Betulinic Acid Induces Apoptosis in Differentiated PC12 Cells Via ROS-Mediated Mitochondrial Pathway
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Betulinic acid (BA), a pentacyclic triterpene of natural origin, has been demonstrated to have varied biologic activities including anti-viral, anti-inflammatory, and anti-malarial effects; it has also been found to induce apoptosis in many types of cancer. However, little is known about the effect of BA on normal cells. In this study, the effects of BA on normal neuronal cell apoptosis and the mechanisms involved were studied using differentiated PC12 cells as a model. Treatment with 50 μM BA for 24 h apparently induced PC12 cell apoptosis. In the early stage of apoptosis, the level of intracellular reactive oxygen species (ROS) increased. Afterwards, the loss of the mitochondrial membrane potential, the release of cytochrome c and the activation of caspase-3 occurred. Treatment with antioxidants could significantly reduce BA-induced PC12 cell apoptosis. In conclusion, we report for the first time that BA induced the mitochondrial apoptotic pathway in differentiated PC12 cells through ROS.
KeywordsBA PC12 cells Apoptosis Mitochondrial ROS
This study was supported by grants from the National Natural Science Foundation of China (No. 81171147), “Xingwei Project” Key Personal Medical Research Foundation of Health Department of Jiangsu Province (No. RC201156), “Six Categories of Key Person” Research Foundation of Jiangsu Province (No. 069), and the Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (No. JX10231801).
Compliance with Ethical Standards
Conflict of interest
The authors declare no conflicts of interests.
- 3.Son LB, Kaplun AP, Spilevskii AA, Andiia-Pravdivyi Iu E, Alekseeva SG, Gribor’ev VB, Shvets VI (1998) Synthesis of betulinic acid from betulin and study of its solubilization usingliposomes. Bioorganicheskaia khimiia 24:787–793Google Scholar
- 5.Qian K, Yu D, Chen CH, Huang L, Morris-Natschke SL, Nitz TJ, Salzwedel K, Reddick M, Allaway GP, Lee KH (2009) Anti-AIDS agents. 78. Design, synthesis, metabolic stability assessment, and antiviral evaluation of novel betulinic acid derivatives as potent anti-human immunodeficiency virus (HIV) agents. J Med Chem 52:3248–3258CrossRefPubMedPubMedCentralGoogle Scholar
- 8.Yasukawa K, Takido M, Matsumoto T, Takeuchi M, Nakagawa S (1991) Sterol and triterpene derivatives from plants inhibit the effects of a tumor promoter, and sitosterol and betulinic acid inhibit tumor formation in mouse skin two-stage carcinogenesis. Int Soc Cell 48:72–76Google Scholar
- 17.Hsu TI, Chen YJ, Hung CY, Wang YC, Lin SJ, Su WC, Lai MD, Kim SY, Wang Q, Qian K, Goto M, Zhao Y, Kashiwada Y, Lee KH, Chang WC, Hung JJ (2015) A novel derivative of betulinic acid, SYK023, suppresses lung cancer growth and malignancy. Oncotarget 6:13671–13687CrossRefPubMedPubMedCentralGoogle Scholar
- 23.Blazevski J, Petkovic F, Momcilovic M, Paschke R, Kaluderovic GN, Mostarica Stojkovic M, Miljkovic D (2013) Betulinic acid regulates generation of neuroinflammatory mediators responsible for tissue destruction in multiple sclerosis in vitro. Acta Pharmacol Sin 34:424–431CrossRefPubMedPubMedCentralGoogle Scholar
- 24.Bache M, Zschornak MP, Passin S, Kessler J, Wichmann H, Kappler M, Paschke R, Kaluderovic GN, Kommera H, Taubert H, Vordermark D (2011) Increased betulinic acid induced cytotoxicity and radiosensitivity in glioma cells under hypoxic conditions. Radiat Oncol 6:111CrossRefPubMedPubMedCentralGoogle Scholar
- 42.Das J, Samadder A, Das S, Paul A, Khuda-Bukhsh AR (2016) Nanopharmaceutical approach for enhanced anti-cancer activity of betulinic acid in lung-cancer treatment via activation of PARP: interaction with DNA as a target: anti-cancer potential of nano-betulinic acid in lung cancer. J Pharmacopunct 19:37–44CrossRefGoogle Scholar