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Lubczyńska, A.; Bębenek, E.; Garncarczyk, A.; Wcisło-Dziadecka, D. Anti-Cancer and Anti-Inflammatory Activities of Betulin. Encyclopedia. Available online: https://encyclopedia.pub/entry/49573 (accessed on 12 May 2024).
Lubczyńska A, Bębenek E, Garncarczyk A, Wcisło-Dziadecka D. Anti-Cancer and Anti-Inflammatory Activities of Betulin. Encyclopedia. Available at: https://encyclopedia.pub/entry/49573. Accessed May 12, 2024.
Lubczyńska, Agnieszka, Ewa Bębenek, Agnieszka Garncarczyk, Dominika Wcisło-Dziadecka. "Anti-Cancer and Anti-Inflammatory Activities of Betulin" Encyclopedia, https://encyclopedia.pub/entry/49573 (accessed May 12, 2024).
Lubczyńska, A., Bębenek, E., Garncarczyk, A., & Wcisło-Dziadecka, D. (2023, September 24). Anti-Cancer and Anti-Inflammatory Activities of Betulin. In Encyclopedia. https://encyclopedia.pub/entry/49573
Lubczyńska, Agnieszka, et al. "Anti-Cancer and Anti-Inflammatory Activities of Betulin." Encyclopedia. Web. 24 September, 2023.
Anti-Cancer and Anti-Inflammatory Activities of Betulin
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This entry is adapted from the peer-reviewed paper 10.3390/pr11092676

Betulin is a lupane-type pentacyclic triterpene. It consists of four six-membered rings arranged in a trans configuration and one five-membered ring. It is characterized by a range of biological properties, including anti-cancer and anti-inflammatory activities. It is also an origin compound for obtaining derivatives with higher biological activity and better bioavailability.

betulin antitumor anti-inflammatory cancer cells apoptosis

1. Chemical Structure of Betulin

Betulin (lup-20(29)-en-3β,28-diol) is a pentacyclic triterpene of the lupane type. It consists of four six-membered rings arranged in a trans configuration and one five-membered ring. It has two hydroxyl groups in its structure: a primary one at the C-28 atom and a secondary one at the C-3 atom, as well as an isopropenyl group at the C-19 carbon (Figure 1). Betulin alcohol can undergo a variety of chemical reactions such as: oxidation, isomerization, esterification, dehydrogenation, dehydration, and hydrogenation. Many biological activities of betulin derivatives have been demonstrated, it has also been noticed how modifications of the structure of this compound can affect the decrease or increase of desired biological properties [1][2][3][4].
Processes 11 02676 g001
Figure 1. Chemical structure of betulin.

2. Antitumor Activity

The anticancer properties of betulin have been confirmed based on many cancer cell lines, including primary ones and in vivo models. However, the mechanism of action of betulin has remained unclear for many years. Only in recent years has the ability to induce apoptosis in cancer cells been recognized as one of the mechanisms of the antiproliferative and cytotoxic action of betulin. Morphological changes occurring under the influence of betulin indicate the transition of cells to apoptosis. These observations were confirmed on melanoma cells (B164A5), lung cancer (A549), T lymphoblastic leukemia (Jurkat), and cervical cancer (HeLa) [1]. In one study on a cell line derived from cervical cancer HeLa, after incubation with betulin at a concentration of 10 μg/mL, single cells showed morphological features characteristic of cells undergoing apoptosis: cell rounding and cell membrane blebbing. In addition, cell staining using DAPI (4′,6-diamidino-2-phenylindole) showed that chromatin condensation and DNA fragmentation (deoxyribonucleic acid) occurred in the cells [5]. A clear increase in the activity of caspase 9 and caspase 3/7 was also observed. The activity of caspase 8 remained unchanged, suggesting a lack of extrinsic apoptosis activation. This confirms that betulin activates the process of a programmed cell death through the intrinsic pathway. After the initial increase in caspase 9 activity, the release of cytochrome c/Smac protein from the perimitochondrial space, mitochondrial membrane depolarization, and translocation of the Bax and Bak proteins occur. However, the involvement of Bcl-2 family proteins in betulin-stimulated apoptosis is not unequivocal [1][5]. Studies on the anticancer mechanism of betulin were also conducted on the kidney cancer cells RCC. They showed that the mechanism of action of betulin is related to the mTOR pathway [6]. Yim, Jung et al. in their study on the same type of RCC4 cancer line confirmed the antiproliferative activity of betulin was dependent on the dose and time of action. In the cells exposed to the action of the compound, an increase in the level of caspases 3, 7, 8, and 9 was observed, as well as increased expression of proteins associated with apoptosis processes such as PARP and the Bcl-2 family. Moreover, betulin has been shown to be able to activate death receptors (TRAIL, TNFR1) and regulate the level of anti- and pro-apoptotic proteins. These observations suggest that the studied compound can induce the apoptotic process in RCC4 kidney cancer cells both through the intracellular pathway and the extracellular pathway [7]. The mechanism of action of betulin is also related to its effect on cell cycle regulating factors. In the lung cancer cells of the A549 and NCI-292 cell lines, an increase in the expression of the factors p21 and p27 was confirmed, with a simultaneous decrease in the concentration of the cyclins B, D1, and E. However, it should be noted that the impact of betulin on genes regulating the cell cycle is not always identical and to a large extent depends on the type of cells [1][8].
Gastrointestinal cancers are among the most common types of cancers in humans. The increase in incidences of stomach, liver, pancreas, and colon cancers, as well as their relatively late detection, present a significant clinical problem. Betulin also demonstrates anti-cancer activity against cell lines of gastrointestinal system cancers. This compound retains high cytotoxic activity (IC50 = 18.7 μM) against stomach cancer EPG85-257P, as well as towards the atypical line resistant to mitoxantrone treatment (EPG85-257RNOV; IC50 = 12.3 μM) and resistant to daunorubicin treatment (EPG85-257RDB; IC50 = 11 μM). Similar activity has been demonstrated against pancreatic cancer lines (EPP85-181P; IC50 = 21.1 μM) and variants resistant to mitoxantrone (EPP85-181RNOV; IC50 = 20.6 μM) and daunorubicin treatments (EPP85-181RDB; IC50 = 26.5 μM). In the case of colon cancers, betulin’s activity varies depending on the type of cell line. The highest activity was observed for the DLD-1 colon adenocarcinoma cell line (IC50 = 6.6 μM) and the HT-29 cell line (IC50 = 4.3 μM) [1]. In the Hep2G liver cancer cell line, it was shown that betulin induces apoptotic death through an intrinsic pathway involving the activation of caspases 3 and 9 [9]. Against SGC7901 stomach cancer cells, the antiproliferative action is based on the translocation of the Bak and Bax proteins, the release of cytochrome c, and the activation of caspase 3 and caspase 9. The observed changes and lack of influence on the level of caspase 8 again suggest the activation of the mitochondrial apoptosis pathway. Additionally, betulin reduces the expression of the gene encoding the anti-apoptotic protein Bcl-2 as well as XIAP, which blocks the activation of procaspase 9 and caspase 3/9. An important observation was also the increase in ROS levels in the cells treated with betulin in a dose- and time-dependent manner [10]. In colon cancer cells, the induction of an intrinsic apoptosis mechanism by betulin has also been confirmed. The study involved HT-29 and HCT116 colon adenocarcinoma cells and a line of normal intestinal epithelial cells. Betulin showed no toxicity towards normal cells, whereas it significantly reduced the proliferation of cancer cells depending on the applied dose [11].

3. Anti-Inflammatory Action

One of the presumed mechanisms of betulin’s anti-inflammatory action is the inhibition of phospholipase A2 (PLA2) activity, one of the key enzymes involved in the inflammatory process [12][13]. The conducted studies also showed that the mechanism of betulin’s anti- inflammatory action may also be associated with the transcriptional nuclear factor κB (NF-κB) [12][14]. In a study using AC16 heart muscle cells, it was proven that the presence of betulin leads to the blockade of the transcriptional activity of the RelA protein. Using AC16 cells, it was confirmed that betulin stimulates the phosphorylation of residue 705 tyrosine in the STAT3 factor. It also caused an increase in mRNA levels for the cytokine signaling suppressor 3 (SOCS3) and stimulated the expression of the anti-apoptotic gene Bcl-xL. In AC16 heart muscle cells subjected to the action of betulin, a decrease in the levels of IL-6, MCP-1, and IL-1 cytokines, considered to be pro-inflammatory, was also observed. Wan et al., in their studies using liver stellate cells (Ito), also proved that the compound in question increases STAT3 phosphorylation [15][16][17].
In an in vivo experiment with induced acute liver inflammation using LPS, the application of betulin significantly caused a decrease in the level of liver enzymes (ALT and AST) in the plasma. Furthermore, it demonstrated an inhibitory effect on the secretion of MPO, IL-1β, and TNF-α in liver tissue [18].
The theory regarding the anti-inflammatory action of betulin has been confirmed in many studies on various models with induced inflammation both in vitro and in vivo. The immunomodulatory action shown by betulin seems particularly interesting in combination with its antitumor activity and indicates its potential in regulating the tumorigenesis processes that are related to inflammatory processes [19].

References

  1. Król, S.K.; Kiełbus, M.; Rivero-Müller, A.; Stepulak, A. Comprehensive review on betulin as a potent anticancer agent. Biomed. Res. Int. 2015, 2015, 584189.
  2. Alakurtti, S.; Mäkelä, T.; Koskimies, S.; Yli-Kauhaluoma, J. Pharmacological properties of the ubiquitous natural product betulin. Eur. J. Pharm. Sci. 2006, 29, 1–13.
  3. Boryczka, S.; Bębenek, E.; Wietrzyk, J.; Kempińska, K.; Jastrzębska, M.; Kusz, J.; Nowak, M. Synthesis, structure and cytotoxic activity of new acetylenic derivatives of betulin. Molecules 2013, 18, 4526–4543.
  4. Tolstikov, G.A.; Flekhter, O.B.; Shultz, E.; Baltina, L.A.; Tolstikov, A.G. Betulin and Its Derivatives. Chemistry and Biological Activity. Chem. Sustain. Dev. 2005, 13, 1–29.
  5. Li, Y.; He, K.; Huang, Y.; Zheng, D.; Gao, C.; Cui, L.; Jin, Y.H. Betulin induces mitochondrial cytochrome c release associated apoptosis in human cancer cells. Mol. Carcinog. 2010, 49, 630–640.
  6. Dehelean, C.A.; Soica, C.; Ledeţi, I.; Aluaş, M.; Zupko, I.G.; Luşcan, A.; Munteanu, M. Study of the betulin enriched birch bark extracts effects on human carcinoma cells and ear inflammation. Chem. Cent. J. 2012, 6, 137.
  7. Yim, N.H.; Jung, Y.P.; Kim, A.; Kim, T.; Ma, J.Y. Induction of apoptotic cell death by betulin in multidrug-resistant human renal carcinoma cells. Oncol. Rep. 2015, 34, 1058–1064.
  8. Oh, S.H.; Choi, J.E.; Lim, S.C. Protection of betulin against cadmium-induced apoptosis in hepatoma cells. Toxicology 2006, 220, 1–12.
  9. Yang, L.; Taiyi, S.J.; Chang, G.; Qing, L.; Ying-hua, J. Caspase-9 Activation—Critical for Betulin-induced Apoptosis of Human Hepatoma Cells. Chem. Res. Chin. Univ. 2010, 26, 792–797.
  10. Li, Y.; Liu, X.; Jiang, D.; Lin, Y.; Wang, Y.; Li, Q.; Jin, Y.H. Betulin induces reactive oxygen species-dependent apoptosis in human gastric cancer SGC7901 cells. Arch. Pharm. Res. 2016, 39, 1257–1265.
  11. Zhou, Z.; Zhu, C.; Cai, Z.; Zhao, F.; He, L.; Lou, X.; Qi, X. Betulin induces cytochrome c release and apoptosis in colon cancer cells via NOXA. Oncol. Lett. 2018, 15, 7319–7327.
  12. Yadav, V.R.; Prasad, S.; Sung, B.; Kannappan, R.; Aggarwal, B.B. Targeting inflammatory pathways by triterpenoids for prevention and treatment of cancer. Toxins 2010, 2, 2428–2466.
  13. Bernard, P.; Scior, T.; Didier, B.; Hiber, M.; Berthon, J.Y. Ethnopharmacology and bioinformatic combination for leads discovery: Application to phospholipase A(2) inhibitors. Phytochemistry 2001, 58, 865–874.
  14. Nennig, S.E.; Schank, J.R. The Role of NFkB in Drug Addiction: Beyond Inflammation. Alcohol Alcohol. 2017, 52, 172–179.
  15. Zhang, S.Y.; Zhao, Q.F.; Fang, N.N.; Yu, J.G. Betulin inhibits pro-inflammatory cytokines expression through activation STAT3 signaling pathway in human cardiac cells. Eur. Rev. Med. Pharmacol. Sci. 2015, 19, 455–460.
  16. Wan, Y.; Jiang, S.; Lian, L.H.; Bai, T.; Cui, P.H.; Sun, X.T.; Nan, J.X. Betulinic acid and betulin ameliorate acute ethanol-induced fatty liver via TLR4 and STAT3 in vivo and in vitro. Int. Immunopharmacol. 2013, 17, 184–190.
  17. Zatorski, H.; Sałaga, M.; Zielińska, M. Czynniki genetyczne w patogenezie, przebiegu i leczeniu nieswoistych chorób zapalnych jelit. Postepy Hig. Med. Dosw. 2015, 69, 335–344.
  18. Laavola, M.; Haavikko, R.; Hämäläinen, M.; Leppänen, T.; Nieminen, R.; Alakurtti, S.; Moilanen, E. Betulin Derivatives Effectively Suppress Inflammation in Vitro and in Vivo. J. Nat. Prod. 2016, 79, 274–280.
  19. Ahmed, S.M.; Luo, L.; Namani, A.; Wang, X.J.; Tang, X. Nrf2 signaling pathway: Pivotal roles in inflammation. Biochim. Biophys. Acta Mol. Basis Dis. 2017, 1863, 585–597.
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Subjects: Medicine, Research & Experimental
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Agnieszka Lubczyńska
,
Ewa Bębenek
,
Agnieszka Garncarczyk
,
Dominika Wcisło-Dziadecka
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Revisions: 2 times (View History)
Update Date: 26 Sep 2023
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