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Farooqi, A.A.;  Turgambayeva, A.;  Tashenova, G.;  Tulebayeva, A.;  Bazarbayeva, A.;  Kapanova, G.;  Abzaliyeva, S. Betulinic Acid in Cancer Chemoprevention. Encyclopedia. Available online: https://encyclopedia.pub/entry/39664 (accessed on 24 December 2025).
Farooqi AA,  Turgambayeva A,  Tashenova G,  Tulebayeva A,  Bazarbayeva A,  Kapanova G, et al. Betulinic Acid in Cancer Chemoprevention. Encyclopedia. Available at: https://encyclopedia.pub/entry/39664. Accessed December 24, 2025.
Farooqi, Ammad Ahmad, Assiya Turgambayeva, Gulnara Tashenova, Aigul Tulebayeva, Aigul Bazarbayeva, Gulnara Kapanova, Symbat Abzaliyeva. "Betulinic Acid in Cancer Chemoprevention" Encyclopedia, https://encyclopedia.pub/entry/39664 (accessed December 24, 2025).
Farooqi, A.A.,  Turgambayeva, A.,  Tashenova, G.,  Tulebayeva, A.,  Bazarbayeva, A.,  Kapanova, G., & Abzaliyeva, S. (2023, January 02). Betulinic Acid in Cancer Chemoprevention. In Encyclopedia. https://encyclopedia.pub/entry/39664
Farooqi, Ammad Ahmad, et al. "Betulinic Acid in Cancer Chemoprevention." Encyclopedia. Web. 02 January, 2023.
Betulinic Acid in Cancer Chemoprevention
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This entry is adapted from the peer-reviewed paper 10.3390/molecules28010067

The pursual of novel anticancer molecules from natural sources has gained worthwhile appreciation, and a significant fraction of conceptual knowledge has revolutionized people's understanding about heterogeneous nature of cancer. Betulinic acid has fascinated interdisciplinary researchers due to its tremendous pharmacological properties. Ground-breaking discoveries have unraveled previously unprecedented empirical proof-of-concept about momentous chemopreventive role of betulinic acid against carcinogenesis and metastasis. Deregulation of cell signaling pathways has been reported to play a linchpin role in cancer progression and colonization of metastatically competent cancer cells to the distant organs for the development of secondary tumors. Importantly, betulinic acid has demonstrated unique properties to mechanistically modulate oncogenic transduction cascades.

cancer apoptosis

1. Introduction

Pioneering research-works over decades have enabled people to dissect multiple mechanisms which underlie carcinogenesis and metastasis [1][2]. Importantly, continuously evolving cancer biology research and the discoveries of new mechanistic paradigms in the study of metastasis have revealed detailed analysis of the molecular underpinnings of this multi-step dissemination process. Cancer cells from primary tumors display hallmark features and unique ability to metastasize to the distant organs [3][4]. Scientists have witnessed extra-ordinary advancements at a breakneck pace and these breakthroughs have increased the optimism for pharmacological targeting of oncogenic pathways for cancer chemoprevention [5][6][7][8]. In accordance with this approach, identification of bioactive molecules having minimum off-target effects and maximum efficacy for cancer chemoprevention has remained an overarching goal for molecular oncologists and medicinal chemists. Hydroxy pentacyclic triterpene acids have gained limelight due to their tremendous medicinal significance and pharmacological research related to these bioactive molecules has gained remarkable momentum. Therefore, the ongoing resolution of the puzzling mysteries underlying carcinogenesis and metastasis has paved the way for targeting of the oncogenic transduction cascades. The expanding scale and inherent complexity of biological data have provided opportunities for innovative therapeutic interventions for different cancers. Different types of proteins participate in the assembly of signaling complexes. Deregulation of cell signaling pathways played central role in multiple stages of carcinogenesis and metastasis.

2. Animal Models: Pharmacological Testing of Betulinic Acid in the Inhibition of Carcinogenesis and Metastasis

AMPK-mTOR-ULK1 cascade centrally regulates betulinic acid-mediated autophagy-dependent apoptotic death. Importantly, levels of cleaved caspase 3, LC3B-II and p-AMPK were found to be enhanced in the tumor tissues of mice subcutaneously inoculated with T24 cells [9].
Betulinic acid restored the sensitivity of K562R cells to imatinib through inhibition of HDAC3. Specifically, betulinic acid promoted the degradation of HDAC3 and promoted an increase in acetylated histones H3 and H4. Imatinib and betulinic acid combinatorially reduced tumor growth in mice subcutaneously inoculated with K562R cells [10].
Betulinic acid efficiently triggered DNA damage (γH2AX) and apoptosis (caspase-3 and p53 phosphorylation) in temozolomide-sensitive and temozolomide-resistant glioblastoma cells. Betulinic acid reduced tumor size and prolonged survival in orthotopic GBM animal models [11].
IGFBP5 physically interacted with RASSF1C and impaired RASSF1C-mediated increase in the levels of PIWIL1 mRNA and protein levels in lung cancer cells. Betulinic acid-mediated anti-proliferative effects were impaired in RASSF1C-overexpressing A549 and NCI-H1299 cells. Moreover, betulinic acid caused downregulation in the levels of PIWIL1 in A549 and H1299 cells. Co-expression of RASSF1C-IGFBP5 made cancer cells highly sensitive to betulinic acid [12].
Betulinic acid effectively reduced GLI1, GLI2 and PTCH1 in RMS-13 cells. Intraperitoneal injections of betulinic acid led to significant retardation in the growth of RMS-13 xenografts. Betulinic acid caused a more regional expression of GLI1 leaving large tumor areas unstained compared to homogeneously stained regions of GLI1 in tumor tissues of untreated mice [13].
For the maintenance of structural architecture, bone homeostasis is mechanistically orchestrated through the push and pull between bone resorptive functions by osteoclasts and bone forming ability by osteoblasts. Essentially, this diametrically opposed process is mediated via receptor activator of NF-қB (RANK)/RANK ligand (RANKL) system. Mostly, osteolytic factors secreted by cancer cells are widely acclaimed to trigger osteoclastic differentiation and activities through RANKL expression by osteoblasts/stromal cells. Importantly, betulinic acid prevented osteoclast-mediated bone resorptive properties by interruption of RANKL-mediated osteoclastogenesis and reduced the secretions of cathepsin K and MMPs from mature osteoclasts. Therefore, intratibial injections of MDA-MB-231 cancer cells induced bone lesions in nude mice. Betulinic acid downregulated the expression of PTHrP in tumor tissues in tibial bone marrow in rodent models. Consequently, administration of betulinic acid through oral route effectively suppressed breast cancer cell-mediated bone loss [14].
Modified derivatives of betulinic acid have been shown to be effective against cancers. SH-479 (modified derivative of betulinic acid) reduced the capacities of MDA-MB-231 cancer cells to induce differentiation of osteoclasts. SH-479 significantly increased CD3 + CD4 + T lymphocytes and concordantly reduced MDSCs in the bone marrow microenvironment (Figure 1) [15].
/media/item_content/202301/63b38440e42a8molecules-28-00067-g004.png
Figure 1. Betulinic acid mediated inhibition of invasion and colonization of cancer cells to the distantly located organs. Cancer cells from the primary tumors are metastatically competent and invade bones and lungs for colonization. Betulinic acid attenuated the invasion and colonization of cancer cells to the bones and lungs. Abbreviations: Myeloid-derived suppressor cells (MDSC), Matrix metalloproteinases (MMPs), Tissue Inhibitor of Metalloproteinase (TIMP).
SYK023, another betulinic acid derivative was found to be effective against animal models of lung cancer driven by EGFRL858R or KrasG12D. SYK023 robustly blocked doxycycline-induced lung cancer formation in EGFRL858R mice. Histological evaluation of EGFRL858R or KrasG12D mice clearly provided evidence of shrinkage of tumor formation in mice treated with SYK023. Synaptopodin, an actin-binding protein has been found to be frequently overexpressed in lung cancer. SYPD was reduced in the lung tissues of KrasG12D mice treated with SYK023 [16].
Sp1 has been noted to transcriptionally upregulate lamin B1 in pancreatic cancer. Lamin B1 overexpression contributed to invasion of pancreatic cancer cells. There was a considerable impairment in the invasive potential of lamin B1-silenced AsPC-1 and PANC-1 cancer cells. Importantly, lamin B1 inhibition significantly attenuated tumor growth of pancreatic cancer cells. Betulinic acid markedly induced shrinkage of tumors derived from AsPC-1 and PANC-1 cancer cells [17].
Vincristine and betulinic acid significantly reduced the pulmonary metastatic nodules in mice injected with B16F10 melanoma cells [18].
Betulinic acid suppressed the levels of MMP-2 and MMP-9, but stimulated the levels of TIMP-2 in HCT116 cells. Tumor growth was significantly suppressed by intraperitoneally administered betulinic acid in a xenograft model of HCT-116 [19].
It has also been reported that betulinic acid exerted inhibitory effects on MMP-2 and MMP-9 in HepG2 cells. Betulinic acid efficiently suppressed multiple large metastatic nodules on the surface of the lungs in mice injected with HepG2 cells [20].
Betulinic acid significantly reduced Ki67-positive and MMP-9-positive cells in the tumor tissues of mice inoculated with 786-O cancer cells [21].
23-hydroxybetulinic acid remarkably reduced CD11b + Gr1+ myeloid-derived suppressor cells in the tumor microenvironments (Figure 1) [22].

3. Concluding Remarks

Preclinical and clinical studies have revealed spatial and temporal intra-tumor heterogeneity in cancers and phenotypically divergent characteristics reflected by cancer cells emphasized on presence of drug resistance, loss of apoptosis and metastasizing potential of cancer cells. Research over the years has sequentially provided deeper comprehension of the cell signaling pathways and use of newer technologies including massively parallel sequencing has provided in-depth analysis regarding origin and evolution of tumors, occurrence of new mutations and underlying mechanisms for resistance against wide ranging molecular therapeutics.

References

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  2. Puisieux, A.; Brabletz, T.; Caramel, J. Oncogenic roles of EMT-inducing transcription factors. Nat. Cell Biol. 2014, 16, 488–494.
  3. Dongre, A.; Weinberg, R.A. New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer. Nat. Rev. Mol. Cell Biol. 2019, 20, 69–84.
  4. Valastyan, S.; Weinberg, R.A. Tumor metastasis: Molecular insights and evolving paradigms. Cell 2011, 147, 275–292.
  5. Clardy, J.; Walsh, C. Lessons from natural molecules. Nature 2004, 432, 829–837.
  6. Mann, J. Natural products in cancer chemotherapy: Past, present and future. Nat. Rev. Cancer 2002, 2, 143–148.
  7. Rodrigues, T.; Reker, D.; Schneider, P.; Schneider, G. Counting on natural products for drug design. Nat. Chem. 2016, 8, 531–541.
  8. Koehn, F.E.; Carter, G.T. The evolving role of natural products in drug discovery. Nat. Rev. Drug Discov. 2005, 4, 206–220.
  9. Zhang, Y.; He, N.; Zhou, X.; Wang, F.; Cai, H.; Huang, S.H.; Chen, X.; Hu, Z.; Jin, X. Betulinic acid induces autophagy-dependent apoptosis via Bmi-1/ROS/AMPK-mTOR-ULK1 axis in human bladder cancer cells. Aging 2021, 13, 21251–21267.
  10. Lu, T.; Wei, D.; Yu, K.; Ma, D.; Xiong, J.; Fang, Q.; Wang, J. Betulinic acid restores imatinib sensitivity in BCR-ABL1 kinase−independent, imatinib-resistant chronic myeloid leukemia by increasing HDAC3 ubiquitination and degradation. Ann. New York Acad. Sci. 2020, 1467, 77–93.
  11. Lo, W.-L.; Hsu, T.-I.; Yang, W.-B.; Kao, T.-J.; Wu, M.-H.; Huang, Y.-N.; Yeh, S.-H.; Chuang, J.-Y. Betulinic Acid-Mediated Tuning of PERK/CHOP Signaling by Sp1 Inhibition as a Novel Therapeutic Strategy for Glioblastoma. Cancers 2020, 12, 981.
  12. Reeves, M.E.; Firek, M.; Chen, S.-T.; Amaar, Y.G. Evidence that RASSF1C Stimulation of Lung Cancer Cell Proliferation Depends on IGFBP-5 and PIWIL1 Expression Levels. PLoS ONE 2014, 9, e101679.
  13. Eichenmüller, M.; Hemmerlein, B.; Von Schweinitz, D.; Kappler, R. Betulinic acid induces apoptosis and inhibits hedgehog signalling in rhabdomyosarcoma. Br. J. Cancer 2010, 103, 43–51.
  14. Park, S.Y.; Kim, H.-J.; Kim, K.R.; Lee, S.K.; Lee, C.K.; Park, K.-K.; Chung, W.-Y. Betulinic acid, a bioactive pentacyclic triterpenoid, inhibits skeletal-related events induced by breast cancer bone metastases and treatment. Toxicol. Appl. Pharmacol. 2014, 275, 152–162.
  15. Tang, L.; Lv, S.J.; Wu, Z.; Qian, M.; Xu, Y.; Gao, X.; Wang, T.; Guo, W.; Hou, T.; Li, X.; et al. Role of betulinic acid derivative SH-479 in triple negative breast cancer and bone microenvironment. Oncol. Lett. 2021, 22, 605.
  16. Hsu, T.-I.; Chen, Y.-J.; Hung, C.-Y.; Wang, Y.-C.; Lin, S.-J.; Su, W.-C.; Lai, M.-D.; Kim, S.-Y.; Wang, Q.; Qian, K.; et al. A novel derivative of betulinic acid, SYK023, suppresses lung cancer growth and malignancy. Oncotarget 2015, 6, 13671–13687.
  17. Li, L.; Du, Y.; Kong, X.; Li, Z.; Jia, Z.; Cui, J.; Gao, J.; Wang, G.; Xie, K. Lamin B1 Is a Novel Therapeutic Target of Betulinic Acid in Pancreatic Cancer. Clin. Cancer Res. 2013, 19, 4651–4661.
  18. Sawada, N.; Kataoka, K.; Kondo, K.; Arimochi, H.; Fujino, H.; Takahashi, Y.; Miyoshi, T.; Kuwahara, T.; Monden, Y.; Ohnishi, Y. Betulinic acid augments the inhibitory effects of vincristine on growth and lung metastasis of B16F10 melanoma cells in mice. Br. J. Cancer. 2004, 90, 1672–1678.
  19. Zeng, A.; Hua, H.; Liu, L.; Zhao, J. Betulinic acid induces apoptosis and inhibits metastasis of human colorectal cancer cells in vitro and in vivo. Bioorganic Med. Chem. 2019, 27, 2546–2552.
  20. Wang, W.; Wang, Y.; Liu, M.; Zhang, Y.; Yang, T.; Li, D.; Huang, Y.; Li, Q.; Bai, G.; Shi, L. Betulinic acid induces apoptosis and suppresses metastasis in hepatocellular carcinoma cell lines in vitro and in vivo. J. Cell. Mol. Med. 2019, 23, 586–595.
  21. YaYang, C.; Li, Y.; Fu, L.; Jiang, T.; Meng, F. Betulinic acid induces apoptosis and inhibits metastasis of human renal carcinoma cells in vitro and in vivo. J. Cell. Biochem. 2018, 119, 8611–8622.
  22. Tian, D.; Yu, Y.; Zhang, L.; Sun, J.; Jiang, W. 23-hydroxybetulinic acid reduces tumorigenesis, metastasis and immunosuppression in a mouse model of hepatocellular carcinoma via disruption of the MAPK signaling pathway. Anti-Cancer Drugs 2022, 33, 815–825.
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Subjects: Oncology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register : Ammad Ahmad Farooqi ,
Assiya Turgambayeva
, Gulnara Tashenova ,
Aigul Tulebayeva
,
Aigul Bazarbayeva
, Gulnara Kapanova , Symbat Abzaliyeva
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Revisions: 2 times (View History)
Update Date: 03 Jan 2023
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