{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T21:49:50Z","timestamp":1790200190792,"version":"4.1.0"},"reference-count":80,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2024,7,19]],"date-time":"2024-07-19T00:00:00Z","timestamp":1721347200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Victor Babes University of Medicine and Pharmacy Timisoara"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Betulinic acid is a lupane-type pentacyclic triterpene mostly found in birch bark and thoroughly explored for its wide range of pharmacological activities. Despite its impressive biological potential, its low bioavailability has challenged many researchers to develop different formulations for achieving better in vitro and in vivo effects. We previously reported the synthesis of fatty acid esters of betulinic acid using butyric, stearic, and palmitic acids (But-BA, St-BA, and Pal-BA) and included them in surfaced-modified liposomes (But-BA-Lip, St-BA-Lip, Pal-BA-Lip). In the current study, we evaluated the cytotoxic effects of both fatty acid esters and their respective liposomal formulations against MCF-7, HT-29, and NCI-H460 cell line. The cytotoxic assessment of BA derivatives revealed that both the fatty esters and their liposomal formulations acted as cytotoxic agents in a dose- and time-dependent manner. But-BA-Lip exerted stronger cytotoxic effects than the parent compound, BA and its liposomal formulation, and even stronger effects than 5-FU against HT-29 cells (IC50 of 30.57 \u03bcM) and NCI-H460 cells (IC50 of 30.74 \u03bcM). BA\u2019s fatty esters and their respective liposomal formulations facilitated apoptosis in cancer cells by inducing nuclear morphological changes and increasing caspase-3\/-7 activity. The HET-CAM assay proved that none of the tested compounds induced any irritative effect, suggesting that they can be used safely for local applications.<\/jats:p>","DOI":"10.3390\/molecules29143399","type":"journal-article","created":{"date-parts":[[2024,7,19]],"date-time":"2024-07-19T13:12:57Z","timestamp":1721394777000},"page":"3399","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Cytotoxic Potential of Betulinic Acid Fatty Esters and Their Liposomal Formulations: Targeting Breast, Colon, and Lung Cancer Cell Lines"],"prefix":"10.3390","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6588-3241","authenticated-orcid":false,"given":"Andreea","family":"Milan","sequence":"first","affiliation":[{"name":"Faculty of Pharmacy, Victor Babes University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timi\u0219oara, Romania"},{"name":"Research Centre for Pharmaco-Toxicological Evaluation, Victor Babes University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timi\u0219oara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marius","family":"Mioc","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Victor Babes University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timi\u0219oara, Romania"},{"name":"Research Centre for Pharmaco-Toxicological Evaluation, Victor Babes University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timi\u0219oara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Mioc","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Victor Babes University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timi\u0219oara, Romania"},{"name":"Research Centre for Pharmaco-Toxicological Evaluation, Victor Babes University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timi\u0219oara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-4301-2279","authenticated-orcid":false,"given":"Armand","family":"Gogulescu","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Victor Babes University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timi\u0219oara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel","family":"Mardale","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Victor Babes University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timi\u0219oara, Romania"},{"name":"Research Centre for Pharmaco-Toxicological Evaluation, Victor Babes University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timi\u0219oara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4824-6769","authenticated-orcid":false,"given":"\u0218tefana","family":"Avram","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Victor Babes University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timi\u0219oara, Romania"},{"name":"Research Centre for Pharmaco-Toxicological Evaluation, Victor Babes University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timi\u0219oara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamara","family":"Maksimovi\u0107","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Victor Babes University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timi\u0219oara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bogdan","family":"Mara","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Victor Babes University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timi\u0219oara, Romania"},{"name":"Institute of Chemistry Coriolan Dr\u0103gulescu, 24 Mihai Viteazu Ave, 300223 Timi\u0219oara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Codru\u021ba","family":"\u0218oica","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Victor Babes University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timi\u0219oara, Romania"},{"name":"Research Centre for Pharmaco-Toxicological Evaluation, Victor Babes University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timi\u0219oara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1053\/j.seminoncol.2010.06.014","article-title":"Cancer Prevention with Natural Compounds","volume":"37","author":"Gullett","year":"2010","journal-title":"Semin. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"229","DOI":"10.3322\/caac.21834","article-title":"Global Cancer Statistics 2022: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA. Cancer J. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1038\/nature05610","article-title":"Patterns of Somatic Mutation in Human Cancer Genomes","volume":"446","author":"Greenman","year":"2007","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1038\/s43018-023-00712-x","article-title":"The Efficacy of Chemotherapy Is Limited by Intratumoral Senescent Cells Expressing PD-L2","volume":"5","author":"Chaib","year":"2024","journal-title":"Nat. Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"119087","DOI":"10.1016\/j.lfs.2021.119087","article-title":"Recent Trends in Cancer Therapy: A Review on the Current State of Gene Delivery","volume":"269","author":"Yahya","year":"2021","journal-title":"Life Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1007\/s13659-020-00293-7","article-title":"Natural Products in Cancer Therapy: Past, Present and Future","volume":"11","author":"Huang","year":"2021","journal-title":"Nat. Products Bioprospect."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1409","DOI":"10.1111\/bph.14816","article-title":"Natural Compounds as Potential Adjuvants to Cancer Therapy: Preclinical Evidence","volume":"177","author":"Lin","year":"2020","journal-title":"Br. J. Pharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1610","DOI":"10.3390\/molecules20011610","article-title":"Triterpenes as Potentially Cytotoxic Compounds","volume":"20","author":"Chudzik","year":"2015","journal-title":"Molecules"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1080\/01926230701320337","article-title":"Apoptosis: A Review of Programmed Cell Death","volume":"35","author":"Elmore","year":"2007","journal-title":"Toxicol. Pathol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"6680","DOI":"10.1038\/sj.onc.1209954","article-title":"Introduction to NF-\u039aB: Players, Pathways, Perspectives","volume":"25","author":"Gilmore","year":"2006","journal-title":"Oncogene"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1007\/s11101-019-09623-1","article-title":"Betulin and Betulinic Acid: Triterpenoids Derivatives with a Powerful Biological Potential","volume":"18","author":"Hordyjewska","year":"2019","journal-title":"Phytochem. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1038\/nm1095-1046","article-title":"Discovery of Betulinic Acid as a Selective Inhibitor of Human Melanoma That Functions by Induction of Apoptosis","volume":"1","author":"Pisha","year":"1995","journal-title":"Nat. Med."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Ghiulai, R., Mioc, M., Racoviceanu, R., Prodea, A., Milan, A., Coricovac, D., Dehelean, C., Avram, \u0218., Zamfir, A.D., and Munteanu, C.V.A. (2022). Structural Investigation of Betulinic Acid Plasma Metabolites by Tandem Mass Spectrometry. Molecules, 27.","DOI":"10.3390\/molecules27217359"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Lou, H., Li, H., Zhang, S., Lu, H., and Chen, Q. (2021). A Review on Preparation of Betulinic Acid and Its Biological Activities. Molecules, 26.","DOI":"10.3390\/molecules26185583"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Adepoju, F.O., Duru, K.C., Li, E., Kovaleva, E.G., and Tsurkan, M.V. (2023). Pharmacological Potential of Betulin as a Multitarget Compound. Biomolecules, 13.","DOI":"10.3390\/biom13071105"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1124\/mol.112.078485","article-title":"Betulinic Acid Decreases Specificity Protein 1 (Sp1) Level via Increasing the Sumoylation of Sp1 to Inhibit Lung Cancer Growth","volume":"82","author":"Hsu","year":"2012","journal-title":"Mol. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/s00210-006-0090-1","article-title":"Betulinic Acid Decreases Expression of Bcl-2 and Cyclin D1, Inhibits Proliferation, Migration and Induces Apoptosis in Cancer Cells","volume":"374","author":"Rzeski","year":"2006","journal-title":"Naunyn. Schmiedebergs. Arch. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Guo, Y., Zhu, H., Weng, M., Wang, C., and Sun, L. (2020). Chemopreventive Effect of Betulinic Acid via MTOR -Caspases\/Bcl2\/Bax Apoptotic Signaling in Pancreatic Cancer. BMC Complement. Med. Ther., 20.","DOI":"10.1186\/s12906-020-02976-7"},{"key":"ref_19","first-page":"641","article-title":"Recent Progress on Betulinic Acid and Its Derivatives as Antitumor Agents: A Mini Review","volume":"19","author":"Zhong","year":"2021","journal-title":"Chin. J. Nat. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"8235","DOI":"10.3390\/ijms15058235","article-title":"Betulinic Acid in Complex with a Gamma-Cyclodextrin Derivative Decreases Proliferation and in Vivo Tumor Development of Non-Metastatic and Metastatic B164A5 Cells","volume":"15","author":"Soica","year":"2014","journal-title":"Int. J. Mol. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Nistor, G., Trandafirescu, C., Prodea, A., Milan, A., Cristea, A., Ghiulai, R., Racoviceanu, R., Mioc, A., Mioc, M., and Ivan, V. (2022). Semisynthetic Derivatives of Pentacyclic Triterpenes Bearing Heterocyclic Moieties with Therapeutic Potential. Molecules, 27.","DOI":"10.3390\/molecules27196552"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1111\/nyas.13570","article-title":"Therapeutic Applications of Betulinic Acid Nanoformulations","volume":"1421","author":"Saneja","year":"2018","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1016\/j.archoralbio.2011.01.011","article-title":"Short- and Medium-Chain Fatty Acids Exhibit Antimicrobial Activity for Oral Microorganisms","volume":"56","author":"Huang","year":"2011","journal-title":"Arch. Oral Biol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Bravo-Santano, N., Ellis, J.K., Calle, Y., Keun, H.C., Behrends, V., and Letek, M. (2019). Intracellular Staphylococcus Aureus Elicits the Production of Host Very Long-Chain Saturated Fatty Acids with Antimicrobial Activity. Metabolites, 9.","DOI":"10.3390\/metabo9070148"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/s11046-008-9124-1","article-title":"Biological Control of Phytopathogenic Fungi by Fatty Acids","volume":"166","author":"Liu","year":"2008","journal-title":"Mycopathologia"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1007\/s00280-018-3538-3","article-title":"Electrophilic Derivatives of Omega-3 Fatty Acids Counteract Lung Cancer Cell Growth","volume":"81","author":"Siena","year":"2018","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.plefa.2013.07.004","article-title":"Anti-Proliferative Effects of a New Docosapentaenoic Acid Monoacylglyceride in Colorectal Carcinoma Cells","volume":"89","author":"Morin","year":"2013","journal-title":"Prostaglandins, Leukot. Essent. Fat. Acids"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1021\/acs.molpharmaceut.6b01027","article-title":"Lipid\u2013Drug Conjugate for Enhancing Drug Delivery","volume":"14","author":"Irby","year":"2017","journal-title":"Mol. Pharm."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"172937","DOI":"10.1016\/j.ejphar.2020.172937","article-title":"Anticancer Activities of Fatty Acids and Their Heterocyclic Derivatives","volume":"871","author":"Filipowska","year":"2020","journal-title":"Eur. J. Pharmacol."},{"key":"ref_30","first-page":"e54338","article-title":"Preparation and Characterization of Lipophilic Doxorubicin Pro-Drug Micelles","volume":"114","author":"Li","year":"2016","journal-title":"J. Vis. Exp."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"121","DOI":"10.20307\/nps.2023.29.3.121","article-title":"A Cytotoxic Lupeol Fatty Acid Ester and Other Pentacyclic Triterpenes from Salvadora Persica Seeds","volume":"29","year":"2023","journal-title":"Nat. Prod. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Milan, A., Mioc, M., Mioc, A., Marangoci, N., Racoviceanu, R., Mardale, G., B\u0103lan-Porc\u0103ra\u0219u, M., Rotunjanu, S., \u015eoica, I., and \u0218oica, C. (2024). Exploring the Antimelanoma Potential of Betulinic Acid Esters and Their Liposomal Nanoformulations. Processes, 12.","DOI":"10.3390\/pr12020416"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1016\/0278-6915(86)90099-2","article-title":"The HET-CAM Test: An Alternative to the Draize Eye Test","volume":"24","author":"Luepke","year":"1986","journal-title":"Food Chem. Toxicol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"6637","DOI":"10.21873\/anticanres.14688","article-title":"Apoptosis Induced by (+)-Betulin Through NF-\u039aB Inhibition in MDA-MB-231 Breast Cancer Cells","volume":"40","author":"Eggers","year":"2020","journal-title":"Anticancer Res."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Mioc, M., Mioc, A., Prodea, A., Milan, A., Balan-Porcarasu, M., Racoviceanu, R., Ghiulai, R., Iovanescu, G., Macasoi, I., and Draghici, G. (2022). Novel Triterpenic Acid\u2014Benzotriazole Esters Act as Pro-Apoptotic Antimelanoma Agents. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23179992"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Kazakova, O., Mioc, A., Smirnova, I., Baikova, I., Voicu, A., Vlaia, L., Maca\u0219oi, I., Mioc, M., Dr\u0103ghici, G., and Avram, \u015e. (2021). Novel Synthesized N-Ethyl-Piperazinyl-Amides of C2-Substituted Oleanonic and Ursonic Acids Exhibit Cytotoxic Effects through Apoptotic Cell Death Regulation. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222010967"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Kazakova, O., \u0218oica, C., Babaev, M., Petrova, A., Khusnutdinova, E., Poptsov, A., Maca\u0219oi, I., Dr\u0103ghici, G., Avram, \u0218., and Vlaia, L. (2021). 3-Pyridinylidene Derivatives of Chemically Modified Lupane and Ursane Triterpenes as Promising Anticancer Agents by Targeting Apoptosis. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms221910695"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.ejphar.2017.09.008","article-title":"Betulinic Acid Derivative BA5, a Dual NF-KB\/Calcineurin Inhibitor, Alleviates Experimental Shock and Delayed Hypersensitivity","volume":"815","author":"Meira","year":"2017","journal-title":"Eur. J. Pharmacol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1739","DOI":"10.1021\/jm0306430","article-title":"Glide: A New Approach for Rapid, Accurate Docking and Scoring. 1. Method and Assessment of Docking Accuracy","volume":"47","author":"Friesner","year":"2004","journal-title":"J. Med. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: Improving the Speed and Accuracy of Docking with a New Scoring Function, Efficient Optimization, and Multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3760","DOI":"10.1016\/j.csbj.2023.07.017","article-title":"Structural Basis of the Specificity and Interaction Mechanism of Bmf Binding to Pro-Survival Bcl-2 Family Proteins","volume":"21","author":"Wang","year":"2023","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1038\/nm.3048","article-title":"ABT-199, a Potent and Selective BCL-2 Inhibitor, Achieves Antitumor Activity While Sparing Platelets","volume":"19","author":"Souers","year":"2013","journal-title":"Nat. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1711","DOI":"10.1038\/sj.cdd.4402178","article-title":"Crystal Structure of ABT-737 Complexed with Bcl-XL: Implications for Selectivity of Antagonists of the Bcl-2 Family","volume":"14","author":"Lee","year":"2007","journal-title":"Cell Death Differ."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1002\/mnfr.200700491","article-title":"Betulinic Acid: A Natural Product with Anticancer Activity","volume":"53","author":"Fulda","year":"2009","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1002\/hed.10231","article-title":"Betulinic Acid: A New Cytotoxic Compound against Malignant Head and Neck Cancer Cells","volume":"25","author":"Thurnher","year":"2003","journal-title":"Head Neck"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/S0304-3835(01)00718-2","article-title":"Selective Cytotoxicity of Betulinic Acid on Tumor Cell Lines, but Not on Normal Cells","volume":"175","author":"Zuco","year":"2002","journal-title":"Cancer Lett."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1002\/(SICI)1097-0215(19990730)82:3<435::AID-IJC18>3.0.CO;2-1","article-title":"Betulinic Acid: A New Cytotoxic Agent against Malignant Brain-Tumor Cells","volume":"82","author":"Fulda","year":"1999","journal-title":"Int. J. Cancer"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.ejmech.2017.09.069","article-title":"An Insight into the Biological Activities of Heterocyclic\u2013Fatty Acid Hybrid Molecules","volume":"141","author":"Venepally","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1007\/s11746-003-0774-1","article-title":"Antioxidative Properties and Enzymatic Synthesis of Ascorbyl FA Esters","volume":"80","author":"Viklund","year":"2003","journal-title":"J. Am. Oil Chem. Soc."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1007\/s11745-004-1215-5","article-title":"Synthesis and Anticancer Activities of Fatty Acid Analogs of Podophyllotoxin","volume":"39","author":"Mustafa","year":"2004","journal-title":"Lipids"},{"key":"ref_51","first-page":"848","article-title":"Synthesis and Biological Evaluation of Some Pentacyclic Lupane Triterpenoid Esters","volume":"65","author":"Pinzaru","year":"2014","journal-title":"Rev. Chim."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.msec.2016.03.080","article-title":"Antitumor Drug Effect of Betulinic Acid Mediated by Polyethylene Glycol Modified Liposomes","volume":"64","author":"Liu","year":"2016","journal-title":"Mater. Sci. Eng. C"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1734","DOI":"10.1016\/j.bmcl.2011.12.102","article-title":"New Ionic Derivatives of Betulinic Acid as Highly Potent Anti-Cancer Agents","volume":"22","author":"Suresh","year":"2012","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"3447","DOI":"10.1016\/j.bmc.2005.03.006","article-title":"Synthesis of Phthalates of Betulinic Acid and Betulin with Cytotoxic Activity","volume":"13","author":"Kvasnica","year":"2005","journal-title":"Bioorg. Med. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.canlet.2006.11.003","article-title":"Broad in Vitro Efficacy of Plant-Derived Betulinic Acid against Cell Lines Derived from the Most Prevalent Human Cancer Types","volume":"251","author":"Kessler","year":"2007","journal-title":"Cancer Lett."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Shu, Q., Wu, J., and Chen, Q. (2019). Synthesis, Characterization of Liposomes Modified with Biosurfactant MEL-A Loading Betulinic Acid and Its Anticancer Effect in HepG2 Cell. Molecules, 24.","DOI":"10.3390\/molecules24213939"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.3390\/ijms9061096","article-title":"Betulinic Acid for Cancer Treatment and Prevention","volume":"9","author":"Fulda","year":"2008","journal-title":"Int. J. Mol. Sci."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Eskandari, E., and Eaves, C.J. (2022). Paradoxical Roles of Caspase-3 in Regulating Cell Survival, Proliferation, and Tumorigenesis. J. Cell Biol., 221.","DOI":"10.1083\/jcb.202201159"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2545","DOI":"10.4314\/tjpr.v19i12.9","article-title":"Betulinic Acid Inhibits Glioma Cell Viability by Downregulation of NF-\u039aB and Enhancement of Apoptosis","volume":"19","author":"Yaozu","year":"2021","journal-title":"Trop. J. Pharm. Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"e190","DOI":"10.1002\/ctm2.190","article-title":"Suppression of LncRNA MALAT1 by Betulinic Acid Inhibits Hepatocellular Carcinoma Progression by Targeting IAPs via MiR-22-3p","volume":"10","author":"Chen","year":"2020","journal-title":"Clin. Transl. Med."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Kutkowska, J., Strzadala, L., and Rapak, A. (2021). Hypoxia Increases the Apoptotic Response to Betulinic Acid and Betulin in Human Non-Small Cell Lung Cancer Cells. Chem. Biol. Interact., 333.","DOI":"10.1016\/j.cbi.2020.109320"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"5083158","DOI":"10.1155\/2019\/5083158","article-title":"Betulinic Acid Induces ROS-Dependent Apoptosis and S-Phase Arrest by Inhibiting the NF- \u03ba B Pathway in Human Multiple Myeloma","volume":"2019","author":"Shen","year":"2019","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1210\/en.2006-0998","article-title":"Palmitate Induced Mitochondrial Deoxyribonucleic Acid Damage and Apoptosis in L6 Rat Skeletal Muscle Cells","volume":"148","author":"Rachek","year":"2007","journal-title":"Endocrinology"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1111\/j.1471-4159.2007.05209.x","article-title":"Loss of Cardiolipin in Palmitate-treated GL15 Glioblastoma Cells Favors Cytochrome c Release from Mitochondria Leading to Apoptosis","volume":"105","author":"Buratta","year":"2008","journal-title":"J. Neurochem."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1007\/s12282-020-01063-6","article-title":"Comparative Effect of Sodium Butyrate and Sodium Propionate on Proliferation, Cell Cycle and Apoptosis in Human Breast Cancer Cells MCF-7","volume":"27","author":"Semaan","year":"2020","journal-title":"Breast Cancer"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1038\/sj.bjp.0704456","article-title":"Le Sodium Butyrate Induces P53-independent, Fas-mediated Apoptosis in MCF-7 Human Breast Cancer Cells","volume":"135","author":"Chopin","year":"2002","journal-title":"Br. J. Pharmacol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1177\/147323000903700323","article-title":"Sodium Butyrate Induces Human Colon Carcinoma HT-29 Cell Apoptosis through a Mitochondrial Pathway","volume":"37","author":"Wang","year":"2009","journal-title":"J. Int. Med. Res."},{"key":"ref_68","first-page":"1476","article-title":"Chitosan-Coated Liposomes Loaded with Butyric Acid Demonstrate Anticancer and Anti-Inflammatory Activity in Human Hepatoma HepG2 Cells","volume":"41","author":"Quagliariello","year":"2018","journal-title":"Oncol. Rep."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1080\/01635580902825597","article-title":"Stearate Preferentially Induces Apoptosis in Human Breast Cancer Cells","volume":"61","author":"Evans","year":"2009","journal-title":"Nutr. Cancer"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1016\/S0278-6915(00)00091-0","article-title":"A Modified HET\u2013CAM Assay Approach to the Assessment of Anti-Irritant Properties of Plant Extracts","volume":"38","author":"Wilson","year":"2000","journal-title":"Food Chem. Toxicol."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Rednic, R., Macasoi, I., Pinzaru, I., Dehelean, C.A., Tomescu, M.-C., Susan, M., and Feier, H. (2022). Pharmaco-Toxicological Assessment of the Combined Cytotoxic Effects of Digoxin and Betulinic Acid in Melanoma Cells. Life, 12.","DOI":"10.3390\/life12111855"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Ghiulai, R., Mioc, A., Racoviceanu, R., Mioc, M., Milan, A., Prodea, A., Semenescu, A., Dehelean, C., Barbu Tudoran, L., and Avram, \u0218. (2022). The Anti-Melanoma Effect of Betulinic Acid Functionalized Gold Nanoparticles: A Mechanistic In Vitro Approach. Pharmaceuticals, 15.","DOI":"10.3390\/ph15111362"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Maghiari, A.L., Coricovac, D., Pinzaru, I.A., Maca\u0219oi, I.G., Marcovici, I., Simu, S., Navolan, D., and Dehelean, C. (2020). High Concentrations of Aspartame Induce Pro-Angiogenic Effects in Ovo and Cytotoxic Effects in HT-29 Human Colorectal Carcinoma Cells. Nutrients, 12.","DOI":"10.3390\/nu12123600"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"105194","DOI":"10.1016\/j.tiv.2021.105194","article-title":"Application of in Vitro Methods to Evaluate the Safety of Baby Care Products","volume":"75","author":"Wang","year":"2021","journal-title":"Toxicol. Vitr."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/0278-6915(85)90030-4","article-title":"Hen\u2019s Egg Chorioallantoic Membrane Test for Irritation Potential","volume":"23","author":"Luepke","year":"1985","journal-title":"Food Chem. Toxicol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1093\/nar\/28.1.235","article-title":"The Protein Data Bank","volume":"28","author":"Berman","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Dallakyan, S., and Olson, A.J. (2015). Small-Molecule Library Screening by Docking with PyRx. Chemical Biology: Methods and Protocols, Humana Press.","DOI":"10.1007\/978-1-4939-2269-7_19"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"6177","DOI":"10.1021\/jm051256o","article-title":"Extra Precision Glide: Docking and Scoring Incorporating a Model of Hydrophobic Enclosure for Protein\u2212Ligand Complexes","volume":"49","author":"Friesner","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1750","DOI":"10.1021\/jm030644s","article-title":"Glide: A New Approach for Rapid, Accurate Docking and Scoring. 2. Enrichment Factors in Database Screening","volume":"47","author":"Halgren","year":"2004","journal-title":"J. Med. Chem."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1007\/s10822-013-9644-8","article-title":"Protein and Ligand Preparation: Parameters, Protocols, and Influence on Virtual Screening Enrichments","volume":"27","author":"Adzhigirey","year":"2013","journal-title":"J. Comput. Aided. Mol. Des."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/29\/14\/3399\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:19:51Z","timestamp":1760109591000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/29\/14\/3399"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,19]]},"references-count":80,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2024,7]]}},"alternative-id":["molecules29143399"],"URL":"https:\/\/doi.org\/10.3390\/molecules29143399","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,19]]}}}