Nat Prod Sci.  2018 Dec;24(4):219-224. 10.20307/nps.2018.24.4.219.

The Cytotoxic Constituents of Betula platyphylla and their Effects on Human Lung A549 Cancer Cells

• Yang EJ
• An JH
• Son YK
• Yeo JH
• Song KS

• KMID: 2432414
• DOI: http://doi.org/10.20307/nps.2018.24.4.219

Abstract

During the screening for cytotoxic compounds from plants grown in Korea, Betula platyphylla (BP) showed potent activity against the adenocarcinomic human alveolar basal epithelial A549 cell line. To identify the cytotoxic components from BP, the CHâ‚‚Clâ‚‚ fraction with the most significant cytotoxic effect was applied to the column chromatographies. Seven compounds were isolated: lupeol (1), betulinic acid (2), (−)-rhododendrol (3), platyphyllenone (4), platyphyllone (5), (−)-centrolobol (6), and oleanolic acid (7). Among them, three diarylheptanoids (4 - 6) exhibited cytotoxicity toward A549 cells. Especially, 50 µM of 4 reduced A549 cell viability to 18.93 ± 0.82% compared to control (100.00 ± 21.48%). Lactate dehydrogenase (LDH) leakage and intracellular reactive oxygen species (ROS) production were also induced by 50 µM 4. This is the first report on the cytotoxic effect of BP-derived diarylheptanoids 4-6 against A549 cells. The compound 4 may be useful for the development of early hit compounds for non-small cell lung carcinoma, but the consideration about selectivity of 4 is required since 4 also showed the cytotoxicity in the human normal lung epithelial BEAS-2B cell line.

Keyword

Betula platyphylla; diarylheptanoids; platyphyllenone; A549; cytotoxicity

MeSH Terms

Betula*
Cell Line
Cell Survival
Chromatography
Diarylheptanoids
Humans*
Korea
L-Lactate Dehydrogenase
Lung*
Mass Screening
Oleanolic Acid
Reactive Oxygen Species
Diarylheptanoids
L-Lactate Dehydrogenase
Oleanolic Acid
Reactive Oxygen Species

Figure

• 

  Fig. 1 The cytotoxic effects of Betula platyphylla (BP) extract (200 µg/mL) on A549 cells. Doxorubicin (DOX; 5 µM; A549 cell viability, 19.69 ± 2.84%) was used as a positive control. *, p < 0.05 compared with the control group (CNT).

• 

  Fig. 2 The cytotoxic effects of the partitioned fractions from BP on A549 cells. DOX (5 µM; A549 cell viability, 20.57 ± 2.62%) was used as a positive control. *, p < 0.05 compared with CNT.

• 

  Fig. 3 The isolated compounds from the CH2Cl2 fraction of BP.

• 

  Fig. 4 The cytotoxic effects of isolated compounds 1 – 7 from BP on A549 cells. DOX (5 µM; A549 cell viability, 28.39 ± 6.21%) was used as a positive control. *, p < 0.05 compared with CNT.

• 

  Fig. 5 The lactate dehydrogenase (LDH) leakage induced by platyphyllenone (4) in A549 cells. DOX (5 µM; LDH leakage, 10.46 ± 0.90-fold) was used as a positive control. *, p < 0.05 compared with CNT.

• 

  Fig. 6 The effect of platyphyllenone (4) on the production of intracellular reactive oxygen species (ROS) in A549 cells. DOX (5 µM; intracellular ROS, 4.99 ± 0.20-fold) was used as a positive control. *, p < 0.05 compared with CNT.

• 

  Fig. 7 The effects of isolated compounds 1 – 7 on BEAS-2B cell viability. DOX (5 µM) reduced cell viability to 27.04 ± 2.11%. *, p < 0.05 compared with the CNT.

Reference

1. Zhu QG, Zhang SM, Ding XX, He B, Zhang HQ. Oncotarget. 2017; 8:57680–57692.

2. Dong L, Lei D, Zhang H. Oncotarget. 2017; 8:64600–64606.

3. Wang J, Chen J, Guo Y, Wang B, Chu H. Oncotarget. 2017; 8:53854–53872.

4. Siegel RL, Miller KD, Jemal A. CA Cancer J Clin. 2016; 66:7–30.

5. Zarogoulidis K, Zarogoulidis P, Darwiche K, Boutsikou E, Machairiotis N, Tsakiridis K, Katsikogiannis N, Kougioumtzi I, Karapantzos I, Huang H, Spyratos D. J Thorac Dis. 2013; 5:S4. S389–S396.

6. Kroschinsky F, Stölzel F, von Bonin S, Beutel G, Kochanek M, Kiehl M, Schellongowski P. Crit Care. 2017; 21:89.

7. Daga A, Ansari A, Patel S, Mirza S, Rawal R, Umrania V. Asian Pac J Cancer Prev. 2015; 16:4147–4156.

8. Ancuceanu RV, Istudor V. Altern Med Rev. 2004; 9:402–419.

9. Atanasov AG, Waltenberger B, Pferschy-Wenzig EM, Linder T, Wawrosch C, Uhrin P, Temml V, Wang L, Schwaiger S, Heiss EH, Rollinger JM, Schuster D, Breuss JM, Bochkov V, Mihovilovic MD, Kopp B, Bauer R, Dirsch VM, Stuppner H. Biotechnol Adv. 2015; 33:1582–1614.

10. Schelman WR, Mohammed TA, Traynor AM, Kolesar JM, Marnocha RM, Eickhoff J, Keppen M, Alberti DB, Wilding G, Takebe N, Liu G. Invest New Drugs. 2014; 32:295–302.

11. Baggstrom MQ, Qi Y, Koczywas M, Argiris A, Johnson EA, Millward MJ, Murphy SC, Erlichman C, Rudin CM, Govindan R. J Thorac Oncol. 2011; 6:1757–1760.

12. Ready N, Karaseva NA, Orlov SV, Luft AV, Popovych O, Holmlund JT, Wood BA, Leopold L. J Thorac Oncol. 2011; 6:781–785.

13. Eom HJ, Kang HR, Choi SU, Kim KH. Chem Biodivers. 2017; 14.

14. Jiang H, Shen Y, Yasuda E, Chiba M, Terazawa M. Eurasian J For Res. 2001; 3:49–54.

15. Wang SJ, Pei YH, Hua HM. J Asian Nat Prod Res. 2001; 3:157–160.

16. Cho N, Kim HW, Lee HK, Jeon BJ, Sung SH. Biosci Biotechnol Biochem. 2016; 80:166–171.

17. Eom HJ, Kang HR, Kim HK, Jung EB, Park HB, Kang KS, Kim KH. Bioorg Chem. 2016; 66:97–101.

18. Matsuda H, Ishikado A, Nishida N, Ninomiya K, Fujiwara H, Kobayashi Y, Yoshikawa M. Bioorg Med Chem Lett. 1998; 8:2939–2944.

19. Lee M, Park JH, Min DS, Yoo H, Park JH, Kim YC, Sung SH. Biosci Biotechnol Biochem. 2012; 76:1616–1620.

20. Lee M, Sung SH. Pharmacogn Mag. 2016; 12:276–281.

21. Le CF, Kailaivasan TH, Chow SC, Abdullah Z, Ling SK, Fang CM. Int Immunopharmacol. 2017; 44:203–210.

22. Prachayasittikul S, Saraban P, Cherdtrakulkiat R, Ruchirawat S, Prachayasittikul V. EXCLI J. 2010; 9:1–10.

23. Kim JH, Byun JC, Bandi AKR, Hyun CG, Lee NH. J Med Plants Res. 2009; 3:914–920.

24. Kim MH, Nugroho A, Choi J, Park JH, Park HJ. Arch Pharm Res. 2011; 34:971–978.

25. Parmar VS, Vardhan A, Taneja P, Sinha R, Patnaik GK, Tripathi SC, Boll PM, Larsen S. J Chem Soc Perkin Trans 1. 1991; 11:2687–2690.

26. Ibrahim SR, Fouad MA, Abdel-Lateff A, Okino T, Mohamed GA. Nat Prod Res. 2014; 28:1765–1771.

27. Sunnerheim-Sjöberg K, Knutsson PG. J Chem Ecol. 1995; 21:1339–1348.

28. Ohta S, Koyama M, Aoki T, Suga T. Bull Chem Soc Jpn. 1985; 58:2423–2424.

29. Onoja E, Ndukwe IG. J Nat Prod Plant Resour. 2013; 3:57–60.

30. Awan ZI, Habib-ur-Rehman KAY, Minhas FA. IOSR J Appl Chem. 2013; 5:58–66.

31. Fuchino H, Konishi S, Satoh T, Yagi A, Saitsu K, Tatsumi T, Tanaka N. Chem Pharm Bull (Tokyo). 1996; 44:1033–1038.

32. Terazawa M, Koga T, Okuyama H, Miyake M. J Jap Wood Res Soc. 1973; 19:47–48.

33. Kim SH, Park JH, Kim TB, Lee HH, Lee KY, Kim YC, Sung SH. Bioorg Med Chem Lett. 2010; 20:2824–2827.

34. Liao CR, Kuo YH, Ho YL, Wang CY, Yang CS, Lin CW, Chang YS. Molecules. 2014; 19:9515–9534.

35. You YJ, Nam NH, Kim Y, Bae KH, Ahn BZ. Phytother Res. 2003; 17:341–344.

36. Rao SD, Rao BN, Devi PU, Rao AK. Orient J Chem. 2017; 33:173–180.

37. Jang GU, Choi SU, Lee KR. Yakhak Hoeji. 2005; 49:244–248.

38. Sidova V, Zoufaly P, Pokorny J, Dzubak P, Hajduch M, Popa I, Urban M. PLoS One. 2017; 12:e0171621.

39. Dinić J, Novaković M, Podolski-Renić A, Vajs V, Tešević V, Isaković A, Pešić M. Chem Biol Interact. 2016; 249:36–45.

40. Chokchaisiri R, Pimkaew P, Piyachaturawat P, Chalermglin R, Suksamrarn A. Rec Nat Prod. 2014; 8:46–50.

41. Tsao SM, Yin MC. J Agric Food Chem. 2015; 63:3196–3204.

42. Dong GZ, Jeong JH, Lee YI, Lee SY, Zhao HY, Jeon R, Lee HJ, Ryu JH. Arch Pharm Res. 2017; 40:509–517.

43. Tung NH, Kwon HJ, Kim JH, Ra JC, Ding Y, Kim JA, Kim YH. Bioorg Med Chem Lett. 2010; 20:1000–1003.

44. Ilic-Tomic T, Sokovic M, Vojnovic S, Ciric A, Veljic M, Nikodinovic-Runic J, Novakovic M. Planta Med. 2017; 83:117–125.

45. Park D, Kim HJ, Jung SY, Yook CS, Jin C, Lee YS. Chem Pharm Bull. 2010; 58:238–241.

46. Yadav D, Singh SC, Verma RK, Saxena K, Verma R, Murthy PK, Gupta MM. Phytomedicine. 2013; 20:124–132.

47. Novaković M, Novaković I, Cvetković M, Sladić D, Tešević V. Braz J Bot. 2015; 38:441–446.

48. Novaković M, Pešić M, Trifunović S, Vučković I, Todorović N, Podolski-Renić A, Dinić J, Stojković S, Tešević V, Vajs V, Milosavljević S. Phytochemistr. 2014; 97:46–54.