REVIEW PAPER
 
KEYWORDS
TOPICS
ABSTRACT
Introduction and objective:
Neoplastic diseases are a common cause of death, especially in developed countries. Various methods are used in cancer therapy including natural substances. Terpenes and terpenoids play a special role, including betulin and betulinic acid with the pentacyclic structure of lupane. They have a wide range of pharmacological activity, among which anti-cancer activity attracts the greatest attention.

Abbreviated description of the state of knowledge:
he review discusses the pharmacological effects of betulin and its derivatives on tumours, and focuses on the potential of its application in the treatment of melanoma. The review study also presents future prospects for the use of this natural substance. Betulin and its derivatives have the ability to influence the processes of apoptosis, angiogenesis and autophagy. Additionally, they have the ability to sensitize, increasing the sensitivity to commonly used methods of cancer treatment. To-date, numerous studies have been carried out on the synthesis of betulinic acid derivatives, which would show greater polarity and activity compared to the starting compound. Due to their greater bioavailability, the modified compounds showed a stronger anti-tumour effect.

Conclusion:
The results of the above-mentioned studies confirm the anti-cancer properties of betulin. Regarding melanoma, betulin shows significant therapeutic efficacy. This gives new perspectives for the treatment of the most dangerous skin cancer.

Cabaj J, Bąk W, Wróblewska-Łuczka P. Anticancer effect of betulin and its derivatives, with particular emphasis on the treatment of melanoma. J Pre-Clin Clin Res. 2021; 15(2): 73–79. doi: 10.26444/jpccr/135691
 
REFERENCES (65)
1.
Roser M, Ritchie H. Cancer. https://ourworldindata.org/can..., access: 2021.01.24.
 
2.
Siegel RL, Miller KD, Jemal A. Cancer statistics. CA A Cancer J Clin. 2019; 69: 7–34. https://doi.org/10.3322/caac.2....
 
3.
Kumar V, Abbas AK, Aster JC, red. wyd. pol. Olszewski WT. Robbins Patologia. Edra Urban & Partner. 2019.
 
4.
Schadendorf D, van Akkooi ACJ, Berking C, et al. Melanoma. Lancet. 2018; 392(10151): 971–984. doi: 10.1016/S0140-6736(18)31559-9.
 
5.
Bębenek E, Chodurek E, Orchel A, et al. Antiproliterative activty of novel acetylenic derivatives of betulin against G-361 human melanoma cells. Acta Pol Pharm. 2015; 72(4): 699–703.
 
6.
Moreira A, Heinzerling L, Bhardwaj N, et al. Current Melanoma Treatments: Where Do We Stand? Cancers. 2021; 13: 221. https://doi.org/10.3390/cancer....
 
7.
Król SK, Kiełbus M, Rivero-Müller A, et al. Comprehensive review on betulin as a potent anticancer agent. Biomed Res Int. 2015; 2015: 584189. doi: 10.1155/2015/584189.
 
8.
Kim C, Kim B. Anti-Cancer Natural Products and Their Bioactive Compounds Inducing ER Stress-Mediated Apoptosis: A Review. Nutrients. 2018; 10(8): 1021. https://doi.org/10.3390/nu1008....
 
9.
Hordyjewska A, Ostapiuk A, Horecka A, et al. Betulin and betulinic acid: triterpenoids derivatives with a powerful biological potential. Phy tochem Rev. 2019; 18: 929–951. https://doi.org/10.1007/s11101....
 
10.
Li S, Kuo HD, Yin R, et al. Epigenetics/epigenomics of triterpenoids in cancer prevention and in health. Biochem Pharmacol. 2020; 175: 113890. https://doi.org/10.1016/j.bcp.....
 
11.
Nguyen NH, Ha TKQ, Yang JL, et al. Triterpenoids from the genus Gynostemma: Chemistry and pharmacological activities. J Ethnopharmacol. 2021; 268: 113574. https://doi.org/10.1016/j.jep.....
 
12.
Amiri S, Dastghaib S, Ahmadi M, et al. Betulin and its derivatives as novel compounds with different pharmacological effects. Biotechnol Adv. 2020; 38: 107409. https://doi.org/10.1016/j.biot....
 
13.
Kuznetsova SA, Skvortsova GP, Maliar IN, et al. Extraction of betulin from birch bark and study of its physico-chemical and pharmacological properties. Russ J Bioorg Chem. 2014; 40: 742–747. https://doi.org/10.1134/S10681....
 
14.
Pospíšil M, Kovář P, Vácha R, et al. Study of the betulin molecule in a water environment; ab initio and molecular simulation calculations. J Mol Model. 2012; 18: 367–376. https://doi.org/10.1007/s00894....
 
15.
Trumbull ER, Bianchi E, Eckert DJ, et al. Tumour Inhibitory Agents from Vauquelinia corymbosa (Rosaceae), J Pharm Sci. 1976; 65(9): 1407–1408. doi: 10.1002/jps.2600650938.
 
16.
Khan MF, Nahar N, Rashid RB, et al. Computational investigations of physicochemical, pharmacokinetic, toxicological properties and molecular docking of betulinic acid, a constituent of Corypha taliera (Roxb.) with Phospholipase A2 (PLA2). BMC Complement Altern Med. 2018; 18(1): 48. https://doi.org/10.1186/s12906....
 
17.
D’Arcy MS. Cell death: a review of the major forms of apoptosis, necrosis and autophagy. Cell Biol Int. 2019; 43: 582–592. https://doi.org/10.1002/cbin.1....
 
18.
Pistritto G, Trisciuoglio D, Ceci C, et al. Apoptosis as anticancer mechanism: function and dysfunction of its modulators and targeted therapeutic strategies. Aging (Albany NY). 2016; 8(4): 603–619. https://doi.org/10.18632/aging....
 
19.
Singh R, Letai A, Sarosiek K. Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins. Nat Rev Mol Cell Biol. 2019; 20: 175–193. https://doi.org/10.1038/s41580....
 
20.
Hsieh CC, Shen CH, The Potential of Targeting P53 and HSP90 Overcoming Acquired MAPKi-Resistant Melanoma. Curr. Treat. Options in Oncol. 2019; 20: 22 https://doi.org/10.1007/s11864....
 
21.
Box NF, Vukmer TO, Terzian T. Targeting p53 in melanoma. Pigment Cell Melanoma Res. 2014; https://doi.org/10.1111/pcmr.1....
 
22.
Pfeffer CM, Singh A. Apoptosis: A Target for Anticancer Therapy. Int J Mol Sci. 2018; 19(2): 448. https://doi.org/10.3390/ijms19....
 
23.
Fulda S, Scaffidi C, Suzin S, et al. Activation of mitochondria and release of mitochondrial apoptogenic factors by betulinic acid. J Biol Chem. 1998; 273(15): 33942–8. doi: 10.1074/jbc.273.51.33942.
 
24.
Kumar P, Bhadauria AS, Singh AK, Saha S. Betulinic acid as apoptosis activator: Molecular mechanisms, mathematical modeling and chemical modifications. Life Sci. 2018; 209: 24–33. https://doi.org/10.1016/j.lfs.....
 
25.
Rabi T, Shukla S, Gupta S. Betulinic acid suppresses constitutive and TNF-alpha-induced NF-kappaB activation and induces apoptosis in human prostate carcinoma PC-3 cells. Mol Carcinog. 2008; 47: 964–973. doi: 10.1002/mc.20447.
 
26.
Kasperczyk H, La Ferla-Bruhl K, Westhoff M, et al. Betulinic acid as new activator of NF-kappaB: molecular mechanisms and implications for cancer therapy. Oncogene. 2005; 24(46): 6945–6956. doi: 10.1038/sj.onc.1208842.
 
27.
Wick W, Grimmel C, Wagenknecht B, et al. Betulinic acid-induced apoptosis in glioma cells: A sequential requirement for new protein synthesis, formation of reactive oxygen species, and caspase processing. J Pharmacol Exp Therapeut. 1999; 289: 1306–1312.
 
28.
Rajabi M, Mousa SA. The Role of Angiogenesis in Cancer Treatment. Biomedicines. 2017; 5(2): 34. https://doi.org/10.3390/biomed....
 
29.
Viallard C, Larrivée B. Tumour angiogenesis and vascular normalization: alternative therapeutic targets. Angiogenesis. 2017; 20(4): 409–426. https://doi.org/10.1007/s10456....
 
30.
Karna E, Szoka Ł, Pałka J. Betulinic acid inhibits the expression of hypoxia-inducible factor 1 alpha and vascular endothelial growth factor in human endometrial adenocarcinoma cells. Mol Cell Biochem. 2010; 340(1–2): 15–20. doi: 10.1007/s11010-010-0395-8.
 
31.
Shin J, Lee HJ, Jung DB, et al. Suppression of STAT3 and HIF-1 alpha mediates anti-angiogenic activity of betulinic acid in hypoxic PC-3 prostate cancer cells. PLoS One. 2011; 6(6): e21492. doi: 10.1371/journal.pone.0021492.
 
32.
Zhang H, Li L, Huang X, et al. Combination of betulinic acid and chidamide inhibits acute myeloid leukemia by suppression of the HIF1α pathway and generation of reactive oxygen species. Oncotarget. 2017; 8(55): 94743–94758. doi: 10.18632/oncotarget.21889.
 
33.
Yang C, Li Y, Fu L, et al. Betulinic acid induces apoptosis and inhibits metastasis of human renal carcinoma cells in vitro and in vivo. J Cell Biochem. 2018; 119: 8611–8622. https://doi.org/10.1002/jcb.27....
 
34.
Lenart K, Szyda A, Kiełbasiński M, Duś D, et al. Kliniczne skutki oporności wielolekowej w nowotworach; Onkologia w praktyce klinicznej 2005, tom 1, nr 1.
 
35.
Yuan DY, Meng Z, Xu K, et al. Betulinic acid increases radiosensitization of oral squamous cell carcinoma through inducing Sp1 sumoylation and PTEN expression. Oncol Rep. 2017; 38(4): 2360–2368. doi: 10.3892/o r. 2 017. 5 8 7 2.
 
36.
Zhan XK, Li JL, Zhang S, et al. Betulinic acid exerts potent antitumour effects on paclitaxel-resistant human lung carcinoma cells (H460) via G2/M phase cell cycle arrest and induction of mitochondrial apoptosis. Oncol Lett. 2018; 16(3): 3628–3634. doi: 10.3892/ol.2018.9097.
 
37.
Cai Y, Zheng Y, Gu J, et al. Betulinic acid chemosensitizes breast cancer by triggering ER stress-mediated apoptosis by directly targeting GRP78. Cell Death Dis. 2018; 9(6): 636. https://doi.org/10.1038/s41419....
 
38.
Wang YJ, Liu JB, Dou YC. Sequential treatment with betulinic acid followed by 5-fluorouracil shows synergistic cytotoxic activity in ovarian cancer cells. Int J Clin Exp Pathol. 2015; 8(1): 252–259.
 
39.
Yun CW, Lee SH. The Roles of Autophagy in Cancer. Int J Mol Sci. 2018; 19(11): 3466. https://doi.org/10.3390/ijms19....
 
40.
Li YJ, Lei YH, Yao N, et al. Autophagy and multidrug resistance in cancer. Chin J Cancer. 2017; 36(1): 52. https://doi.org/10.1186/s40880...- 0219-2.
 
41.
Liu W, Li S, Qu Z, et al. Betulinic acid induces autophagy-mediated apoptosis through suppression of the PI3K/AKT/mTOR signaling pathway and inhibits hepatocellular carcinoma. Am J Transl Res. 2019; 11(11): 6952– 696 4.
 
42.
Kma DL, Baruah DTJ. The interplay of ROS and the PI3K/Akt pathway in autophagy regulation. Biotechnol Appl Biochem. 2021. https://doi.org/10.1002/bab.21....
 
43.
Pisha E, Chai H, Lee IS, et al. Discovery of betulinic acid as a selective inhibitor of human melanoma that functions by induction of apoptosis. Nat Med. 1995; 1(10): 1046–1051. doi: 10.1038/nm1095-1046.
 
44.
Selzer E, Pimentel E, Wacheck V, et al. Effects of Betulinic Acid Alone and in Combination with Irradiation in Human Melanoma Cells. J Invest Dermatol. 2000; 114(5): 935–940. doi: 10.1046/j.1523-1747.2000.00972.x.
 
45.
Galgon T, Wohlrab W, Dräger, B. Betulinic acid induces apoptosis in skin cancer cells and differentiation in normal human keratinocytes. Exp Dermatol. 2005; 14(10): 736–743. https://doi.org/10.1111/j.1600....
 
46.
Tan Y, Yu R, Pezzuto JM. Betulinic acid-induced programmed cell death in human melanoma cells involves mitogen-activated protein kinase activation. Clin Cancer Res. 2003; 9(7): 2866–2875.
 
47.
Gheorgheosu D, Jung M, Ören B, et al. Betulinic acid suppresses NGAL-induced epithelial-to-mesenchymal transition in melanoma, Biol Chem. 2013; 394(6): 773–781. https://doi.org/10.1515/hsz-20....
 
48.
Orchel A, Kulczycka A, Chodurek E, et al. Influence of betulin and 28-O-propynoylbetulin on proliferation and apoptosis of human melanoma cells (G-361). Postepy Hig Med Dosw. 2014; 68: 191–177. doi: 10.5604/17322693.1088757.
 
49.
Drąg-Zalesińska M, Drąg M, Poręba M, et al. Anticancer properties of ester derivatives of betulin in human metastatic melanoma cells (Me-45). Cancer Cell Int. 2017; 17: 4. https://doi.org/10.1186/s12935....
 
50.
Pfarr K, Danciu C, Arlt O, et al. Simultaneous and dose dependent melanoma cytotoxic and immune stimulatory activity of betulin. PLoS One. 2015; 10(3): e0118802. https://doi.org/10.1371/journa....
 
51.
Mioc M, Zinuca PI, Ghiulai R, et al. The Cytotoxic Effects of Betulin-Conjugated Gold Nanoparticles as Stable Formulations in Normal and Melanoma Cells. Front Pharmacol. 2018; 9: 429. doi: 10.3389/f phar.2018.00429.
 
52.
Danciu C, Pinzaru I, Coricovac D, et al. Betulin silver nanoparticles qualify as efficient antimelanoma agents in in vitro and in vivo studies. Eur J Pharm Biopharm. 2019; 134: 1–19. https://doi.org/10.1016/j.ejpb... 06.
 
53.
Wei L, Lu J, Xu H, et al. Silver nanoparticles: synthesis, properties, and therapeutic applications. Drug Discov Today. 2015; 20(5): 595–601. https://doi.org/10.1016/j.drud....
 
54.
Chrobak E, Kadela-Tomanek M, Bębenek E, et al. New phosphate derivatives of betulin as anticancer agents: Synthesis, crystal structure, and molecular docking study. Bioorg Chem. 2019; 87: 613–628. doi: 10.1016/j.bioorg.2019.03.060.
 
55.
Hoenke S, Heise NV, Kahnt M, et al. Betulinic acid derived amides are highly cytotoxic, apoptotic and selective. Eur J Med Chem. 2020; 207: 112815. https://doi.org/10.1016/j.ejme....
 
56.
Sharma H, Mishra PK, Talegaonkar S, et al. Metal nanoparticles: a theranostic nanotool against cancer, Drug Discov Today. 2015; 20(9): 1143–1151. https://doi.org/10.1016/j.drud....
 
57.
Roliński J. The role of dendritic cells in haematologic neoplasms immunotherapy. Post Nauk Med. 2000; 4: 47–50.
 
58.
Gołąb J, Jakóbisiak M, Lasek W, et al. Immunologia. Warszawa: Wydawnictwo Naukowe PWN; 2017.
 
59.
Soica C, Dehelean C, Danciu C, et al. Betulin complex in γ-cyclodextrin derivatives: properties and antineoplasic activities in in vitro and in vivo tumour models. Int J Mol Sci. 2012; 13(11): 14992–15011. doi: 10.3390/ijms131114992.
 
60.
Weber LA, Puff C, Kalbitz J, et al. Concentration profiles and safety of topically applied betulinic acid and NVX-207 in eight healthy horses-A randomized, blinded, placebo-controlled, crossover pilot study. J Vet Pharmacol Ther. 2021; 44(1): 47–57. https://doi.org/10.1111/jvp.12....
 
61.
Liebscher G, Vanchangiri K, Mueller T, et al. In vitro anticancer activity of Betulinic acid and derivatives thereof on equine melanoma cell lines from grey horses and invivo safety assessment of the compound NVX-207 in two horses. Chemico-Biological Interactions. 2016; 246: 20– 29. https://doi.org/10.1016/j.cbi.....
 
62.
Weber LA, Meißner J, Delarocque J, et al. Betulinic acid shows anticancer activity against equine melanoma cells and permeates isolated equine skin in vitro. BMC Vet Res. 2020; 16(44): 1– 9. https://doi.org/10.1186/s12917....
 
63.
Weber LA, Funtan A, Paschke R, et al. In vitro assessment of triterpenoids NVX-207 and betulinyl-bis-sulfamate as a topical treatment for equine skin cancer. PLOS ONE. 2020; 15(11): e0241448. https://doi.org/10.1371/journa....
 
64.
Spivak AY, Nedopekina DA, Gubaidullin RR, et al. Pentacyclic triterpene acid conjugated with mitochondria-targeting cation F16: Synthesis and evaluation of cytotoxic activities. Med Chem Res. 2021; 30: 940–951 https://doi.org/10.1007/s00044....
 
65.
Dubinin MV, Semenova AA, Ilzorkina AI, et al. Mitochondria-targeted prooxidant effects of betulinic acid conjugated with delocalized lipophilic cation F16. Free Radic Biol Med. 2021; 31: S0891-5849(21)00196-9. https://doi.org/10.1016/j.free....
 
eISSN:1898-7516
ISSN:1898-2395
Journals System - logo
Scroll to top