Alkenylated phenolics from Syzygium lineatum with antiproliferative activity against chronic myeloid leukemia cells

Franklin V. Ibana Von Novi O. de Leon Joe Anthony H. Manzano Agnes L. Castillo Allan Patrick G. Macabeo   

Open Access   

Published:  Jun 07, 2024

DOI: 10.7324/JAPS.2024.170186
Abstract

Syzygium lineatum is traditionally used by Filipinos as an anticancer regimen and food flavouring in the Philippines. However, its medicinal potential is yet to be validated. Herein, we report the antiproliferative and cytotoxic activities of S. lineatum extracts, sub-extracts, and alkenylated phenolic constituents gingkol (1) and bilobol (2) along with β-sitosterol (3) and a mixture of fatty acids (46) in vitro and in silico. Fractions 2 and 4 (SlPE4) from the biologically active petroleum ether sub-extract (SlPE), showed moderately strong antiproliferative activity against chronic myeloid leukemia (CML) cells (K-562). Chromatographic purification of fraction SlPE4 yielded antiproliferative compounds 1 and 2 against K-562 cells while SlPE2 afforded 3–6. Bilobol (2), an alkenylated resorcinol, showed better selectivity in vitro compared to the phenolic congener, gingkol (1) highlighting the importance of increased hydroxylation in the aromatic structure of the compounds. To elucidate their putative mechanisms of action, molecular docking studies were performed versus establishing the CML targets BCR::ABL1 tyrosine kinase, c-Src kinase, and protein kinase B. In silico results showed moderate to good binding affinities of 1 and 2 in the active sites of the target kinases. Overall, the study validates the purported Philippine traditional anticancer use of S. lineatum, especially its constituents gingkol (1) and bilobol (2).


Keyword:     Syzygium lineatum anticancer chronic myeloid leukemia cells molecular docking gingkol bilobol


Citation:

Ibana FV, de Leon VNO, Manzano JAH, Castillo AL, Macabeo APG. Alkenylated phenolics from Syzygium lineatum with antiproliferative activity against chronic myeloid leukemia cells. J Appl Pharm Sci. 2024. Online First. http://doi.org/10.7324/JAPS.2024.170186

Copyright: © The Author(s). This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Reference

1. Mattiuzzi C, Lippi G. Current cancer epidemiology. J Epidemiol Glob Health. 2019;9(4):217. https://doi.org/10.2991/jegh.k.191008.001

2. Wang X, Zhang H, Chen X. Drug resistance and combating drug resistance in cancer. Cancer Drug Resist. 2019;2(2):141. https://doi.org/10.20517/cdr.2019.10

3. Seebacher NA, Stacy AE, Porter GM, Merlot AM. Clinical development of targeted and immune based anti-cancer therapies. J Exp ClinCancer Res. 2019;38(1):1-39. https://doi.org/10.1186/s13046-019-1094-2

4. Newman DJ, Cragg GM. Natural products as sources of new drugs over the nearly four decades from 01/1981 to 09/2019. J Nat Prod. 2020;83(3):770-803. https://doi.org/10.1021/acs.jnatprod.9b01285

5. Hashem S, Ali TA, Akhtar S, Nisar S, Sageena G, Ali S, et al. Targeting cancer signaling pathways by natural products: exploring promising anti-cancer agents. Biomed Pharmacother. 2022;150:113054. https://doi.org/10.1016/j.biopha.2022.113054

6. Thielen N, Ossenkoppele GJ, Schuurhuis GJ, Janssen JJ. New insights into the pathogenesis of chronic myeloid leukaemia: towards a path to cure. Neth J Med. 2011;69(10):430-40.

7. Dong Y, Shi O, Zeng Q, Lu X, Wang W, Li Y, et al. Leukemia incidence trends at the global, regional, and national level between 1990 and 2017. Exp Hematol Oncol. 2020;9(1):1-11. https://doi.org/10.1186/s40164-020-00170-6

8. Amir M, Javed S. A review on the therapeutic role of TKIs in case of CML in combination with epigenetic drugs. Front Genet. 2021;12:742802. https://doi.org/10.3389/fgene.2021.742802

9. Wolfe HR, Rein LAM. The evolving landscape of frontline therapy in chronic phase chronic myeloid leukemia (CML). Curr Hematol Malig Rep. 2021;16(5):448-54. https://doi.org/10.1007/s11899-021-00655-z

10. Zhou C, Liu L, Zhuang J, Wei J, Zhang T, Gao C, et al. A systems biology-based approach to uncovering molecular mechanisms underlying effects of traditional Chinese medicine Qingdai in chronic myelogenous leukemia, involving integration of network pharmacology and molecular docking technology. Med Sci Monit. 2018;24:4305. https://doi.org/10.12659/MSM.908104

11. Chai Y, Chen F, Li Z, Yang P, Zhou Q, Liu W, et al. Mechanism of salidroside in the treatment of chronic myeloid leukemia based on the network pharmacology and molecular docking. Clin Transl Oncol. 2023;25:384-95. https://doi.org/10.1007/s12094-022-02990-w

12. Braun TP, Eide CA, Druker BJ. Response and resistance to BCR-ABL1-targeted therapies. Cancer Cell. 2020;37(4):530-42. https://doi.org/10.1016/j.ccell.2020.03.006

13. Macabeo APG, Lopez ADA, Schmidt S, Heilmann J, Dahse HM, Alejandro GJD, et al. Antitubercular and cytotoxic constituents from Goniothalamus gitingensis. Res Nat Prod. 2014;8(1):41.

14. Macabeo APG, Letada AG, Budde S, Faderl C, Dahse HM, Franzblau SG, et al. Antitubercular and cytotoxic chlorinated seco-cyclohexenes from Uvaria alba. J Nat Prod. 2017;80(12):3319-23. https://doi.org/10.1021/acs.jnatprod.7b00679

15. Macabeo APG, Flores AIG, Fernandez RAT, Budde S, Faderl C, Dahse HM, et al. Antitubercular and cytotoxic polyoxygenated cyclohexane derivatives from Uvaria grandiflora. Nat Prod Res. 2021;35(23):5229-32. https://doi.org/10.1080/14786419.2020.1741579

16. Quimque, MT, Notarte KI, Letada A, Fernandez RA, Pilapil DY, Pueblos, KR, et al. Potential cancer-and Alzheimer's disease-targeting phosphodiesterase inhibitors from Uvaria alba: insights from in vitro and consensus virtual screening. ACS Omega. 2021;6(12):8403-17. https://doi.org/10.1021/acsomega.1c00137

17. Boy HIA, Rutilla AJH, Santos KA, Ty AMT, Yu AI, Mahboob T, et al. Recommended medicinal plants as source of natural products: a review. Digit Chin Med. 2018;1(2):131-42. https://doi.org/10.1016/S2589-3777(19)30018-7

18. Whittaker RJ, Bush MB, Partomihardjo T, Asquith NM, Richards K. Ecological aspects of plant colonisation of the Krakatau Islands. Geo J. 1992;28:201-11. https://doi.org/10.1007/BF00177233

19. Zarate-Manicad MC. Phytochemical analysis of Lubeg (Syzygium lineatum (DC). Merr & LM Perry) species in Apayao. Int J Novel Res Life Sci. 2016;3(6):1-5.

20. Batiha GES, Alkazmi LM, Wasef LG, Beshbishy AM, Nadwa EH, Rashwan EK. Syzygium aromaticum L.(Myrtaceae): traditional uses, bioactive chemical constituents, pharmacological and toxicological activities. Biomolecules. 2020;10(2):1-16. https://doi.org/10.3390/biom10020202

21. Ismail A, Ahmad WANW. Syzygium polyanthum (Wight) Walp: a potential phytomedicine. Pharmacogn J. 2019;11(2):429-38. https://doi.org/10.5530/pj.2019.11.67

22. Maroyi, A. Syzygium cordatum Hochst. Ex Krauss: an overview of its ethnobotany, phytochemistry and pharmacological properties. Molecules. 2018;23(5):1084. https://doi.org/10.3390/molecules23051084

23. Chua LK, Lim CL, Ling APK, Chye SM, Koh RY. Anticancer potential of Syzygium species: a review. Plant Foods Hum Nutr. 2019;74:18-27. https://doi.org/10.1007/s11130-018-0704-z

24. Lee HJ, Song JH, Kim JH. Synthesis of resorcinol/formaldehyde gel particles by the sol-emulsion-gel technique. Mater Lett. 1998;37(4-5):197-200. https://doi.org/10.1016/S0167-577X(98)00091-3

25. Krauth F, Dahse HM, Rüttinger HH, Frohberg P. Synthesis and characterization of novel 1, 2, 4-triazine derivatives with antiproliferative activity. Bioorg Med Chem. 2010;18(5):1816-21. https://doi.org/10.1016/j.bmc.2010.01.053

26. Malaluan IN, Manzano JAH, Muñoz JER, Bautista TJL, Dahse HM, Quimque MTJ, et al. Antituberculosis and antiproliferative activities of the extracts and tetrahydrobisbenzylisoquinoline alkaloids from Phaeanthus ophthalmicus: in vitro and in silico investigations. Philipp J Sci. 2022;151(1):371-81. https://doi.org/10.56899/151.01.28

27. Manzano JAH, Cruz CLM III, Quimque MTJ, Macabeo APG. In silico potentials of Alpinia galanga constituents against human placental aromatase vital in postmenopausal estrogen-dependent breast cancer pathogenesis. Philipp J Sci. 2022;151(6A):2101-15. https://doi.org/10.56899/151.6A.04

28. Princiotto S, Musso L, Manetti F, Marcellini V, Maga G, Crespan E, et al. Synthesis and biological activity evaluation of 3-(hetero) arylideneindolin-2-ones as potential c-Src inhibitors. J Enzyme Inhib Med Chem. 2022;37(1):2382-94. https://doi.org/10.1080/14756366.2022.2117317

29. Bibi S, Arslanhan MD, Langenfeld F, Jeanningros S, Cerny-Reiterer, Hadzijusufovic, E, et al. Co-operating STAT5 and AKT signaling pathways in chronic myeloid leukemia and mastocytosis: possible new targets of therapy. Haematologica. 2014;99(3):417-29. https://doi.org/10.3324/haematol.2013.098442

30. Daniel JP, Mesquita FP, Da Silva EL, de Souza PFN, Lima LB, de Oliveira LLB, et al. Anticancer potential of mebendazole against chronic myeloid leukemia: in silico and in vitro studies revealed new insights about the mechanism of action. Front Pharmacol. 2022;13:952250. https://doi.org/10.3389/fphar.2022.952250

31. Quimque MTJ, Notarte KIR, de Leon VNO, Manzano JAH, Muñoz JER, Pilapil DYH, et al. Computationally repurposed natural products targeting SARS-CoV-2 attachment and entry mechanisms. In: Frontiers of COVID-19: scientific and clinical aspects of the novel coronavirus. Cham, Swtizerland: Springer International Publishing; 2019. pp 505-37. https://doi.org/10.1007/978-3-031-08045-6_25

32. Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, et al. UCSF Chimera-a visualization system for exploratory research and analysis. J Comput Chem. 2004;25(13):1605-12. https://doi.org/10.1002/jcc.20084

33. Lipinski CA. Lead-and drug-like compounds: the rule-of-five revolution. Drug Discov Today Technol. 2004;1(4):337-41. https://doi.org/10.1016/j.ddtec.2004.11.007

34. Daina A, Michielin O, Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep. 2017;7(1):42717. https://doi.org/10.1038/srep42717

35. Fernandez RA, Quimque MT, Notarte KI, Manzano JA, Pilapil IV DY, de Leon VN, et al. Myxobacterial depsipeptide chondramides

interrupt SARS-CoV-2 entry by targeting its broad, cell tropic spike protein. J Biomol Struct Dyn. 2021;40(22):12209-20. https://doi.org/10.1080/07391102.2021.1969281

36. Aisha AFA, Abu-Salah KM, Alrokayan SA, Siddiqui MJ, Ismail Z, Majid AMSA. Syzygium aromaticum extracts as good source of betulinic acid and potential anti-breast cancer. Rev Bras. 2012;22:335-43. https://doi.org/10.1590/S0102-695X2011005000185

37. Oyedeji OO, Shode FO, Oyedeji AO, Songca SP, Gwebu ET, Hill GM, et al. Semi-synthesis of nitrogen derivatives of oleanolic acid and effect on breast carcinoma MCF-7 cells. Anticancer Res. 2014;34:4135-9.

38. Ling LT, Radhakrishnan AK, Subramaniam T, Cheng HM, Palanisamy UD. Assessment of antioxidant capacity and cytotoxicity of selected Malaysian plants. Molecules. 2010;15:2139-51. https://doi.org/10.3390/molecules15042139

39. Rabeta MS, Chan S, Neda GD, Lam KL, Ong MT. Anticancer effect of underutilized fruits. Int Food Res J. 2013;20(2):551-6.

40. Liu H, Schmitz JC, Wei J, Cao S, Beumer JH, Strychor S, et al. Clove extract inhibits tumor growth and promotes cell cycle arrest and apoptosis. Oncol Res. 2014;21:247-59. https://doi.org/10.3727/096504014X13946388748910

41. Jabbour E, Kantarjian H. Chronic myeloid leukemia: 2018 update on diagnosis, therapy and monitoring. Am J Hematol. 2018;93:442-59. https://doi.org/10.1002/ajh.25011

42. Sung H, Ferlay J, Siegel R L, Laversanne, M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209-49. https://doi.org/10.3322/caac.21660

43. Xiao J, Mao F, Yang F, Zhao Y, Zhang C, Yamamoto K. Interaction of dietary polyphenols with bovine milk proteins: molecular structure-affinity relationship and influencing bioactivity aspects. Mol Nutr Food Res. 2011;55(11):1637-45. https://doi.org/10.1002/mnfr.201100280

44. Magpantay HD, Malaluan IN, Manzano JAH, Quimque MT, Pueblos KR, Moor N, et al. Antibacterial and COX-2 inhibitory tetrahydrobisbenzylisoquinoline alkaloids from the Philippine medicinal plant Phaeanthus ophthalmicus. Plants. 2021;10(3):462. https://doi.org/10.3390/plants10030462

45. Liu Y, Qian J, Li J, Xing M, Grierson D, Sun C, et al. Hydroxylation decoration patterns of flavonoids in horticultural crops: chemistry, bioactivity, and biosynthesis. Hortic Res. 2022;9:uhab068. https://doi.org/10.1093/hr/uhab068

46. Quimque MT, Notarte KI, Adviento XA, Cabunoc MH, de Leon VN, Lugtu EJ, et al. Polyphenolic natural products active in silico against SARS-CoV-2 spike receptor binding domains and non-structural proteins-a review. Comb Chem High Throughput Screen. 2023;26(3):459-88. https://doi.org/10.2174/1386207325666210917113207

47. Manzano JAH, LLames LCJ, Macabeo APG. Tetrahydobisbenzylisoquinoline alkaloids inhibit target enzymes associated with type 2 diabetes and obesity. J Appl Pharm Sci. 2024;14(01):230-7. https://doi.org/10.7324/JAPS.2023.154518

48. Haidary AM, Ahmed ZA, Abdul-Ghafar J, Rahmani S, Noor S, Erfani F, et al. Philadelphia chromosome positive chronic myeloid leukemia with 5q deletion at diagnosis. Mol Cytogenet. 2021;14(16):1-4. https://doi.org/10.1186/s13039-021-00539-0

49. Shanmuganathan N, Hiwase DK, Ross DM. Treatment of chronic myeloid leukemia: assessing risk, monitoring response, and optimizing outcome. Leuk Lymphoma. 2017;58:2799-810. https://doi.org/10.1080/10428194.2017.1312377

50. Rosti G, Castagnetti F, Gugliotta G, Baccarani M. Tyrosine kinase inhibitors in chronic myeloid leukaemia: which, when, for whom? Nat Rev Clin Oncol. 2017;14:141-54. https://doi.org/10.1038/nrclinonc.2016.139

51. Jiao Q, Bi L, Ren Y, Song S, Wang Q, Wang Y. Advances in studies of tyrosine kinase inhibitors and their acquired resistance. Mol Cancer. 2018;17(1):1-12. https://doi.org/10.1186/s12943-018-0801-5

52. McLachlan RW, Kraemer A, Helwani FM, Kovacs EM, Yap AS. E-cadherin adhesion activates c-Src signaling at cell-cell contacts. Mol Biol Cell. 2007;18:3214-23. https://doi.org/10.1091/mbc.e06-12-1154

53. Martelli AM, Evangelisti C, Chappell W, Abrams SL, Bäsecke J, Stivala F, et al. Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway. Leukemia. 2011;25(7):1064-79. https://doi.org/10.1038/leu.2011.46

54. Gowda R, Madhunapantula SV, Desai D, Amin S, Robertson GP. Simultaneous targeting of COX-2 and AKT using selenocoxib-1-GSH to inhibit melanoma. Mol Cancer Ther. 2013;12(1):3-15. https://doi.org/10.1158/1535-7163.MCT-12-0492

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