Betulinic Acid and its Anticancer Effects

Year 2020, Volume: 10 Issue: 3, 128 - 134, 24.12.2020

Merve Nur Ataş Arzu Ergen

https://doi.org/10.26650/experimed.2020.0048

Abstract

In recent years, interest in naturally occurring compounds in plants has been increasing. Due to the benefits of these compounds, various studies have been carried out for their therapeutic use in cancer treatment as well as in daily use. These studies have aimed to develop chemotherapeutics that are natural and can stimulate apoptosis due to the side effects of chemotherapeutics used in current cancer treatments. One of these compounds, betulinic acid, is lupane-type pentacyclic triterpenoid, a secondary metab-olite found in the bark of various trees. Betulinic acid has strong anticancer properties as well as antiviral and anti-inflammatory effects. It performs its anticancer functions by promoting the mi-tochondrial apoptosis, regulating cell cycle and angiogenesis, and activating or deactivating many pathways which are important for cancer development. Molecules that directly affect mitochondria such as betulinic acid, hold great promise in preventing drug re-sistance that may occur in the treatment process. In addition, the fact that betulinic acid directly affects cancer cells and has no toxic effect on healthy cells makes it a potential anticancer molecule in developing chemotherapy strategies.This review aims to discuss the structural and biological properties of betulinic acid and the anticancer effects in various cancer types.

Keywords

Betulinic acid, cancer, apoptosis

Betülinik Asit ve Antikanser Etkiler

Abstract

Son yıllarda, bitkilerin yapısında doğal olarak bulunan bileşiklere duyulan ilgi giderek artmaktadır. Bu bileşiklerin sağladıkları fay-dalar nedeniyle günlük kullanımın yanı sıra kanser tedavisinde terapötik olarak kullanılmasına yönelik çeşitli çalışmalar yapılmak-tadır. Bu çalışmalar, güncel kanser tedavilerinde kullanılan kemo-terapötiklerin ortaya çıkardığı yan etkiler nedeniyle doğal kaynaklı ve apoptozu uyarabilen kemoterapötiklerin geliştirilmesini amaç-lamaktadır. Bu bileşiklerden biri olan betülinik asit, lupan tipi pen-tasiklik triterpenoid olup çeşitli ağaçların kabuklarında bulunan bir sekonder metabolittir. Betülinik asit, antiviral ve antiinflamatuvar etkiler gibi biyolojik aktivitelerin yanı sıra güçlü bir antikanser ak-tiviteye sahiptir. Bu antikanser aktivitesini, mitokondriyal apopto-zu teşvik ederek, hücre siklusunu ve anjiyogenezi düzenleyerek ve kanser gelişimi için önemli birçok yolağı aktive veya inaktive ederek gerçekleştirir. Betülinik asit gibi doğrudan mitokondriyi et-kileyen moleküller, tedavi sürecinde oluşabilecek ilaç direncini en-gellemek için büyük umut vaad etmektedir. Ayrıca betülinik asidin kanser hücrelerini doğrudan etkileyip sağlıklı hücrelere karşı toksik etkisinin olmaması geliştirilmekte olan kemoterapi stratejilerinde onu potansiyel antikanser molekül haline getirmektedir. Bu derlemede, betülinik asidin yapısal ve biyolojik özellikleri ile çeşitli kanser türlerindeki antikanser etkilerinin tartışılması amaç-lanmaktadır.

Keywords

Betülinik asit, kanser, apoptoz

References

• 1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Glo-bal cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68: 394-424. [CrossRef ]
• 2. de Castro Sant' Anna C, Junior AGF, Soares P, Tuji F, Paschoal E, Chaves LC, et al. Molecular biology as a tool for the treatment of cancer. Clin Exp Med 2018; 18: 457-64. [CrossRef ]
• 3. Francia R, Monaco A, Saggese M, Iaccarino G, Crisci S, Frigeri F, et al. Pharmacological profile and Pharmacogenomics of anti-cancer drugs used for targeted therapy. Curr Cancer Drug Targets 2018; 18(5): 499-511.
• 4. Lichota A, Gwozdzinski K. Anticancer activity of natural compoun-ds from plant and marine environment. Int J Mol Sci 2018; 19(11): 3533. [CrossRef ]
• 5. Delgoda R, Murray JE. Evolutionary Perspectives on the Role of Plant Secondary Metabolites. In: Badal S, Delgoda R, editors. Phar-macognosy, Academic Press, 2017. p. 93-100. [CrossRef ]
• 6. Kabera JN, Semana E, Mussa AR, He X. Plant Secondary Metabo-lites: Biosynthesis, Classification, Function and Pharmacological Properties. J Pharm Pharmacol 2014; 2: 377-92.
• 7. Tholl D. Biosynthesis and biological functions of terpenoids in plants. Adv Biochem Eng Biotechnol 2015; 148: 63-106. [CrossRef ]
• 8. Zhang X, Hu J, Chen Y. Betulinic acid and the pharmacological effects of tumor suppression. Mol Med Rep 2016; 14: 4489-95. [CrossRef ]
• 9. Csuk R. Betulinic acid and its derivatives: A patent review (2008-2013). Expert Opin Ther Pat 2014; 24: 913-23. [CrossRef ]
• 10. Kumar P, Bhadauria AS, Singh AK, Saha S. Betulinic acid as apopto-sis activator: Molecular mechanisms, mathematical modeling and chemical modifications. Life Sci 2018; 209: 24-33. [CrossRef ]
• 11. Fulda S, Kroemer G. Targeting mitochondrial apoptosis by betu-linic acid in human cancers. Drug Discov Today 2009; 14: 885-90. [CrossRef ]
• 12. Cháirez-Ramírez M, Moreno-Jiménez M, González-Laredo R, Galle-gos-Infante J, Rocha-Guzmán N. Lupane-type triterpenes and the-ir anti-cancer activities against most common malignant tumors: A review. EXCLI J 2016; 15: 758-71.
• 13. Ríos J, Máñez S. New Pharmacological Opportunities for Betulinic Acid. Planta Med 2018; 84: 8-19. [CrossRef ]
• 14. An T, Zha W, Zi J. Biotechnological production of betulinic acid and derivatives and their applications. Appl Microbiol Biotechnol 2020; 104: 3339-48. [CrossRef ]
• 15. Hordyjewska A, Ostapiuk A, Horecka A, Kurzepa J. Betulin and be-tulinic acid: triterpenoids derivatives with a powerful biological potential. Phytochem Rev 2019; 18: 929-51. [CrossRef ]
• 16. Gali-Muhtasib H, Hmadi R, Kareh M, Tohme R, Darwiche N. Cell de-ath mechanisms of plant-derived anticancer drugs: Beyond apop-tosis. Apoptosis 2015; 20: 1531-62. [CrossRef ]
• 17. Debatin K-M. Apoptosis pathways in cancer and cancer therapy. Cancer Immunol Immunother 2004; 53: 153-9. [CrossRef ]
• 18. Zhang X, Zhang S, Zhu S, Chen S, Han J, Gao K, et al. Identification of mitochondria-targeting anticancer compounds by an in vitro strategy. Anal Chem 2014; 86: 5232-7. [CrossRef ]
• 19. Lee D, Lee SR, Kang KS, Ko Y, Pang C, Yamabe N, et al. Betulinic Acid Suppresses Ovarian Cancer Cell Proliferation through Induction of Apoptosis. Biomolecules 2019; 9: 257. [CrossRef ]
• 20. Wang X, Lu X, Zhu R, Zhang K, Li S, Chen Z, et al. Betulinic Acid Induces Apoptosis in Differentiated PC12 Cells Via ROS-Mediated Mitochondrial Pathway. Neurochem Res 2017; 42: 1130-40. [CrossRef ]
• 21. Xu Y, Li J, Li Q-J, Feng Y-L, Pan F. Betulinic acid promotes TRAIL functi-on on liver cancer progression inhibition through p53/Caspase-3 sig-naling activation. Biomed Pharmacother 2017; 88: 349-58. [CrossRef ]
• 22. Shankar E, Zhang A, Franco D, Gupta S. Betulinic Acid-Mediated Apoptosis in Human Prostate Cancer Cells Involves p53 and Nuclear Factor-Kappa B (NF-κB) Pathways. Molecules 2017; 22. [CrossRef ]
• 23. Pandey MK, Sung B, Aggarwal BB. Betulinic acid suppresses STAT3 activation pathway through induction of protein tyrosine phosphatase SHP-1 in human multiple myeloma cells. Int J Cancer 2010; 127: 282-92. [CrossRef ]
• 24. Chintharlapalli S, Papineni S, Ramaiah SK, Safe S. Betulinic acid inhibits prostate cancer growth through inhibition of specificity protein transcription factors. Cancer Res 2007; 67: 2816-23. [CrossRef ]
• 25. Zeng A, Hua H, Liu L, Zhao J. Betulinic acid induces apoptosis and inhibits metastasis of human colorectal cancer cells in vitro and in vivo. Bioorg Med Chem 2019; 27(12): 2546-52. [CrossRef ]
• 26. Pisha E, Chai H, Lee IS, Chagwedera TE, Farnsworth NR, Cordell GA, et al. Discovery of betulinic acid as a selective inhibitor of human melanoma that functions by induction of apoptosis. Nat Med 1995; 1: 1046-51. [CrossRef ]
• 27. Fulda S, Friesen C, Los M, Scaffidi C, Mier W, Benedict M, et al. Betulinic Acid Triggers CD95 (APO-1/Fas)- and p53-independent Apoptosis via Activation of Caspases in Neuroectodermal Tumors. Cancer Res 1997; 57(21): 4956-64.
• 28. Fulda S, Scaffidi C, Susin SA, Krammer PH, Kroemer G, Peter ME, et al. Activation of mitochondria and release of mitochondrial apop-togenic factors by betulinic acid. J Biol Chem 1998; 273: 33942-8. [CrossRef ]
• 29. Wang CM, Yeh KL, Tsai SJ, Jhan YL, Chou CH. Anti-proliferative activity of triterpenoids and sterols isolated from Alstonia scho-laris against non-small-cell lung carcinoma cells. Molecules 2017; 22(12): 2119. [CrossRef ]
• 30. Ko JL, Lin CH, Chen HC, Hung WH, Chien PJ, Chang HY, et al. Effects and mechanisms of betulinic acid on improving EGFR TKI-resistance of lung cancer cells. Environ Toxicol 2018; 33: 1153-9. [CrossRef ]
• 31. Zhao H, Mu X, Zhang X, You Q. Lung cancer inhibition by betulinic acid nanoparticles via adenosine 5'-Triphosphate (ATP)-binding cassette transporter G1 gene downregulation. Med Sci Monit 2020; 26: e922092-1.
• 32. Kumar P, Gautam AK, Kumar U, Bhadauria AS, Singh AK, Kumar D, et al. Mechanistic exploration of the activities of poly(lactic- co -gl-ycolic acid)-loaded nanoparticles of betulinic acid against hepa-tocellular carcinoma at cellular and molecular levels. Arch Physiol Biochem 2020; 1-13. [CrossRef ]
• 33. De las Pozas A, Reiner T, De Cesare V, Trost M, Perez-Stable C. Inhibiting Multiple Deubiquitinases to Reduce Androgen Receptor Expression in Prostate Cancer Cells. Sci Rep 2018; 8: 13146 . [CrossRef ]
• 34. Shin J, Lee HJ, Jung DB, Jung JH, Lee HJ, Lee EO, et al. Suppression of STAT3 and HIF-1 Alpha mediates Anti-Angiogenic activity of Be-tulinic acid in Hypoxic PC-3 prostate cancer cells. PLoS One 2011; 6(6): e21492. [CrossRef ]
• 35. Asif M, Shafaei A, Abdul Majid AS, Ezzat MO, Dahham SS, Ahamed MBK, et al. Mesua ferrea stem bark extract induces apoptosis and inhibits metastasis in human colorectal carcinoma HCT 116 cells, through modulation of multiple cell signalling pathways. Chin J Nat Med 2017; 15: 505-14. [CrossRef ]
• 36. Rzeski W, Stepulak A, Szymański M, Sifringer M, Kaczor J, Wejksza K, et al. Betulinic acid decreases expression of bcl-2 and cyclin D1, inhibits proliferation, migration and induces apoptosis in cancer cells. Naunyn Schmiedebergs Arch Pharmacol 2006; 374: 11-20. [CrossRef ]
• 37. Tan YM, Yu R, Pezzuto JM. Betulinic acid-induced programmed cell death in human melanoma cells involves mitogen-activated pro-tein kinase activation. Clin Cancer Res 2003; 9: 2866-75.
• 38. Zeng AQ, Yu Y, Yao YQ, Yang FF, Liao M, Song LJ, et al. Betulinic acid impairs metastasis and reduces immunosuppressive cells in breast cancer models. Oncotarget 2018; 9: 3794-804. [CrossRef ]
• 39. Zheng Y, Liu P, Wang N, Wang S, Yang B, Li M, et al. Betulinic Acid Suppresses Breast Cancer Metastasis by Targeting GRP78-Medi-ated Glycolysis and ER Stress Apoptotic Pathway. Oxid Med Cell Longev 2019; 2019. [CrossRef ]
• 40. Weber D, Zhang M, Zhuang P, Zhang Y, Wheat J, Currie G, et al. The efficacy of betulinic acid in triple-negative breast cancer. SAGE Open Med 2014; 2: 205031211455197. [CrossRef ]
• 41. Xu T, Pang Q, Wang Y, Yan X. Betulinic acid induces apoptosis by regulating PI3K/Akt signaling and mitochondrial pathways in hu-man cervical cancer cells. Int J Mol Med 2017; 40: 1669-78. [Cross-Ref ]
• 42. Liu W, Li S, Qu Z, Luo Y, Chen R, Wei S, et al. Betulinic acid induces autophagy-mediated apoptosis through suppression of the PI3K/AKT/mTOR signaling pathway and inhibits hepatocellular carcino-ma. Am J Transl Res 2019; 11: 6952-64.
• 43. Kim HJ, Cho HS, Ban HS, Nakamura H. Suppression of HIF-1α accu-mulation by betulinic acid through proteasome activation in hy-poxic cervical cancer. Biochem Biophys Res Commun 2020; 523: 726-32. [CrossRef ]
• 44. Zhang H, Li L, Li M, Huang X, Xie W, Xiang W, et al. Combination of betulinic acid and chidamide inhibits acute myeloid leukemia by suppression of the HIF1α pathway and generation of reactive oxygen species. Oncotarget 2017; 8: 94743-58. [CrossRef ]
• 45. Liao L, Liu C, Xie X, Zhou J. Betulinic acid induces apoptosis and impairs migration and invasion in a mouse model of ovarian can-cer. J Food Biochem 2020; 44: e13278. [CrossRef ]
• 46. Yang C, Li Y, Fu L, Jiang T, Meng F. Betulinic acid induces apopto-sis and inhibits metastasis of human renal carcinoma cells in vitro and in vivo. J Cell Biochem 2018; 119: 8611-22. [CrossRef ]
• 47. Lu T, Wei D, Yu K, Ma D, Xiong J, Fang Q, et al. Betulinic acid restores imatinib sensitivity in BCR‐ABL1 kinase−independent, imatinib‐resistant chronic myeloid leukemia by increasing HDAC3 ubiqu-itination and degradation. Ann N Y Acad Sci 2020; 1467: 77-93. [CrossRef ]
• 48. Yuan DY, Meng Z, Xu K, Li QF, Chen C, Li KY, et al. Betulinic acid increases radiosensitization of oral squamous cell carcinoma th-rough inducing Sp1 sumoylation and PTEN expression. Oncol Rep 2017; 38: 2360-8. [CrossRef ]
• 49. Amiri S, Dastghaib S, Ahmadi M, Mehrbod P, Khadem F, Behrouj H, et al. Betulin and its derivatives as novel compounds with dif-ferent pharmacological effects. Biotechnol Adv 2020; 38: 107409. [CrossRef ]
• 50. D'Adamo S, Schiano di Visconte G, Lowe G, Szaub-Newton J, Beac-ham T, Landels A, et al. Engineering the unicellular alga Phaeoda-ctylum tricornutum for high-value plant triterpenoid production. Plant Biotechnol J 2019; 17: 75-87. [CrossRef ]