{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T18:44:09Z","timestamp":1778784249724,"version":"3.51.4"},"reference-count":85,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2022,5,28]],"date-time":"2022-05-28T00:00:00Z","timestamp":1653696000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Deanship of Scientific Research, Qassim University"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Onosma bracteata Wall. is an important medicinal and immunity-enhancing herbs. This plant is commonly used in the preparation of traditional Ayurvedic drugs to treat numerous diseases. Inspired by the medicinal properties of this plant, the present study aimed to investigate the antiproliferative potential and the primary molecular mechanisms of the apoptotic induction against human osteosarcoma (MG-63) cells. Among all the fractions isolated from O. bracteata, ethyl acetate fraction (Obea) showed good antioxidant activity in superoxide radical scavenging assay and lipid peroxidation assay with an EC50 value of 95.12 and 80.67 \u00b5g\/mL, respectively. Silica gel column chromatography of ethyl acetate (Obea) fraction of O. bracteata yielded a pure compound, which was characterized by NMR, FTIR, and HR-MS analysis and was identified as 1,2-benzene dicarboxylic acid, bis (2-methyl propyl) ester (BDCe fraction). BDCe fraction was evaluated for the antiproliferative potential against human osteosarcoma MG-63, human neuroblastoma IMR-32, and human lung carcinoma A549 cell lines by MTT assay and exhibited GI50 values of 37.53 \u03bcM, 56.05 \u03bcM, and 47.12 \u03bcM, respectively. In MG-63 cells, the BDCe fraction increased the level of ROS and simultaneously decreased the mitochondria membrane potential (MMP) potential by arresting cells at the G0\/G1 phase, suggesting the initiation of apoptosis. Western blotting analysis revealed the upregulation of p53, caspase3, and caspase9 while the expressions of p-NF-\u03baB, p-Akt and Bcl-xl were decreased. RT-qPCR studies also showed upregulation in the expression of p53 and caspase3 and downregulation in the expression of CDK2, Bcl-2 and Cyclin E genes. Molecular docking analysis displayed the interaction between BDCe fraction with p53 (\u2212151.13 kcal\/mol) and CDK1 (\u2212133.96 kcal\/mol). The results of the present work suggest that the BDCe fraction has chemopreventive properties against osteosarcoma (MG-63) cells through the induction of cell cycle arrest and apoptosis via Akt\/NF-\u03baB\/p53 pathways. This study contributes to the understanding of the utilization of BDCe fraction in osteosarcoma treatment.<\/jats:p>","DOI":"10.3390\/molecules27113478","type":"journal-article","created":{"date-parts":[[2022,5,29]],"date-time":"2022-05-29T23:43:03Z","timestamp":1653867783000},"page":"3478","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Targeting Akt\/NF-\u03baB\/p53 Pathway and Apoptosis Inducing Potential of 1,2-Benzenedicarboxylic Acid, Bis (2-Methyl Propyl) Ester Isolated from Onosma bracteata Wall. against Human Osteosarcoma (MG-63) Cells"],"prefix":"10.3390","volume":"27","author":[{"given":"Ajay","family":"Kumar","sequence":"first","affiliation":[{"name":"Department of Botanical and Environmental Sciences, Guru Nanak Dev University, Amritsar 143005, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandeep","family":"Kaur","sequence":"additional","affiliation":[{"name":"Department of Botanical and Environmental Sciences, Guru Nanak Dev University, Amritsar 143005, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7466-975X","authenticated-orcid":false,"given":"Sukhvinder","family":"Dhiman","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Prithvi Pal","family":"Singh","sequence":"additional","affiliation":[{"name":"Chemical Technology Division, CSIR-IHBT, Palampur 176061, India"},{"name":"Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gaurav","family":"Bhatia","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Pt. Jawaharlal Nehru Government Medical College and Hospital Chamba, Chamba 176310, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sharad","family":"Thakur","sequence":"additional","affiliation":[{"name":"Biotechnology Division, COVID-19 Project, CSIR-IHBT, Palampur 176061, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1155-0094","authenticated-orcid":false,"given":"Hardeep Singh","family":"Tuli","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala 133207, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7693-8690","authenticated-orcid":false,"given":"Upendra","family":"Sharma","sequence":"additional","affiliation":[{"name":"Chemical Technology Division, CSIR-IHBT, Palampur 176061, India"},{"name":"Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Subodh","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5709-4130","authenticated-orcid":false,"given":"Abdulmajeed G.","family":"Almutary","sequence":"additional","affiliation":[{"name":"Department of Medical Biotechnology, College of Applied Medical Sciences, Qassim University, Buraydah 52266, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9306-609X","authenticated-orcid":false,"given":"Abdullah M.","family":"Alnuqaydan","sequence":"additional","affiliation":[{"name":"Department of Medical Biotechnology, College of Applied Medical Sciences, Qassim University, Buraydah 52266, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0851-4845","authenticated-orcid":false,"given":"Arif","family":"Hussain","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Manipal Academy of Higher Education, Dubai Campus, Dubai 345050, United Arab Emirates"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2989-121X","authenticated-orcid":false,"given":"Shafiul","family":"Haque","sequence":"additional","affiliation":[{"name":"Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan 45142, Saudi Arabia"},{"name":"Bursa Uluda\u011f University Faculty of Medicine, G\u00f6r\u00fckle Campus, 16059 Nil\u00fcfer, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7469-4752","authenticated-orcid":false,"given":"Kuldeep","family":"Dhama","sequence":"additional","affiliation":[{"name":"Division of Pathology, ICAR-Indian Veterinary Research Institute, Bareilly 243122, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Satwinderjeet","family":"Kaur","sequence":"additional","affiliation":[{"name":"Department of Botanical and Environmental Sciences, Guru Nanak Dev University, Amritsar 143005, India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1007\/s40744-016-0046-y","article-title":"Review of Osteosarcoma and Current Management","volume":"3","author":"Durfee","year":"2016","journal-title":"Rheumatol. Ther."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Corre, I., Verrecchia, F., Crenn, V., Redini, F., and Trichet, V. (2020). The Osteosarcoma Microenvironment: A Complex but Targetable Ecosystem. Cells, 9.","DOI":"10.3390\/cells9040976"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1051\/sicotj\/2017028","article-title":"Osteosarcoma: A comprehensive review","volume":"4","author":"Misaghi","year":"2018","journal-title":"SICOT-J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2982","DOI":"10.7150\/jca.30750","article-title":"A Retrospective Clinicopathological Study of Osteosarcoma Patients with Metachronous Metastatic Relapse","volume":"10","author":"Bao","year":"2019","journal-title":"J. Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fchem.2020.598100","article-title":"Moving Beyond the Pillars of Cancer Treatment: Perspectives From Nanotechnology","volume":"8","author":"Siamof","year":"2020","journal-title":"Front. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"iv137","DOI":"10.1093\/annonc\/mdp154","article-title":"Osteosarcoma: ESMO Clinical Recommendations for diagnosis, treatment and follow-up","volume":"20","author":"Bielack","year":"2009","journal-title":"Ann. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"38022","DOI":"10.18632\/oncotarget.16723","article-title":"Combination therapy in combating cancer","volume":"8","author":"Mokhtari","year":"2017","journal-title":"Oncotarget"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1093\/carcin\/21.3.379","article-title":"Significance of multiple mutations in cancer","volume":"21","author":"Loeb","year":"2000","journal-title":"Carcinogenesis"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"12118","DOI":"10.1073\/pnas.1810017115","article-title":"Intracellular transport is accelerated in early apoptotic cells","volume":"115","author":"Li","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Rinkenbaugh, A.L., and Baldwin, A.S. (2016). The NF-\u03baB Pathway and Cancer Stem Cells. Cells, 5.","DOI":"10.3390\/cells5020016"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"6817","DOI":"10.1038\/sj.onc.1209942","article-title":"Nuclear factor-\u03baB and inhibitor of \u03baB kinase pathways in oncogenic initiation and progression","volume":"25","author":"Baldwin","year":"2006","journal-title":"Oncogene"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e44259","DOI":"10.1371\/journal.pone.0044259","article-title":"Anti-Cancer Activity of a Novel Small Molecule Compound That Simultaneously Activates p53 and Inhibits NF-\u03baB Signaling","volume":"7","author":"Hwang","year":"2012","journal-title":"PLoS ONE"},{"key":"ref_13","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_14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-019-49374-9","article-title":"In Vitro and In Vivo Evaluation of the Anticancer and Anti-inflammatory Activities of 2-Himachelen-7-ol isolated from Cedrus Libani","volume":"9","author":"Elias","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.3389\/fonc.2019.01153","article-title":"Modulation of Multiple Signaling Pathways of the Plant-Derived Natural Products in Cancer","volume":"9","author":"Sun","year":"2019","journal-title":"Front. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fphar.2019.01614","article-title":"Phytochemicals in Cancer Treatment: From Preclinical Studies to Clinical Practice","volume":"10","author":"Choudhari","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1007\/s10600-013-0611-3","article-title":"Essential oil composition of Anchusa italica from Iran","volume":"49","author":"Kazemi","year":"2013","journal-title":"Chem. Nat. Compd."},{"key":"ref_18","unstructured":"Ved, D.K., Sureshchandra, S.T., Barve, V., Srinivas, V., Sangeetha, S., Ravikumar, K., Kartikeyan, R., Kulkarni, V., Kumar, A.S., and Venugopal, S.N. (2020, December 13). Bengaluru: FRLHT\u2019s ENVIS Centre on Medicinal Plants. Available online: https:\/\/envis.frlht.org\/frlhtenvis.nic.in."},{"key":"ref_19","first-page":"216","article-title":"Phytochemical Screening and Antibacterial Activity of Opuntia dillenii and Onosma bracteatum","volume":"3","author":"Zeb","year":"2015","journal-title":"J. Microbiol. Exp."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"140","DOI":"10.4103\/0973-7847.120513","article-title":"A review of phytochemistry and ethnopharmacology","volume":"7","author":"Kumar","year":"2013","journal-title":"Pharmacogn. Rev."},{"key":"ref_21","first-page":"1","article-title":"The Effect of Onosma bracteatum in cancer cells","volume":"5","author":"Albaqami","year":"2018","journal-title":"MOJ Bioequiv. Availab."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Farooq, U., Pan, Y., Disasa, D., and Qi, J. (2019). Novel Anti-Aging Benzoquinone Derivatives from Onosma bracteatum Wall. Molecules, 24.","DOI":"10.3390\/molecules24071428"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"14983","DOI":"10.1007\/s11356-020-11466-9","article-title":"Onosma bracteata Wall. induces G0\/G1 arrest and apoptosis in MG-63 human osteosarcoma cells via ROS generation and AKT\/GSK3\u03b2\/cyclin E pathway","volume":"28","author":"Kumar","year":"2021","journal-title":"Environ. Sci. Pollut. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"57297","DOI":"10.1039\/C4RA11205A","article-title":"Sulfonated graphene as highly efficient and reusable acid carbocatalyst for the synthesis of ester plasticizers","volume":"4","author":"Garg","year":"2014","journal-title":"RSC Adv."},{"key":"ref_25","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_26","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1007\/s12017-018-8497-7","article-title":"Withania somnifera as a Potential Anxiolytic and Anti-inflammatory Candidate Against Systemic Lipopolysaccharide-Induced Neuroinflammation","volume":"20","author":"Gupta","year":"2018","journal-title":"NeuroMolecular Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1007\/s12298-015-0285-3","article-title":"Antiproliferative and Apoptosis Inducing Effects of Non-Polar Fractions from Lawsonia inermis L. in Cervical (HeLa) Cancer Cells","volume":"21","author":"Kumar","year":"2015","journal-title":"Physiol. Mol. Biol. Plants"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"7740","DOI":"10.1039\/C9RA10539E","article-title":"The role of reactive oxygen species in tumor treatment","volume":"10","author":"Jia","year":"2020","journal-title":"RSC Adv."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2977","DOI":"10.1016\/j.bbamcr.2016.09.012","article-title":"Activation of apoptosis signalling pathways by reactive oxygen species","volume":"1863","year":"2016","journal-title":"Biochim. Biophys. Acta (BBA)-Mol. Cell Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1146\/annurev-genet-102108-134850","article-title":"The role of mitochondria in apoptosis","volume":"43","author":"Wang","year":"2009","journal-title":"Annu. Rev. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1007\/s10495-015-1169-2","article-title":"Cell death mechanisms of plant-derived anticancer drugs: Beyond apoptosis","volume":"20","author":"Hmadi","year":"2015","journal-title":"Apoptosis"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1016\/j.biopha.2018.03.141","article-title":"The natural phenolic peperobtusin A induces apoptosis of lymphoma U937 cells via the Caspase dependent and p38 MAPK signaling pathways","volume":"102","author":"Shi","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Costea, T., Nagy, P., Ganea, C., Sz\u00f6ll\u0151si, J., and Mocanu, M.-M. (2019). Molecular Mechanisms and Bioavailability of Polyphenols in Prostate Cancer. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20051062"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Kopustinskiene, D.M., Jakstas, V., Savickas, A., and Bernatoniene, J. (2020). Flavonoids as anticancer agents. Nutrients, 12.","DOI":"10.3390\/nu12020457"},{"key":"ref_35","first-page":"5","article-title":"Isolation and characterization of substituted dibutyl phthalate from Ipomoea carnea stem","volume":"5","author":"Khatiwora","year":"2013","journal-title":"Der. Pharma. Chemica."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Giuliani, A., Zuccarini, M., Cichelli, A., Khan, H., and Reale, M. (2020). Critical Review on the Presence of Phthalates in Food and Evidence of Their Biological Impact. Int. J. Environ. Res. Public Health, 17.","DOI":"10.3390\/ijerph17165655"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1007\/s11274-011-0872-6","article-title":"Taxonomy, purification and chemical characterization of four bioactive compounds from new Streptomyces sp. TN256 strain","volume":"28","author":"Smaoui","year":"2011","journal-title":"World J. Microbiol. Biotechnol."},{"key":"ref_38","first-page":"238","article-title":"An antimicrobial phthalate derivative from Bacillus cereus, the symbiotic bacterium associated with a novel entomopathogenic nematode, Rhabditis (Oscheius) sp","volume":"7","author":"Anju","year":"2015","journal-title":"Int. J. Pharm. Pharm. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Huang, L., Zhu, X., Zhou, S., Cheng, Z., Shi, K., Zhang, C., and Shao, H. (2021). Phthalic Acid Esters: Natural Sources and Biological Activities. Toxins, 13.","DOI":"10.3390\/toxins13070495"},{"key":"ref_40","first-page":"67","article-title":"Distribution characteristics and health risk assessment of PAEs in urban soils of Changji City, Xinjiang, China","volume":"22","author":"Liu","year":"2020","journal-title":"China J. Nat."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1080\/07388551.2020.1789838","article-title":"Bioactive natural derivatives of phthalate ester","volume":"40","author":"Roy","year":"2020","journal-title":"Crit. Rev. Biotechnol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3673","DOI":"10.1016\/j.fct.2012.07.019","article-title":"Study on chemical composition, anti-inflammatory and anti-microbial activities of extracts from Chinese pear fruit (Pyrus bretschneideri Rehd.)","volume":"50","author":"Li","year":"2012","journal-title":"Food Chem. Toxicol."},{"key":"ref_43","first-page":"148","article-title":"Chemical constituents from the root of Croton lachynocarpus","volume":"34","author":"Pan","year":"2014","journal-title":"Guangxi Zhiwu\/Guihaia."},{"key":"ref_44","first-page":"231","article-title":"Algicidal activities of Cladophora fracta on red tide-forming microalgae Heterosigma akashiwo and Gymnodinium breve","volume":"37","author":"Dong","year":"2016","journal-title":"Allelopath. J."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.micpath.2017.06.033","article-title":"Isolation of anticancer and antimicrobial metabolites from Epicoccum nigrum; endophyte of Ferula sumbul","volume":"110","author":"Perveen","year":"2017","journal-title":"Microb. Pathog."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1016\/j.jff.2015.09.054","article-title":"Onosma aucheriana: A source of biologically active molecules for novel food ingredients and pharmaceuticals","volume":"19","author":"Diamanto","year":"2015","journal-title":"J. Funct. Foods"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1038\/s41571-020-0341-y","article-title":"Targeting apoptosis in cancer therapy","volume":"17","author":"Carneiro","year":"2020","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.jep.2003.09.048","article-title":"Antiproliferation, antioxidation and induction of apoptosis by Garcinia mangostana (mangosteen) on SKBR3 human breast cancer cell line","volume":"90","author":"Moongkarndi","year":"2003","journal-title":"J. Ethnopharmacol."},{"key":"ref_49","first-page":"4115","article-title":"High expression of long non-coding RNA LOC730101 correlates with distant metastasis and exhibits a poor prognosis in patients with osteosarcoma","volume":"22","author":"Li","year":"2018","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_50","first-page":"1484","article-title":"Shikonin causes apoptosis by disrupting intracellular calcium homeostasis and mitochondrial function in human hepatoma cells","volume":"15","author":"Wang","year":"2017","journal-title":"Exp. Ther. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12943-019-0960-z","article-title":"Recent advances in understanding tumor stroma-mediated chemoresistance in breast cancer","volume":"18","author":"Plava","year":"2019","journal-title":"Mol. Cancer"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1159\/000480528","article-title":"Quercetin Inhibits Cell Migration and Invasion in Human Osteosarcoma Cells","volume":"43","author":"Lan","year":"2017","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1002\/ptr.1899","article-title":"Cytotoxicityin vitro of naphthazarin derivatives fromOnosma arenaria","volume":"20","year":"2006","journal-title":"Phytotherapy Res."},{"key":"ref_54","first-page":"1","article-title":"Cytotoxic effects of new bioactive compounds isolated from a Nigerian anticancer plant Melastomastrum capitatum Fern. leaf extract","volume":"8","author":"Ukwubile","year":"2020","journal-title":"Sci. Afr."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1023\/A:1009616228304","article-title":"Role of reactive oxygen species (ROS) in apoptosis induction","volume":"5","author":"Simon","year":"2000","journal-title":"Apoptosis"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"765","DOI":"10.3109\/10408444.2015.1074159","article-title":"Free radicals and related reactive species as mediators of tissue injury and disease: Implications for Health","volume":"45","author":"Kehrer","year":"2015","journal-title":"Crit. Rev. Toxicol."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Yue, J., and L\u00f3pez, J.M. (2020). Understanding MAPK signaling pathways in apoptosis. Int. J. Mol. Sci., 7.","DOI":"10.3390\/ijms21072346"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/j.bjp.2018.03.003","article-title":"\u03b2-Hydroxyisovalerylshikonin promotes reactive oxygen species production in HCT116 colon cancer cells, leading to caspase-mediated apoptosis","volume":"28","author":"Dilshara","year":"2018","journal-title":"Rev. Bras. Farm."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1002\/tox.22259","article-title":"Triptolide induced cell death through apoptosis and autophagy in murine leukemia WEHI-3 cellsin vitroand promoting immune responses in WEHI-3 generated leukemia mice in vivo","volume":"32","author":"Chan","year":"2016","journal-title":"Environ. Toxicol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fphar.2020.01301","article-title":"Antioxidant Phytoconstituents From Onosma bracteata Wall. (Boraginaceae) Ameliorate the CCl4 Induced Hepatic Damage: In Vivo Study in Male Wistar Rats","volume":"11","author":"Kumar","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Kaur, S., Kumar, A., Thakur, S., Kumar, K., Sharma, R., Sharma, A., Singh, P., Sharma, U., Kumar, S., and Landi, M. (2020). Antioxidant, Antiproliferative and Apoptosis-Inducing Efficacy of Fractions from Cassia fistula L. Leaves. Antioxidants, 9.","DOI":"10.3390\/antiox9020173"},{"key":"ref_62","first-page":"11101","article-title":"p53 mediated apoptosis in osteosarcoma MG-63 cells by inhibition of FANCD2 gene expression","volume":"8","author":"Xia","year":"2015","journal-title":"Int. J. Clin. Exp. Med."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"S55","DOI":"10.1016\/j.semcancer.2015.02.005","article-title":"Evasion of anti-growth signaling: A key step in tumorigenesis and potential target for treatment and prophylaxis by natural compounds","volume":"35","author":"Amin","year":"2015","journal-title":"Semin. Cancer Biol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13046-018-0705-7","article-title":"New therapeutic strategies to treat human cancers expressing mutant p53 proteins","volume":"37","author":"Blandino","year":"2018","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"204","DOI":"10.22271\/phyto.2019.v8.i3e.04","article-title":"Phytochemical profiling and antioxidant activity of the extracts of Pachygone ovata (Poir.) Miers ex Hook.f. & Thomson","volume":"8","author":"Amalarasi","year":"2019","journal-title":"J. Pharmacogn. Phytochem."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1254\/jphs.12149FP","article-title":"Inhibition of the PI3K\/AKT-NF-\u03baB Pathway With Curcumin Enhanced Radiation-Induced Apoptosis in Human Burkitt\u2019s Lymphoma","volume":"121","author":"Qiao","year":"2013","journal-title":"J. Pharmacol. Sci."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2735","DOI":"10.3892\/etm.2016.3642","article-title":"Shikonin inhibits inflammation and chondrocyte apoptosis by regulation of the PI3K\/Akt signaling pathway in a rat model of osteoarthritis","volume":"12","author":"Fu","year":"2016","journal-title":"Exp. Ther. Med."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2173","DOI":"10.1159\/000445573","article-title":"Osthole Induces Cell Cycle Arrest and Inhibits Migration and Invasion via PTEN\/Akt Pathways in Osteosarcoma","volume":"38","author":"Wang","year":"2016","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1471-2407-10-437","article-title":"Correlation of NF-\u03baB signal pathway with tumor metastasis of human head and neck squamous cell carcinoma","volume":"10","author":"Yan","year":"2010","journal-title":"BMC Cancer"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.biochi.2020.10.013","article-title":"Loss of WD2 subdomain of Apaf-1 forms an apoptosome structure which blocks activation of caspase-3 and caspase","volume":"180","author":"Noori","year":"2020","journal-title":"Biochimie"},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Jannus, F., Medina-O\u2019Donnell, M., Rivas, F., D\u00edaz-Ruiz, L., Rufino-Palomares, E.E., Lupi\u00e1\u00f1ez, J.A., Parra, A., and Reyes-Zurita, F.J. (2020). A Diamine-PEGylated Oleanolic Acid Derivative Induced Efficient Apoptosis through a Death Receptor and Mitochondrial Apoptotic Pathway in HepG2 Human Hepatoma Cells. Biomolecules, 10.","DOI":"10.3390\/biom10101375"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.jfda.2019.06.002","article-title":"Mulberry fruits extracts induce apoptosis and autophagy of liver cancer cell and prevent hepatocarcinogenesis in vivo","volume":"28","author":"Cheng","year":"2019","journal-title":"J. Food Drug Anal."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Jing, L., Ma, H., Fan, P., Gao, R., and Jia, Z. (2015). Antioxidant potential, total phenolic and total flavonoid contents of Rhododendron anthopogonoides and its protective effect on hypoxia-induced injury in PC12 cells. BMC Complement. Altern. Med., 15.","DOI":"10.1186\/s12906-015-0820-3"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1016\/S0006-291X(72)80218-3","article-title":"The occurrence of superoxide anion in the reaction of reduced phenazine methosulfate and molecular oxygen","volume":"46","author":"Nishikimi","year":"1972","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/0003-2697(79)90738-3","article-title":"Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction","volume":"95","author":"Ohkawa","year":"1979","journal-title":"Anal. Biochem."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.canlet.2005.11.023","article-title":"Apoptosis of HL-60 cells induced by extracts from Narcissus tazetta var. chinensis","volume":"242","author":"Liu","year":"2006","journal-title":"Cancer Lett."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1007\/s10495-005-6075-6","article-title":"Morphological criteria to distinguish cell death induced by apoptotic and necrotic treatments","volume":"10","author":"Stockert","year":"2005","journal-title":"Apoptosis"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1007\/BF00142078","article-title":"Lack of gp120-induced anergy and apoptosis in chimpanzees is correlated with resistance to AIDS","volume":"1","author":"Banda","year":"1996","journal-title":"Apoptosis"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.phytochem.2013.12.001","article-title":"Capsaicin production by Alternaria alternata, an endophytic fungus from Capsicum annum; LC\u2013ESI\u2013MS\/MS analysis","volume":"98","author":"Devari","year":"2014","journal-title":"Phytochemistry"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1101\/gad.12.6.806","article-title":"Essential contribution of caspase 3\/CPP32 to apoptosis and its associated nuclear changes","volume":"12","author":"Woo","year":"1998","journal-title":"Genes Dev."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1740","DOI":"10.1111\/j.1349-7006.2009.01236.x","article-title":"Effect of the alcoholic extract of Ashwagandha leaves and its components on proliferation, migration, and differentiation of glioblastoma cells: Combinational approach for enhanced differentiation","volume":"100","author":"Shah","year":"2009","journal-title":"Cancer Sci."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1016\/j.bcp.2009.09.006","article-title":"Oleanane triterpenoid CDDO-Me inhibits growth and induces apoptosis in prostate cancer cells through a ROS-dependent mechanism","volume":"79","author":"Deeb","year":"2010","journal-title":"Biochem. Pharmacol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2014\/474953","article-title":"Antiproliferative and Apoptotic Effects ofSesbania grandifloraLeaves in Human Cancer Cells","volume":"2014","author":"Pajaniradje","year":"2014","journal-title":"BioMed Res. Int."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"W363","DOI":"10.1093\/nar\/gki481","article-title":"PatchDock and SymmDock: Servers for rigid and symmetric docking","volume":"33","author":"Inbar","year":"2005","journal-title":"Nucleic Acids Res."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"W367","DOI":"10.1093\/nar\/gkw315","article-title":"The RING 2.0 web server for high quality residue interaction networks","volume":"44","author":"Piovesan","year":"2016","journal-title":"Nucleic Acids Res."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/11\/3478\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:20:26Z","timestamp":1760138426000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/11\/3478"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,28]]},"references-count":85,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2022,6]]}},"alternative-id":["molecules27113478"],"URL":"https:\/\/doi.org\/10.3390\/molecules27113478","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,28]]}}}