Letter to the editor

Recent studies on betulinic acid and its biological and pharmacological activity

Sook Young Lee¹, Haeng Hoon Kim², Sang Un Park³[*]

EXCLI J 2015;14:Doc199



Dear Editor,

Betulinic acid (3β-hydroxy-lup-20(29)-en-28-oic acid, BA), a pentacyclic lupane-type triterpene, is widely distributed in the plant kingdom (Mukherjee et al., 2006[20]; Fulda, 2008[8]). Johann Tobias Lowitz isolated the reduced form of BA from plants in 1788 and found that it was a prominent outer-bark constituent in white-barked birch trees (Bag and Dash, 2011[2]). BA has a wide range of biological and medicinal properties, including anti-human immunodeficiency virus (HIV), antibacterial, antimalarial, anti-inflammatory, anthelmintic, antinociceptive, anti-herpes simplex viruses-1 (HSV-1), immune-modulatory, antiangiogenic, and anticancer activity (Yogeeswari and Sriram, 2005[38]; Gheorgheosu et al, 2014[10]). Furthermore, the anti-tumor activity of BA can help overcome resistance by inducing apoptosis in a variety of human cancers.

Semi-synthetic derivatives of natural plant products continue to play an important role in drug discovery and development (Pan et al., 2010[22]). To improve the potency of BA, many derivatives have been synthesized and evaluated for biological/medicinal applications (Jonnalagadda et al., 2013[13]; Csuk, 2014[5]). Because of its range of biological properties, BA has attracted much attention in recent years in the pharmaceutical industry. Here, we summarize key recent studies performed to evaluate the biological and pharmacological activities of BA and its derivatives (Table 1(Tab. 1)). (References in Table 1: Lingaraju et al., 2015[18]; Xu et al., 2014[35]; Kim et al., 2014[15]; Tiwari et al, 2014[29]; Xia et al., 2014[34]; Soica et al., 2014[27]; Sousa et al., 2014[28]; Jin et al., 2014[12]; Godugu et al., 2014[11]; Park et al., 2014[23]; Yi et al., 2014[37]; Castro et al., 2014[4]; Afzal et al., 2014[1]; Gao et al., 2014[9]; Zhao et al., 2013[39]; Ding et al., 2013[7]; Baratto et al., 2013[3]; Damle et al., 2013[6]; Li et al., 2013[17]; Wan et al., 2013[31]; Kaur and Arora, 2013[14]; Quan et al., 2013[25]; Reiner et al., 2013[26]; Qian et al., 2012[24]; Yang et al., 2012[36]; Wang et al., 2012[33]; Tzakos et al., 2012[30]; Liu and Luo, 2012[19]; Nader and Baraka, 2012[21]; Wan et al., 2012[32]; Kim et al., 2012[15]).

Acknowledgements

This study was supported by the Regional Innovation Center for Dental Science & Engineering, Chosun University, Gwangju, Korea (B0008940).

References

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2. Bag BG, Dash SS. First self-assembly study of betulinic acid, a renewable nano-sized, 6-6-6-6-5 pentacyclic monohydroxy triterpenic acid. Nanoscale. 2011;3:4564-6.

3. Baratto LC, Porsani MV, Pimentel IC, Pereira Netto AB, Paschke R, Oliveira BH. Preparation of betulinic acid derivatives by chemical and biotransformation methods and determination of cytotoxicity against selected cancer cell lines. Eur J Med Chem. 2013;68:121-31.

4. Castro AJ, Frederico MJ, Cazarolli LH, Bretanha LC, Tavares Lde C, Buss Zda S, et al. Betulinic acid and 1,25(OH)₂vitamin D3 share intracellular signal transduction in glucose homeostasis in soleus muscle. Int J Biochem Cell Biol. 2014;48:18-27.

5. Csuk R. Betulinic acid and its derivatives: a patent review (2008-2013). Expert Opin Ther Pat. 2014;24:913-23.

6. Damle AA, Pawar YP, Narkar AA. Anticancer activity of betulinic acid on MCF-7 tumors in nude mice. Indian J Exp Biol. 2013;51:485-91.

7. Ding W, Sun M, Luo S, Xu T, Cao Y, Yan X, et al. A 3D QSAR study of betulinic acid derivatives as anti-tumor agents using topomer CoMFA: model building studies and experimental verification. Molecules. 2013;18:10228-41.

8. Fulda S. Betulinic aAid for cancer treatment and prevention. Int J Mol Sci. 2008;9:1096-107.

9. Gao M, Lau PM, Kong SK. Mitochondrial toxin betulinic acid induces in vitro eryptosis in human red blood cells through membrane permeabilization. Arch Toxicol. 2014;88:755-68.

10. Gheorgheosu D, Duicu O, Dehelean C, Soica C, Muntean D. Betulinic acid as a potent and complex antitumor phytochemical: a minireview. Anticancer Agents Med Chem. 2014;14:936-45.

11. Godugu C, Patel AR, Doddapaneni R, Somagoni J, Singh M. Approaches to improve the oral bioavailability and effects of novel anticancer drugs berberine and betulinic acid. PLoS One. 2014;9:e89919.

12. Jin KS, Oh YN, Hyun SK, Kwon HJ, Kim BW. Betulinic acid isolated from Vitis amurensis root inhibits 3-isobutyl-1-methylxanthine induced melanogenesis via the regulation of MEK/ERK and PI3K/Akt pathways in B16F10 cells. Food Chem Toxicol. 2014;68:38-43.

13. Jonnalagadda SC, Corsello MA, Sleet CE. Betulin-betulinic acid natural product based analogs as anti-cancer agents. Anticancer Agents Med Chem. 2013;13:1477-99.

14. Kaur R, Arora S. Interactions of betulinic acid with xenobiotic metabolizing and antioxidative enzymes in DMBA-treated Sprague Dawley female rats. Free Radic Biol Med. 2013;65:131-42.

15. Kim HI, Quan FS, Kim JE, Lee NR, Kim HJ, Jo SJ, et al. Inhibition of estrogen signaling through depletion of estrogen receptor alpha by ursolic acid and betulinic acid from Prunella vulgaris var. lilacina. Biochem Biophys Res Commun. 2014;451:282-7.

16. Kim J, Lee YS, Kim CS, Kim JS. Betulinic acid has an inhibitory effect on pancreatic lipase and induces adipocyte lipolysis. Phytother Res. 2012;26:1103-6.

17. Li L, Du Y, Kong X, Li Z, Jia Z, Cui J, et al. Lamin B1 is a novel therapeutic target of betulinic acid in pancreatic cancer. Clin Cancer Res. 2013;19:4651-61.

18. Lingaraju MC, Pathak NN, Begum J, Balaganur V, Bhat RA, Ramachandra HD, et al. Betulinic acid attenuates lung injury by modulation of inflammatory cytokine response in experimentally-induced polymicrobial sepsis in mice. Cytokine. 2015;71:101-8.

19. Liu Y, Luo W. Betulinic acid induces Bax/Bak-independent cytochrome c release in human nasopharyngeal carcinoma cells. Mol Cells. 2012;33:517-24.

20. Mukherjee R, Kumar V, Srivastava SK, Agarwal SK, Burman AC. Betulinic acid derivatives as anticancer agents: structure activity relationship. Anticancer Agents Med Chem. 2006;6:271-9.

21. Nader MA, Baraka HN. Effect of betulinic acid on neutrophil recruitment and inflammatory mediator expression in lipopolysaccharide-induced lung inflammation in rats. Eur J Pharm Sci. 2012;46:106-13.

22. Pan L, Chai H, Kinghorn AD. The continuing search for antitumor agents from higher plants. Phytochem Lett. 2010;3:1-8.

23. Park SY, Kim HJ, Kim KR, Lee SK, Lee CK, Park KK, et al. Betulinic acid, a bioactive pentacyclic triterpenoid, inhibits skeletal-related events induced by breast cancer bone metastases and treatment. Toxicol Appl Pharmacol. 2014;275:152-62.

24. Qian LB, Fu JY, Cai X, Xia ML. Betulinic acid inhibits superoxide anion-mediated impairment of endothelium-dependent relaxation in rat aortas. Indian J Pharmacol. 2012;44:588-92.

25. Quan HY, Kim do Y, Kim SJ, Jo HK, Kim GW, Chung SH. Betulinic acid alleviates non-alcoholic fatty liver by inhibiting SREBP1 activity via the AMPK-mTOR-SREBP signaling pathway. Biochem Pharmacol. 2013;85:1330-40.

26. Reiner T, Parrondo R, de Las Pozas A, Palenzuela D, Perez-Stable C. Betulinic acid selectively increases protein degradation and enhances prostate cancer-specific apoptosis: possible role for inhibition of deubiquitinase activity. PLoS One. 2013;8(2):e56234.

27. Soica C, Danciu C, Savoiu-Balint G, Borcan F, Ambrus R, Zupko I, et al. Betulinic acid in complex with a gamma-cyclodextrin derivative decreases proliferation and in vivo tumor development of non-metastatic and metastatic B164A5 cells. Int J Mol Sci. 2014;15:8235-55.

28. Sousa MC, Varandas R, Santos RC, Santos-Rosa M, Alves V, Salvador JA. Antileishmanial activity of semisynthetic lupane triterpenoids betulin and betulinic acid derivatives: synergistic effects with miltefosine. PLoS One. 2014;9(3):e89939.

29. Tiwari R, Puthli A, Balakrishnan S, Sapra BK, Mishra KP. Betulinic acid-induced cytotoxicity in human breast tumor cell lines MCF-7 and T47D and its modification by tocopherol. Cancer Invest. 2014;32:402-8.

30. Tzakos AG, Kontogianni VG, Tsoumani M, Kyriakou E, Hwa J, Rodrigues FA, et al. Exploration of the antiplatelet activity profile of betulinic acid on human platelets. J Agric Food Chem. 2012;60:6977-83.

31. Wan Y, Jiang S, Lian LH, Bai T, Cui PH, Sun XT, et al. Betulinic acid and betulin ameliorate acute ethanol-induced fatty liver via TLR4 and STAT3 in vivo and in vitro. Int Immunopharmacol. 2013;17:184-90.

32. Wan Y, Wu YL, Lian LH, Xie WX, Li X, Ouyang BQ, et al. The anti-fibrotic effect of betulinic acid is mediated through the inhibition of NF-κB nuclear protein translocation. Chem Biol Interact. 2012;195:215-23.

33. Wang P, Li Q, Li K, Zhang X, Han Z, Wang J, et al. Betulinic acid exerts immunoregulation and anti-tumor effect on cervical carcinoma (U14) tumor-bearing mice. Pharmazie. 2012;67:733-9.

34. Xia A, Xue Z, Li Y, Wang W, Xia J, Wei T, et al. Cardioprotective effect of betulinic Acid on myocardial ischemia reperfusion injury in rats. Evid Based Complement Alternat Med. 2014;2014:573745.

35. Xu T, Pang Q, Zhou D, Zhang A, Luo S, Wang Y, et al. Proteomic investigation into betulinic acid-induced apoptosis of human cervical cancer HeLa cells. PLoS One. 2014;9(8):e105768.

36. Yang LJ, Chen Y, He J, Yi S, Wen L, Zhao J, et al. Betulinic acid inhibits autophagic flux and induces apoptosis in human multiple myeloma cells in vitro. Acta Pharmacol Sin. 2012;33:1542-8.

37. Yi J, Xia W, Wu J, Yuan L, Wu J, Tu D, et al. Betulinic acid prevents alcohol-induced liver damage by improving the antioxidant system in mice. J Vet Sci. 2014;15:141-8.

38. Yogeeswari P, Sriram D. Betulinic acid and its derivatives: a review on their biological properties. Curr Med Chem. 2005;12:657-66.

39. Zhao GJ, Tang SL, Lv YC, Ouyang XP, He PP, Yao F, et al. Antagonism of betulinic acid on LPS-mediated inhibition of ABCA1 and cholesterol efflux through inhibiting nuclear factor-kappaB signaling pathway and miR-33 expression. PLoS One. 2013;8(9):e74782.

 

 

 

Table 1: Recent studies on betulinic acid and its biological and pharmacological activities

[*] Corresponding Author:

Sang Un Park, Department of Crop Science, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon, 305-764, Korea; Phone: +82-42-822-2631, Fax: +82-42-822-2631, eMail: supark@cnu.ac.kr