in the Human Acute Lymphoblastic Leukemia Cell Line, Reh","volume":"5","author":"Wall","year":"2000","journal-title":"Int. J. Mol. Med."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"2105","DOI":"10.1182\/blood.V97.7.2105","article-title":"Synergistic Induction of Apoptosis in Human Leukemia Cells (U937) Exposed to Bryostatin 1 and the Proteasome Inhibitor Lactacystin Involves Dysregulation of the PKC\/MAPK Cascade","volume":"97","author":"Vrana","year":"2001","journal-title":"Blood"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1564","DOI":"10.1038\/sj.leu.2401532","article-title":"Bryostatin 1 Enhances Paclitaxel-Induced Mitochondrial Dysfunction and Apoptosis in Human Leukemia Cells (U937) Ectopically Expressing Bcl-XL","volume":"13","author":"Wang","year":"1999","journal-title":"Leukemia"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1124\/mol.110.064741","article-title":"Bryostatin 1 Inhibits Phorbol Ester-Induced Apoptosis in Prostate Cancer Cells by Differentially Modulating Protein Kinase c (PKC) \u03b4 Translocation and Preventing PKC\u03b4-Mediated Release of Tumor Necrosis Factor-\u03b1","volume":"78","author":"Xiao","year":"2010","journal-title":"Mol. Pharmacol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.exphem.2008.09.008","article-title":"A Proapoptotic Signaling Pathway Involving RasGRP, Erk, and Bim in B Cells","volume":"37","author":"Stang","year":"2009","journal-title":"Exp. Hematol."},{"key":"ref_95","first-page":"802","article-title":"Preclinical Pharmacology of the Natural Product Anticancer Agent Bryostatin 1, an Activator of Protein Kinase C","volume":"56","author":"Zhang","year":"1996","journal-title":"Cancer Res."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/S0378-4347(98)00007-3","article-title":"High-Performance Liquid Chromatographic Assay for the Novel Antitumor Drug, Bryostatin-1, Incorporating a Serum Extraction Technique","volume":"709","author":"Khan","year":"1998","journal-title":"J. Chromatogr. B Biomed. Sci. Appl."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.ab.2004.10.030","article-title":"Validation and Implementation of a Method for Determination of Bryostatin 1 in Human Plasma by Using Liquid Chromatography\/Tandem Mass Spectrometry","volume":"337","author":"Zhao","year":"2005","journal-title":"Anal. Biochem."},{"key":"ref_98","first-page":"61","article-title":"Review of the Newest HPLC Methods with Mass Spectrometry Detection for Determination of Immunosuppressive Drugs in Clinical Practice","volume":"14","author":"Korecka","year":"2009","journal-title":"Ann. Transplant."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1038\/bjc.1998.36","article-title":"Bryostatin 1-Tamoxifen Combinations Show Synergistic Effects on the Inhibition of Growth of P388 Cells in Vitro","volume":"77","author":"McGown","year":"1998","journal-title":"Br. J. Cancer"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"771","DOI":"10.3324\/haematol.2011.049155","article-title":"The Cytotoxicity of Anti-CD22 Immunotoxin Is Enhanced by Bryostatin 1 in B-Cell Lymphomas through CD22 Upregulation and PKC-\u03b2II Depletion","volume":"97","author":"Biberacher","year":"2012","journal-title":"Haematologica"},{"key":"ref_101","first-page":"1498","article-title":"The in Vivo Effect of Bryostatin-1 on Paclitaxel-Induced Tumor Growth, Mitotic Entry, and Blood Flow","volume":"6","author":"Koutcher","year":"2000","journal-title":"Clin. Cancer Res."},{"key":"ref_102","first-page":"1337","article-title":"Successful Treatment of Human Chronic Lymphocytic Leukemia Xenografts with Combination Biological Agents Auristatin PE and Bryostatin 1","volume":"4","author":"Mohammad","year":"1998","journal-title":"Clin. Cancer Res."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"6730","DOI":"10.1158\/1078-0432.CCR-05-0450","article-title":"Enhancement of Cisplatin Sensitivity of Cisplatin-Resistant Human Cervical Carcinoma Cells by Bryostatin 1","volume":"11","author":"Mohanty","year":"2005","journal-title":"Clin. Cancer Res."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"2118","DOI":"10.1016\/S0021-9258(17)42143-0","article-title":"Differential Regulation of Protein Kinase c Isozymes by Bryostatin 1 and Phorbol 12-Myristate 13-Acetate in NIH 3T3 Fibroblasts","volume":"269","author":"Szallasi","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.cyto.2010.08.010","article-title":"Bryostatin-I: A Dendritic Cell Stimulator for Chemokines Induction and a Promising Adjuvant for a Peptide Based Cancer Vaccine","volume":"52","author":"Yan","year":"2010","journal-title":"Cytokine"},{"key":"ref_106","first-page":"682","article-title":"Successful Treatment of Murine Melanoma with Bryostatin 1","volume":"51","author":"Schuchter","year":"1991","journal-title":"Cancer Res."},{"key":"ref_107","first-page":"4950","article-title":"The Addition of Bryostatin 1 to Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (CHOP) Chemotherapy Improves Response in a CHOP-Resistant Human Diffuse Large Cell Lymphoma Xenograft Model","volume":"6","author":"Mohammad","year":"2000","journal-title":"Clin. Cancer Res."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"155498","DOI":"10.1016\/j.cyto.2021.155498","article-title":"Rebound Increases in Chemokines by CXCR2 Antagonist in Breast Cancer Can Be Prevented by PKC\u03b4 and PKC\u03b5 Activators","volume":"142","author":"Erin","year":"2021","journal-title":"Cytokine"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1747","DOI":"10.1182\/blood.V74.5.1747.1747","article-title":"Bryostatin 1 Induces Differentiation of B-Chronic Lymphocytic Leukemia Cells","volume":"74","author":"Drexler","year":"1989","journal-title":"Blood"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1182\/blood.V75.6.1319.1319","article-title":"Bryostatin 1, a Unique Biologic Response Modifier: Anti-Leukemic Activity in Vitro","volume":"75","author":"Jones","year":"1990","journal-title":"Blood"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1007\/BF01525985","article-title":"Immunomodulation in Patients Receiving Intravenous Bryostatin 1 in a Phase I Clinical Study: Comparison with Effects of Bryostatin 1 on Lymphocyte Function in Vitro","volume":"39","author":"Scheid","year":"1994","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1074\/jbc.M110.135921","article-title":"Bryostatin-1, a Naturally Occurring Antineoplastic Agent, Acts as a Toll-like Receptor 4 (TLR-4) Ligand and Induces Unique Cytokines and Chemokines in Dendritic Cells","volume":"286","author":"Ariza","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1016\/S0006-2952(98)00107-5","article-title":"PKC-Independent Modulation of Multidrug Resistance in Cells with Mutant (V185) but Not Wild-Type (G185) P-Glycoprotein by Bryostatin 1","volume":"56","author":"Spitaler","year":"1998","journal-title":"Biochem. Pharmacol."},{"key":"ref_114","first-page":"1305","article-title":"Bryostatin 1 Down-Regulates Mdr1 and Potentiates Vincristine Cytotoxicity in Diffuse Large Cell Lymphoma Xenografts","volume":"4","author":"Smith","year":"1998","journal-title":"Clin. Cancer Res."},{"key":"ref_115","first-page":"915","article-title":"P53 and Protein Kinase c Independent Induction of Growth Arrest and Apoptosis by Bryostatin 1 in a Highly Metastatic Mammary Epithelial Cell Line: In Vitro versus in Vivo Activity","volume":"1","author":"Wang","year":"1998","journal-title":"Int. J. Mol. Med."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/j.bbrc.2019.03.014","article-title":"Bryostatin-1 Inhibits Cell Proliferation of Hepatocarcinoma and Induces Cell Cycle Arrest by Activation of GSK3\u03b2","volume":"512","author":"Wang","year":"2019","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_117","first-page":"1077","article-title":"Bryostatin 1 Causes Attenuation of TPA-Mediated Tumor Promotion in Mouse Skin","volume":"17","author":"Zeng","year":"2017","journal-title":"Mol. Med. Rep."},{"key":"ref_118","first-page":"5929","article-title":"Phase I and Correlative Study of Combination Bryostatin 1 and Vincristine in Relapsed B-Cell Malignancies","volume":"9","author":"Dowlati","year":"2003","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"5809","DOI":"10.1158\/1078-0432.CCR-05-2730","article-title":"Phase I Study of Bryostatin 1 and Fludarabine in Patients with Chronic Lymphocytic Leukemia and Indolent (Non-Hodgkin\u2019s) Lymphoma","volume":"12","author":"Roberts","year":"2006","journal-title":"Clin. Cancer Res."},{"key":"ref_120","first-page":"109","article-title":"Weekly Bryostatin-1 in Metastatic Renal Cell Carcinoma: A Phase II Study","volume":"9","author":"Haas","year":"2003","journal-title":"Clin. Cancer Res."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1038\/bjc.1993.352","article-title":"A Phase I Study of Intravenous Bryostatin 1 in Patients with Advanced Cancer","volume":"68","author":"Prendiville","year":"1993","journal-title":"Br. J. Cancer"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"1812","DOI":"10.1093\/jnci\/85.22.1812","article-title":"Phase I Study of Bryostatin 1: Assessment of Interleukin 6 and Tumor Necrosis Factor Induction in Vivo","volume":"85","author":"Philip","year":"1993","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_123","first-page":"1328","article-title":"Sequential Treatment of a Resistant Chronic Lymphocytic Leukemia Patient with Bryostatin 1 Followed by 2-Chlorodeoxyadenosine: Case Report","volume":"6","author":"Ahmad","year":"2000","journal-title":"Clin. Cancer Res."},{"key":"ref_124","first-page":"38","article-title":"A Phase II Trial of Bryostatin 1 in the Treatment of Metastatic Colorectal Cancer1","volume":"7","author":"Zonder","year":"2001","journal-title":"Clin. Cancer Res."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1023\/A:1020694425356","article-title":"A Randomized Phase II Study of Two Schedules of Bryostatin-1 (NSC339555) in Patients with Advanced Malignant Melanoma\u2014A National Cancer Institute of Canada Clinical Trials Group Study","volume":"20","author":"Tozer","year":"2002","journal-title":"Investig. New Drugs"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1200\/JCO.1998.16.1.56","article-title":"Phase I Study of Bryostatin 1 in Patients with Relapsed Non-Hodgkin\u2019s Lymphoma and Chronic Lymphocytic Leukemia","volume":"16","author":"Varterasian","year":"1998","journal-title":"J. Clin. Oncol."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1038\/bjc.1995.356","article-title":"A Phase I Trial of Bryostatin 1 in Patients with Advanced Malignancy Using a 24 Hour Intravenous Infusion","volume":"72","author":"Jayson","year":"1995","journal-title":"Br. J. Cancer"},{"key":"ref_128","first-page":"825","article-title":"Phase II Trial of Bryostatin 1 in Patients with Relapsed Low-Grade Non-Hodgkin\u2019s Lymphoma and Chronic Lymphocytic Leukemia","volume":"6","author":"Varterasian","year":"2000","journal-title":"Clin. Cancer Res."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"7059","DOI":"10.1158\/1078-0432.CCR-06-1419","article-title":"Phase I Study of Bryostatin 1 and Gemcitabine","volume":"12","author":"Gadgeel","year":"2006","journal-title":"Clin. Cancer Res."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.1038\/bjc.1998.680","article-title":"A Phase II Study of Bryostatin 1 in Metastatic Malignant Melanoma","volume":"78","author":"Propper","year":"1998","journal-title":"Br. J. Cancer"},{"key":"ref_131","first-page":"2123","article-title":"Phase I Trial and Correlative Laboratory Studies of Bryostatin 1 (NSC 339555) and High-Dose 1-B-D-Arabinofuranosylcytosine in Patients with Refractory Acute Leukemia","volume":"8","author":"Cragg","year":"2002","journal-title":"Clin. Cancer Res."},{"key":"ref_132","first-page":"611","article-title":"Phase Ib Trial of Bryostatin 1 in Patients with Refractory Malignancies","volume":"4","author":"Grant","year":"1998","journal-title":"Clin. Cancer Res."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1007\/s10637-010-9557-5","article-title":"Phase II Trial of Bryostatin-1 in Combination with Cisplatin in Patients with Recurrent or Persistent Epithelial Ovarian Cancer: A California Cancer Consortium Study","volume":"30","author":"Morgan","year":"2010","journal-title":"Investig. 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