Skip to main content
Log in

Bioactivity evaluations of betulin identified from the bark of Betula platyphylla var. japonica for cancer therapy

  • Research Article
  • Published:
Archives of Pharmacal Research Aims and scope Submit manuscript

Abstract

Identification of bioactive natural products with anticancer activity as well as alleviating effects on chemotherapy-induced side effects has significant implications for cancer treatment. Betula platyphylla var. japonica, commonly known as Asian white birch, has been used in Chinese traditional medicine for a variety of purposes. In this study, the medicinal properties of betulin from B. platyphylla var. japonica useful for cancer management were investigated. LC/MS analysis revealed that betulin is a main chemical component of the EtOH extract of B. platyphylla var. japonica bark, and betulin was isolated from EtOH extract using an LC/MS-guided isolation method. Its structure was identified with 1H and 13C NMR spectroscopic data and LC/MS analysis and then compared to the previously reported spectroscopic and physical data. We first verified the cytotoxicity of betulin against three human lung adenocarcinoma cell lines, A549, H1264, and Calu-6, with IC50 values ranging from 18.7 to 39.6 μM. Regarding alleviation of side effects associated with anticancer chemotherapy, betulin ameliorated cisplatin-induced renal cell damage to 80% of the control value from the concentration of 5 μM. In addition, betulin showed anti-gastritis activity against ethanol-induced gastric damage in rats and notably reduced the gastric damage index compared to control in a concentration-dependent manner. These findings provide the first experimental evidence for potential use of B. platyphylla var. japonica as a functional food for cancer treatment that simultaneously alleviates the side effects of chemotherapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Aayadi H, Mittal SPK, Deshpande A, Gore M, Ghaskadbi SS (2017) Cytoprotective effect exerted by geraniin in HepG2 cells is through microRNA mediated regulation of BACH-1 and HO-1. BMB Rep 50:560–565

    Article  PubMed  PubMed Central  Google Scholar 

  • Auguste LJ, Lackner R, Ratner L, Stein TA, Bailey B (1990) Prevention of stress-induced erosive gastritis by parenteral administration of arachidonic acid. JPEN J Parenter Enteral Nutr 14:615–617

    Article  PubMed  CAS  Google Scholar 

  • Beemelmanns C, Ramadhar TR, Kim KH, Klassen JL, Cao S, Wyche TP, Hou Y, Poulsen M, Bugni TS, Currie CR (2017) Macrotermycins A-D, glycosylated macrolactams from a termite-associated Amycolatopsis sp. M39. Org Lett 19:1000–1003

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Bhanot A, Sharma R, Noolvi MN (2011) Natural sources as potential anti-cancer agents: a review. Int J Phytomed 3:09

    Google Scholar 

  • Boussios S, Pentheroudakis G, Katsanos K, Pavlidis N (2012) Systemic treatment-induced gastrointestinal toxicity: incidence, clinical presentation and management. Ann Gastroenterol 25:106

    PubMed  PubMed Central  Google Scholar 

  • Brami C, Bao T, Deng G (2016) Natural products and complementary therapies for chemotherapy-induced peripheral neuropathy: a systematic review. Crit Rev Oncol Hematol 98:325–334

    Article  PubMed  Google Scholar 

  • Chabner BA, Roberts TG Jr (2005) Chemotherapy and the war on cancer. Nat Rev Cancer 5:65

    Article  PubMed  CAS  Google Scholar 

  • Chunhua M, Long H, Zhu W, Liu Z, Jie R, Zhang Y, Wang Y (2017) Betulin inhibited cigarette smoke-induced COPD in mice. Biomed Pharmacother 85:679–686

    Article  PubMed  CAS  Google Scholar 

  • Dasari S, Tchounwou PB (2014) Cisplatin in cancer therapy: molecular mechanisms of action. Eur J Pharmacol 740:364–378

    Article  PubMed  CAS  Google Scholar 

  • De Angelis C (2008) Side effects related to systemic cancer treatment: are we changing the Promethean experience with molecularly targeted therapies? Curr Oncol 15:198

    Article  PubMed  PubMed Central  Google Scholar 

  • Du J, Tang XL (2014) Natural products against cancer: a comprehensive bibliometric study of the research projects, publications, patents and drugs. J Can Res Ther 10:27

    Article  CAS  Google Scholar 

  • Elmore S (2007) Apoptosis: a review of programmed cell death. Toxicol Pathol 35:495–516

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Eom HJ, Kang HR, Kim HK, Jung EB, Park HB, Kang KS, Kim KH (2016) Bioactivity-guided isolation of antioxidant triterpenoids from Betula platyphylla var. japonica bark. Bioorg Chem 66:97–101

    Article  PubMed  CAS  Google Scholar 

  • Eom HJ, Kang HR, Choi SU, Kim KH (2017) Cytotoxic Triterpenoids from the Barks of Betula platyphylla var. japonica. Chem Biodivers 14:e1600400

    Article  CAS  Google Scholar 

  • Fitzmaurice C, Allen C, Barber RM, Barregard L, Bhutta ZA, Brenner H, Dicker DJ, Chimed Orchir O, Dandona R, Dandona L (2017) Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: a systematic analysis for the global burden of disease study. JAMA Oncol 3:524–548

    Article  PubMed  Google Scholar 

  • Florea AM, Büsselberg D (2011) Cisplatin as an anti-tumor drug: cellular mechanisms of activity, drug resistance and induced side effects. Cancers 3:1351–1371

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Fukuhara K, Terakura M, Katsuragi K (2011) Severe gastric and duodenal ulcer after chemotherapy of mFOLFOX6 and bevacizumab. Gan to kagaku ryoho Cancer chemother 38:457–459

    Google Scholar 

  • Hamlet A, Lindholm C, Nilsson O, Olbe L (1998) Aspirin-induced gastritis, like Helicobacter pylori-induced gastritis disinhibits acid secretion in humans: relation to cytokine expression. Scand J Gastroenterol 33:346–356

    Article  PubMed  CAS  Google Scholar 

  • Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674

    Article  PubMed  CAS  Google Scholar 

  • Heo J (1980) Donguibogam. Namsadang, Seoul

    Google Scholar 

  • Huh JE, Hong JM, Baek YH, Lee JD, Choi DY, Park DS (2011) Anti-inflammatory and anti-nociceptive effect of Betula platyphylla var. japonica in human interleukin-1β-stimulated fibroblast-like synoviocytes and in experimental animal models. J Ethnopharmacol 135:126–134

    Article  PubMed  Google Scholar 

  • Jeon WY, Shin IS, Shin HK, Lee MY (2014) Gastroprotective effect of the traditional herbal medicine, Sipjeondaebo-tang water extract, against ethanol-induced gastric mucosal injury. BMC Complement Altern Med 14:373

    Article  PubMed  PubMed Central  Google Scholar 

  • Johnson I, Wright H, Svoboda G (1959) Experimental basis for clinical evaluation of anti tumor principles derived from Vinca-Rosea Linn. J Lab Clin Med 54:830

    Google Scholar 

  • Ju EM, Lee SE, Hwang HJ, Kim JH (2004) Antioxidant and anticancer activity of extract from Betula platyphylla var. japonica. Life Sci 74:1013–1026

    Article  PubMed  CAS  Google Scholar 

  • Jung EJ, Chung KH, Kim CW (2017) Identification of simvastatin-regulated targets associated with JNK activation in DU145 human prostate cancer cell death signaling. BMB Rep 50:466–471

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kaku H, Kumagai S, Onoue H, Takada A, Shoji T, Miura F, Yoshizaki A, Sato S, Kigawa J, Arai T (2012) Objective evaluation of the alleviating effects of Goshajinkigan on peripheral neuropathy induced by paclitaxel/carboplatin therapy: a multicenter collaborative study. Exp Ther Med 3:60–65

    Article  PubMed  CAS  Google Scholar 

  • Kang HR, Lee D, Benndorf R, Jung WH, Beemelmanns C, Kang KS, Kim KH (2016) Termisoflavones A-C, Isoflavonoid Glycosides from Termite-Associated Streptomyces sp. RB1. J Nat Prod 79:3072–3078

    Article  PubMed  CAS  Google Scholar 

  • Kao KC, Ho YL, Lin I, Ho LK, Chang YS (2004) Flavone glycosides from Strobilanthes formosanus. J Chin Chem Soc 51:199–204

    Article  CAS  Google Scholar 

  • Kim JI, Park SW, Lim JJ, Sohn SI, Shin JS, Park SC, Jang YP, Chung EK, Lee HW, Lee KT (2017) Gastroprotective effects of the isopropanol extract of Artemisia princeps and its gastroretentive floating tablets on gastric mucosal injury. Acta Pharm 67:479–494

    Article  PubMed  CAS  Google Scholar 

  • Lee S, Jung K, Lee D, Lee SR, Lee KR, Kang KS, Kim KH (2015) Protective effect and mechanism of action of lupane triterpenes from Cornus walteri in cisplatin-induced nephrotoxicity. Bioorg Med Chem Lett 25:5613–5618

    Article  PubMed  CAS  Google Scholar 

  • Lee SR, Park JY, Yu JS, Lee SO, Ryu JY, Choi SZ, Kang KS, Yamabe N, Kim KH (2016) Odisolane, a novel oxolane derivative, and antiangiogenic constituents from the fruits of mulberry (Morus alba L.). J Agric Food Chem 64:3804–3809

    Article  PubMed  CAS  Google Scholar 

  • Liang J, Dou Y, Wu X, Li H, Wu J, Huang Q, Luo D, Yi T, Liu Y, Su Z, Chen J (2018) Prophylactic efficacy of patchoulene epoxide against ethanol-induced gastric ulcer in rats: influence on oxidative stress, inflammation and apoptosis. Chem Biol Interact 283:30–37

    Article  PubMed  CAS  Google Scholar 

  • Liu B, Ezeogu L, Zellmer L, Yu B, Xu N, Joshua Liao D (2015) Protecting the normal in order to better kill the cancer. Cancer Med 4:1394–1403

    Article  PubMed  PubMed Central  Google Scholar 

  • Ma C, Long H (2016) Protective effect of betulin on cognitive decline in streptozotocin (STZ)-induced diabetic rats. Neurotoxicology 57:104–111

    Article  PubMed  CAS  Google Scholar 

  • Mann J (2002) Natural products in cancer chemotherapy: past, present and future. Nat Rev Cancer 2:143

    Article  PubMed  CAS  Google Scholar 

  • Matsuda H, Ishikado A, Nishida N, Ninomiya K, Fujiwara H, Kobayashi Y, Yoshikawa M (1998) Hepatoprotective, superoxide scavenging, and antioxidative activities of aromatic constituents from the bark of Betula platyphylla var. japonica. Bioorg Med Chem Lett 8:2939–2944

    Article  PubMed  CAS  Google Scholar 

  • Mori K, Tominaga K, Yokoyama K, Suga Y, Kishiro I, Tsurui M (1995) Efficacy of famotidine in patients with acute gastric mucosal injury after continuous infusion of cisplatin plus vindesine. J Cancer Res Clin Oncol 121:367–370

    Article  PubMed  CAS  Google Scholar 

  • Peng Y, Zhong Y, Li G (2016) Tubeimoside-1 suppresses breast cancer metastasis through downregulation of CXCR4 chemokine receptor expression. BMB Rep 49:502–507

    Article  PubMed  PubMed Central  Google Scholar 

  • Periasamy G, Teketelew G, Gebrelibanos M, Sintayehu B, Gebrehiwot M, Karim A, Geremedhin G (2014) Betulinic acid and its derivatives as anti-cancer agent: a review. Arch Appl Sci Res 6:47–58

    Google Scholar 

  • Saif MW, Lansigan F, Ruta S, Lamb L, Mezes M, Elligers K, Grant N, Jiang Z, Liu S, Cheng Y (2010) Phase I study of the botanical formulation PHY906 with capecitabine in advanced pancreatic and other gastrointestinal malignancies. Phytomedicine 17:161–169

    Article  PubMed  CAS  Google Scholar 

  • Taher M, Aminuddin A, Susanti D, Aminudin NI, On S, Ahmad F, Hamidon H (2016) Cytotoxic, anti-Inflammatory and adipogenic effects of inophyllum D, calanone, isocordato-oblongic acid, and morelloflavone on cell lines. Nat Prod Sci 22:122–128

    Article  CAS  Google Scholar 

  • Tol J, Cats A, Mol L, Koopman M, Bos MMEM, Van Der Hoeven JJM, Antonini NF, Van Krieken JHJM, Punt CJA (2008) Gastrointestinal ulceration as a possible side effect of bevacizumab which may herald perforation. Invest New Drugs 26:393–397

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Vassilomanolakis M, Koumakis G, Barbounis V, Demiri M, Panopoulos C, Chrissohoou M, Apostolikas N, Efremidis AP (2005) First-line chemotherapy with docetaxel and cisplatin in metastatic breast cancer. Breast 14:136–141

    Article  PubMed  CAS  Google Scholar 

  • Verma S, Kumar VL (2018) Artesunate affords protection against aspirin-induced gastric injury by targeting oxidative stress and proinflammatory signaling. Pharmacol Rep 70:390–397

    Article  PubMed  CAS  Google Scholar 

  • Yao X, Panichpisal K, Kurtzman N, Nugent K (2007) Cisplatin nephrotoxicity: a review. Am J Med Sci 334:115–124

    Article  PubMed  Google Scholar 

  • Yu JS, Baek J, Park HB, Moon E, Kim SY, Choi SU, Kim KH (2016) A new rearranged eudesmane sesquiterpene and bioactive sesquiterpenes from the twigs of Lindera glauca (Sieb. et Zucc.) Blume. Arch Pharm Res 39:1628–1634

    Article  PubMed  CAS  Google Scholar 

  • Yu JS, Moon E, Kim KH (2017) A new cerebroside from the twigs of Lindera glauca (Sieb. et Zucc.) Blume. Bioorg Chem 74:122–125

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (2015R1C1A1A02037383) and by the Ministry of Education (NRF-2012R1A5A2A28671860).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ki Hyun Kim.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 372 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

So, H.M., Eom, H.J., Lee, D. et al. Bioactivity evaluations of betulin identified from the bark of Betula platyphylla var. japonica for cancer therapy. Arch. Pharm. Res. 41, 815–822 (2018). https://doi.org/10.1007/s12272-018-1064-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12272-018-1064-9

Keywords

Navigation