Anticancer Activity of Asiatic Acid from Centella Asiatica: A Comprehensive Systematic Review of In Vitro and In Vivo Studies

  • Fiki Muhammad Ridho Faculty of Dental Medicine, Universitas Airlangga, Surabaya-Indonesia
  • Panggih Fahrudin Indonesian Traditional Medicine Program, Faculty of Vocational Studies, Universitas Negeri Yogyakarta, Yogyakarta-Indonesia
  • Andika Julyanto Syachputra Master Program in Biology, Faculty of Biology, Universitas Gadjah Mada, Yogyakarta-Indonesia
  • Iren Angelia Aruan Faculty of Pharmacy, Institut Sains dan Teknologi Nasional, Jakarta-Indonesia
  • Kamailiya Ulfah Faculty of Veterinary Medicine, Universitas Airlangga, Surabaya-Indonesia
  • Alfi Syahri Surgical Medical Nursing Specialist Program, Faculty of Nursing, Universitas Airlangga, Surabaya-Indonesia; Doctoral Program in Nursing, Faculty of Nursing, Universitas Airlangga, Surabaya-Indonesia; Lecturer at Faculty of Nursing, Institut Kesehatan Deli Husada, Deli Serdang-Indonesia
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Abstract

AbstractCentella asiatica, containing asiatic acid (AsA), represents one such candidate demonstrating promising anticancer effects. This study aims to comprehensively review the anticancer activity of AsA in published in vitro and in vivo studies. A systematic review method was employed and several databases, including Scopus, PubMed, ScienceDirect, and Google Scholar, were used to conduct a comprehensive and systematic search of the literature based in vitro and in vivo studies in November 2023 following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Thirty-three articles were included, distributed across twenty-five in vitro studies, three in vivo studies, and five both in vitro and in vivo studies. Based on the findings in the reviewed articles, we report that AsA, a triterpene derived from C. asiatica, exhibits anticancer effects demonstrated both in various cancer cell lines and in cancer cell-induced animal model, through several mechanisms, including anti-inflammatory effects, antioxidant effects, inhibition of cell proliferation, inhibition of invasion and migration, and induction of apoptosis and autophagy. Conclusions based on findings in in vitro and in vivo studies, AsA has strong potential to be used and developed as an inhibitor of various types of cancer cells.

Keywords: anticancer, asiatic acid, cancer, centella asiatica, herbal

 

AbstrakCentella asiatica, yang mengandung asam asiatik (AsA), mewakili salah satu kandidat yang menunjukkan efek antikanker yang menjanjikan. Penelitian ini bertujuan untuk meninjau secara komprehensif aktivitas antikanker AsA dalam studi in vitro dan in vivo. Metode yang digunakan adalah tinjauan sistematis pada beberapa basis data, termasuk Scopus, PubMed, ScienceDirect, dan Google Scholar, untuk melakukan pencarian literatur yang komprehensif dan sistematis berdasarkan studi in vitro dan in vivo yang dilakukan pada November 2023 dan mengikuti pedoman Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Tiga puluh tiga artikel diinklusikan, terdiri dari dua puluh lima studi in vitro, tiga studi in vivo, dan lima studi in vitro dan in vivo. Berdasarkan temuan dalam artikel yang ditinjau, kami melaporkan bahwa AsA, triterpen yang berasal dari C. asiatica, menunjukkan efek antikanker baik di berbagai sel kanker maupun pada model hewan yang diinduksi sel kanker, melalui beberapa mekanisme, termasuk efek antiinflamasi, efek antioksidan, penghambatan proliferasi sel, penghambatan invasi dan migrasi, serta induksi apoptosis dan autofagi. Kesimpulan berdasarkan temuan dalam studi in vitro dan in vivo, AsA memiliki potensi yang kuat untuk digunakan dan dikembangkan sebagai penghambat berbagai jenis sel kanker.

Kata kunci: antikanker, asam asiatik, kanker, centella asiatica, herbal

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References

1. Brown JS, Amend SR, Austin RH, Gatenby RA, Hammarlund EU, Pienta KJ (2023) Updating the Definition of Cancer. Molecular Cancer Research 21:1142–1147

2. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F (2021) Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA A Cancer J Clinicians 71:209–249

3. Amy Lee Y-C, Hashibe M (2014) Tobacco, Alcohol, and Cancer in Low and High Income Countries. Annals of Global Health 80:378

4. Danaei G, Vander Hoorn S, Lopez AD, Murray CJ, Ezzati M (2005) Causes of cancer in the world: comparative risk assessment of nine behavioural and environmental risk factors. The Lancet 366:1784–1793

5. Schiller JT, Lowy DR (2014) Virus Infection and Human Cancer: An Overview. In: Chang MH, Jeang K-T (eds) Viruses and Human Cancer. Springer Berlin Heidelberg, Berlin, Heidelberg, pp 1–10

6. Iglesias ML, Schmidt A, Ghuzlan AA, Lacroix L, Vathaire FD, Chevillard S, Schlumberger M (2017) Radiation exposure and thyroid cancer: a review. Arch Endocrinol Metab 61:180–187

7. Gopal S, Achenbach CJ, Yanik EL, Dittmer DP, Eron JJ, Engels EA (2014) Moving Forward in HIV-Associated Cancer. JCO 32:876–880

8. Ghasemiesfe M, Barrow B, Leonard S, Keyhani S, Korenstein D (2019) Association Between Marijuana Use and Risk of Cancer: A Systematic Review and Meta-analysis. JAMA Netw Open 2:e1916318

9. Kratz CP, Achatz MI, Brugières L, et al (2017) Cancer Screening Recommendations for Individuals with Li-Fraumeni Syndrome. Clinical Cancer Research 23:e38–e45

10. Nalepa G, Clapp DW (2018) Fanconi anaemia and cancer: an intricate relationship. Nat Rev Cancer 18:168–185

11. Brambullo T, Colonna MR, Vindigni V, Piaserico S, Masciopinto G, Galeano M, Costa AL, Bassetto F (2022) Xeroderma Pigmentosum: A Genetic Condition Skin Cancer Correlated—A Systematic Review. BioMed Research International 2022:1–12

12. Mirecka A, Paszkowska-Szczur K, Scott RJ, et al (2014) Common variants of xeroderma pigmentosum genes and prostate cancer risk. Gene 546:156–161

13. Suh S, Kim K-W (2019) Diabetes and Cancer: Cancer Should Be Screened in Routine Diabetes Assessment. Diabetes Metab J 43:733

14. Singh N, Baby D, Rajguru J, Patil P, Thakkannavar S, Pujari V (2019) Inflammation and cancer. Ann Afr Med 18:121

15. Nikolaos Tzenios (2023) Obesity as a risk factor for cancer. EPRA 101–104

16. Bahrami H, Tafrihi M (2023) Global trends of cancer: The role of diet, lifestyle, and environmental factors. Cancer Innovation 2:290–301

17. Abbas Z, Rehman S (2018) An Overview of Cancer Treatment Modalities. Neoplasm. https://doi.org/10.5772/intechopen.76558

18. Mun EJ, Babiker HM, Weinberg U, Kirson ED, Von Hoff DD (2018) Tumor-Treating Fields: A Fourth Modality in Cancer Treatment. Clinical Cancer Research 24:266–275

19. Ahmad Khan MS, Ahmad I (2019) Herbal Medicine. In: New Look to Phytomedicine. Elsevier, pp 3–13

20. Zahara K, Bibi Y, Tabassum S (2014) Clinical and therapeutic benefits of Centella asiatica. PAB 3:152–159

21. Belwal T, Andola HC, Atanassova MS, Joshi B, Suyal R, Thakur S, Bisht A, Jantwal A, Bhatt ID, Rawal RS (2019) Gotu Kola (Centella asiatica). In: Nonvitamin and Nonmineral Nutritional Supplements. Elsevier, pp 265–275

22. Kunjumon R, Johnson AJ, Baby S (2022) Centella asiatica: Secondary metabolites, biological activities and biomass sources. Phytomedicine Plus 2:100176

23. Sun B, Wu L, Wu Y, Zhang C, Qin L, Hayashi M, Kudo M, Gao M, Liu T (2020) Therapeutic Potential of Centella asiatica and Its Triterpenes: A Review. Front Pharmacol 11:568032

24. Lv J, Sharma A, Zhang T, Wu Y, Ding X (2018) Pharmacological Review on Asiatic Acid and Its Derivatives: A Potential Compound. SLAS Technology 23:111–127

25. Mushtaq Z, Imran M, Hussain M, et al (2023) Asiatic acid: a review on its polypharmacological properties and therapeutic potential against various Maladies. International Journal of Food Properties 26:1244–1263

26. Nagoor Meeran MF, Goyal SN, Suchal K, Sharma C, Patil CR, Ojha SK (2018) Pharmacological Properties, Molecular Mechanisms, and Pharmaceutical Development of Asiatic Acid: A Pentacyclic Triterpenoid of Therapeutic Promise. Front Pharmacol 9:892

27. Lee YS, Jin D-Q, Kwon EJ, Park SH, Lee E-S, Jeong TC, Nam DH, Huh K, Kim J-A (2002) Asiatic acid, a triterpene, induces apoptosis through intracellular Ca2+ release and enhanced expression of p53 in HepG2 human hepatoma cells. Cancer Letters 186:83–91

28. Bunpo P, Kataoka K, Arimochi H, Nakayama H, Kuwahara T, Vinitketkumnuen U, Ohnishi Y (2005) Inhibitory effects of asiatic acid and CPT-11 on growth of HT-29 cells. J Med Invest 52:65–73

29. Hsu Y-L, Kuo P-L, Lin L-T, Lin C-C (2005) Asiatic Acid, a Triterpene, Induces Apoptosis and Cell Cycle Arrest through Activation of Extracellular Signal-Regulated Kinase and p38 Mitogen-Activated Protein Kinase Pathways in Human Breast Cancer Cells. J Pharmacol Exp Ther 313:333–344

30. Park BC, Bosire KO, Lee E-S, Lee YS, Kim J-A (2005) Asiatic acid induces apoptosis in SK-MEL-2 human melanoma cells. Cancer Letters 218:81–90

31. Cho CW, Choi DS, Cardone MH, Kim CW, Sinskey AJ, Rha C (2006) Glioblastoma cell death induced by asiatic acid. Cell Biol Toxicol 22:393–408

32. Tang X-L, Yang X-Y, Jung H-J, Kim S-Y, Jung S-Y, Choi D-Y, Park W-C, Park H (2009) Asiatic Acid Induces Colon Cancer Cell Growth Inhibition and Apoptosis through Mitochondrial Death Cascade. Biological & Pharmaceutical Bulletin 32:1399–1405

33. Zhang J, Ai L, Lv T, Jiang X, Liu F (2013) Asiatic acid, a triterpene, inhibits cell proliferation through regulating the expression of focal adhesion kinase in multiple myeloma cells. Oncology Letters 6:1762–1766

34. Chen J-Y, Xu Q-W, Xu H, Huang Z-H (2014) Asiatic Acid Promotes p21 WAF1/CIP1 Protein Stability through Attenuation of NDR1/2 Dependent Phosphorylation of p21 WAF1/CIP1 in HepG2 Human Hepatoma Cells. Asian Pacific Journal of Cancer Prevention 15:963–967

35. Kim KB, Kim K, Bae S, et al (2014) MicroRNA-1290 promotes asiatic acid-induced apoptosis by decreasing BCL2 protein level in A549 non-small cell lung carcinoma cells. Oncology Reports 32:1029–1036

36. Sarumathi A, Saravanan N (2015) Anti-Proliferative Effect of Asiatic Acid on Hep-G2 Cell Line. Genes Review 1:37–44

37. Wu Q, Lv T, Chen Y, Wen L, Zhang J, Jiang X, Liu F (2015) Apoptosis of HL-60 human leukemia cells induced by Asiatic acid through modulation of B-cell lymphoma 2 family proteins and the mitogen-activated protein kinase signaling pathway. Molecular Medicine Reports 12:1429–1434

38. Lu Y, Liu S, Wang Y, Wang D, Gao J, Zhu L (2016) Asiatic acid uncouples respiration in isolated mouse liver mitochondria and induces HepG2 cells death. European Journal of Pharmacology 786:212–223

39. Ren L, Cao Q-X, Zhai F-R, Yang S-Q, Zhang H-X (2016) Asiatic acid exerts anticancer potential in human ovarian cancer cells via suppression of PI3K/Akt/mTOR signalling. Pharmaceutical Biology 54:2377–2382

40. Qi Z, Ci X, Huang J, Liu Q, Yu Q, Zhou J, Deng X (2017) Asiatic acid enhances Nrf2 signaling to protect HepG2 cells from oxidative damage through Akt and ERK activation. Biomedicine & Pharmacotherapy 88:252–259

41. Wang X, Sun J, Liu F, Bian Y, Miao L, Wang X (2017) Asiatic acid attenuates malignancy of human metastatic ovarian cancer cells via inhibition of epithelial-tomesenchymal transition. Trop J Pharm Res 16:1223

42. Hao Y, Huang J, Ma Y, Chen W, Fan Q, Sun X, Shao M, Cai H (2018) Asiatic acid inhibits proliferation, migration and induces apoptosis by regulating Pdcd4 via the PI3K/Akt/mTOR/p70S6K signaling pathway in human colon carcinoma cells. Oncol Lett. https://doi.org/10.3892/ol.2018.8417

43. Sakonsinsiri C, Kaewlert W, Armartmuntree N, Thanan R, Pakdeechote P (2018) Anti-cancer activity of asiatic acid against human cholangiocarcinoma cells through inhibition of proliferation and induction of apoptosis. Cell Mol Biol (Noisy-le-grand) 64:28–33

44. Jo Y-G, Kim M, Shin H, Lee KY, Lee EJ (2019) Asiatic Acid Induces Apoptosis and Autophagy and Reduces MiR-17 and MiR-21 Expression in Pancreatic Cancer Cell Lines. Nat Prod Sci 25:298

45. Liu Y-T, Chuang Y-C, Lo Y-S, Lin C-C, Hsi Y-T, Hsieh M-J, Chen M-K (2020) Asiatic Acid, Extracted from Centella asiatica and Induces Apoptosis Pathway through the Phosphorylation p38 Mitogen-Activated Protein Kinase in Cisplatin-Resistant Nasopharyngeal Carcinoma Cells. Biomolecules 10:184

46. Yan BF, Chen X, Liu J, Liu SJ, Zhang JZ, Zeng Q, Duan JA (2021) Asiatic Acid Induces Mitochondrial Apoptosis via Inhibition of JAK2/STAT3 Signalling Pathway in Human Osteosarcoma. Fol Biol 67:108–117

47. Zhu Z, Cui L, Yang J, Vong CT, Hu Y, Xiao J, Chan G, He Z, Zhong Z (2021) Anticancer effects of asiatic acid against doxorubicin-resistant breast cancer cells via an AMPK-dependent pathway in vitro. Phytomedicine 92:153737

48. Cheng Q, Zhang S, Zhong B, Chen Z, Peng F (2022) Asiatic acid re-sensitizes multidrug-resistant A549/DDP cells to cisplatin by down regulating long non-coding RNA metastasis associated lung adenocarcinoma transcript 1/β-catenin signaling. Bioengineered 13:12972–12984

49. Lai Y-W, Wang S-W, Lin C-L, Chen S-S, Lin K-H, Lee Y-T, Chen W-C, Hsieh Y-H (2023) Asiatic acid exhibits antimetastatic activity in human prostate cancer cells by modulating the MZF-1/Elk-1/Snail signaling axis. European Journal of Pharmacology 951:175770

50. Pantia S, Kangsamaksin T, Janvilisri T, Komyod W (2023) Asiatic Acid Inhibits Nasopharyngeal Carcinoma Cell Viability and Migration via Suppressing STAT3 and Claudin-1. Pharmaceuticals 16:902

51. Park BC, Paek S-H, Lee Y-S, Kim S-J, Lee E-S, Choi HG, Yong CS, Kim J-A (2007) Inhibitory Effects of Asiatic Acid on 7,12-Dimethylbenz[a]anthracene and 12-O-Tetradecanoylphorbol 13-Acetate-Induced Tumor Promotion in Mice. Biological & Pharmaceutical Bulletin 30:176–179

52. Siddique AI, Mani V, Renganathan S, Ayyanar R, Nagappan A, Namasivayam N (2017) Asiatic acid abridges pre-neoplastic lesions, inflammation, cell proliferation and induces apoptosis in a rat model of colon carcinogenesis. Chemico-Biological Interactions 278:197–211

53. Chen X, Huang L, Tang J, Wu D, An N, Ye Z, Lan H, Liu H, Yang C (2023) Asiatic acid alleviates cisplatin-induced renal fibrosis in tumor-bearing mice by improving the TFEB-mediated autophagy-lysosome pathway. Biomedicine & Pharmacotherapy 165:115122

54. Kavitha CV, Jain AK, Agarwal C, Pierce A, Keating A, Huber KM, Serkova NJ, Wempe MF, Agarwal R, Deep G (2015) Asiatic acid induces endoplasmic reticulum stress and apoptotic death in glioblastoma multiforme cells both in vitro and in vivo. Molecular Carcinogenesis 54:1417–1429

55. Wu T, Geng J, Guo W, Gao J, Zhu X (2017) Asiatic acid inhibits lung cancer cell growth in vitro and in vivo by destroying mitochondria. Acta Pharmaceutica Sinica B 7:65–72

56. Li J, Chen K, Huang J, Chu D, Tian M, Huang K, Ma C (2021) Asiatic Acid Induces Endoplasmic Reticulum Stress and Activates the Grp78/IRE1α/JNK and Calpain Pathways to Inhibit Tongue Cancer Growth. Frontiers in Pharmacology 12:

57. Huang C-F, Hung T-W, Yang S-F, Tsai Y-L, Yang J-T, Lin C, Hsieh Y-H (2022) Asiatic acid from centella asiatica exert anti-invasive ability in human renal cancer cells by modulation of ERK/p38MAPK-mediated MMP15 expression. Phytomedicine 100:154036

58. Huang Y, Xie Z, Jiwa H, Zhang J, Wang Y, Xu J, Luo X (2023) Asiatic acid affects the growth of human osteosarcoma cells by regulating PI3K/AKT and NF-κB dual signal pathways. Journal of Functional Foods 111:105885

59. Aller M-A, Arias A, Arias J-I, Arias J (2019) Carcinogenesis: the cancer cell–mast cell connection. Inflamm Res 68:103–116

60. Hashemi Goradel N, Najafi M, Salehi E, Farhood B, Mortezaee K (2019) Cyclooxygenase‐2 in cancer: A review. Journal Cellular Physiology 234:5683–5699

61. Otsuki A, Suzuki M, Katsuoka F, Tsuchida K, Suda H, Morita M, Shimizu R, Yamamoto M (2016) Unique cistrome defined as CsMBE is strictly required for Nrf2-sMaf heterodimer function in cytoprotection. Free Radical Biology and Medicine 91:45–57

62. Taguchi K, Yamamoto M (2020) The KEAP1–NRF2 System as a Molecular Target of Cancer Treatment. Cancers 13:46

63. Lee D-Y, Song M-Y, Kim E-H (2021) Role of Oxidative Stress and Nrf2/KEAP1 Signaling in Colorectal Cancer: Mechanisms and Therapeutic Perspectives with Phytochemicals. Antioxidants 10:743

64. Mansouri A, Reiner Ž, Ruscica M, Tedeschi-Reiner E, Radbakhsh S, Bagheri Ekta M, Sahebkar A (2022) Antioxidant Effects of Statins by Modulating Nrf2 and Nrf2/HO-1 Signaling in Different Diseases. J Clin Med 11:1313

65. Mohanty A, Pharaon RR, Nam A, Salgia S, Kulkarni P, Massarelli E (2020) FAK-targeted and combination therapies for the treatment of cancer: an overview of phase I and II clinical trials. Expert Opinion on Investigational Drugs 29:399–409

66. Cardano M, Tribioli C, Prosperi E (2020) Targeting Proliferating Cell Nuclear Antigen (PCNA) as an Effective Strategy to Inhibit Tumor Cell Proliferation. CCDT 20:240–252

67. Ye X, Ling B, Xu H, Li G, Zhao X, Xu J, Liu J, Liu L (2020) Clinical significance of high expression of proliferating cell nuclear antigen in non-small cell lung cancer. Medicine 99:e19755

68. Sun X, Kaufman PD (2018) Ki-67: more than a proliferation marker. Chromosoma 127:175–186

69. Chota A, George BP, Abrahamse H (2021) Interactions of multidomain pro-apoptotic and anti-apoptotic proteins in cancer cell death. Oncotarget 12:1615–1626

70. Boice A, Bouchier-Hayes L (2020) Targeting apoptotic caspases in cancer. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1867:118688

71. Patergnani S, Danese A, Bouhamida E, Aguiari G, Previati M, Pinton P, Giorgi C (2020) Various Aspects of Calcium Signaling in the Regulation of Apoptosis, Autophagy, Cell Proliferation, and Cancer. IJMS 21:8323

72. Satheesh N, Büsselberg D (2015) The Role of Intracellular Calcium for the Development and Treatment of Neuroblastoma. Cancers 7:823–848

73. Zorova LD, Popkov VA, Plotnikov EY, et al (2018) Mitochondrial membrane potential. Analytical Biochemistry 552:50–59

74. Smaili SS, Hsu Y-T, Youle RJ, Russell JT (2000) Mitochondria in Ca2+ Signaling and Apoptosis. Journal of Bioenergetics and Biomembranes 32:35–46

75. Kalpage HA, Wan J, Morse PT, et al (2020) Cytochrome c phosphorylation: Control of mitochondrial electron transport chain flux and apoptosis. The International Journal of Biochemistry & Cell Biology 121:105704

76. Morales-Cruz M, Figueroa CM, González-Robles T, Delgado Y, Molina A, Méndez J, Morales M, Griebenow K (2014) Activation of caspase-dependent apoptosis by intracellular delivery of cytochrome c-based nanoparticles. J Nanobiotechnol 12:33

77. Momeni HR (2011) Role of calpain in apoptosis. Cell J 13:65–72

78. Storr SJ, Carragher NO, Frame MC, Parr T, Martin SG (2011) The calpain system and cancer. Nat Rev Cancer 11:364–374

79. Sahoo BM, Banik BK, Borah P, Jain A (2022) Reactive Oxygen Species (ROS): Key Components in Cancer Therapies. ACAMC 22:215–222

80. Zhao Y, Ye X, Xiong Z, et al (2023) Cancer Metabolism: The Role of ROS in DNA Damage and Induction of Apoptosis in Cancer Cells. Metabolites 13:796

81. Blundell RA (2006) The Biology of p21Waf1/Cip1 - Review Paper. American J of Biochemistry and Biotechnology 2:33–40

82. Jaiswal PK, Goel A, Mittal RD (2015) Survivin: A molecular biomarker in cancer. Indian J Med Res 141:389–397

83. Mobahat M, Narendran A, Riabowol K (2014) Survivin as a Preferential Target for Cancer Therapy. IJMS 15:2494–2516

84. Pennati M, Folini M, Zaffaroni N (2008) Targeting survivin in cancer therapy. Expert Opinion on Therapeutic Targets 12:463–476

85. Ghafouri-Fard S, Khoshbakht T, Hussen BM, Taheri M, Samadian M (2021) A Review on the Role of miR-1290 in Cell Proliferation, Apoptosis and Invasion. Front Mol Biosci 8:763338

86. Yun C, Lee S (2018) The Roles of Autophagy in Cancer. IJMS 19:3466
Published
2024-12-31
How to Cite
Ridho, F. M., Fahrudin, P., Syachputra, A. J., Aruan, I. A., Ulfah, K., & Syahri, A. (2024). Anticancer Activity of Asiatic Acid from Centella Asiatica: A Comprehensive Systematic Review of In Vitro and In Vivo Studies. Keluwih: Jurnal Kesehatan Dan Kedokteran, 6(1). https://doi.org/10.24123/kesdok.V6i1.6752