Skip to main content
Top
Published in: BMC Complementary Medicine and Therapies 1/2020

Open Access 01-12-2020 | Pancreatic Cancer | Research article

Chemopreventive effect of Betulinic acid via mTOR -Caspases/Bcl2/Bax apoptotic signaling in pancreatic cancer

Authors: Yangyang Guo, Hengyue Zhu, Min Weng, Cheng Wang, Linxiao Sun

Published in: BMC Complementary Medicine and Therapies | Issue 1/2020

Login to get access

Abstract

Background

Pancreatic cancer is aggressive with no symptoms until the advanced stage reached. The increased resistance of pancreatic cancer to chemotherapy demonstrates a dilemma in the clinical field. Hence, it is a matter of great urgency to develop an effective drug to treat patients with pancreatic cancer. Betulinic acid is a major triterpene isolated from spina date seed. Several studies have suggested its low toxicity and side effects to patients with malaria and inflammation. However, relevant studies on betulinic acid in inhibiting cancer were insufficient and the molecular mechanism was unclear. This study aimed to systematically explore the potential anti-cancer functions of betulinic acid in pancreatic cancer, and investigate its underlying molecular mechanism.

Methods

The Counting Kit-8 assay, colony formation, transwell invasion assay, wound healing assay, flow cytometry and xenograft nude mice model were used to evaluate the effect of betulinic acid on the proliferation, invasion and migration ability of pancreatic cancer cells.

Results

Our results showed that betulinic acid obviously suppressed pancreatic cancer both in vitro and in vivo in a dose-dependent manner. We also determined that betulinic acid inhibited pancreatic cancer by specifically targeting mTOR signaling rather than Nrf2 or JAK2.

Conclusions

These findings clarify that betulinic acid is a potential and valuable anticancer agent for pancreatic cancer, and indicate the specific molecular target of betulinic acid.
Appendix
Available only for authorised users
Literature
1.
go back to reference Verma V, Li J, Lin C. Neoadjuvant therapy for pancreatic cancer: systematic review of postoperative morbidity, mortality, and complications. Am J Clin Oncol. 2016;39(3):302–13.CrossRef Verma V, Li J, Lin C. Neoadjuvant therapy for pancreatic cancer: systematic review of postoperative morbidity, mortality, and complications. Am J Clin Oncol. 2016;39(3):302–13.CrossRef
2.
go back to reference Perysinakis I, Avlonitis S, Georgiadou D, Tsipras H, Margaris I. Five-year actual survival after pancreatoduodenectomy for pancreatic head cancer. ANZ J Surg. 2015;85(3):183–6.CrossRef Perysinakis I, Avlonitis S, Georgiadou D, Tsipras H, Margaris I. Five-year actual survival after pancreatoduodenectomy for pancreatic head cancer. ANZ J Surg. 2015;85(3):183–6.CrossRef
3.
go back to reference Torres MP, Rachagani S, Purohit V, Pandey P, Joshi S, Moore ED, et al. Graviola: a novel promising natural-derived drug that inhibits tumorigenicity and metastasis of pancreatic cancer cells in vitro and in vivo through altering cell metabolism. Cancer Lett. 2012;323(1):29–40.CrossRef Torres MP, Rachagani S, Purohit V, Pandey P, Joshi S, Moore ED, et al. Graviola: a novel promising natural-derived drug that inhibits tumorigenicity and metastasis of pancreatic cancer cells in vitro and in vivo through altering cell metabolism. Cancer Lett. 2012;323(1):29–40.CrossRef
4.
go back to reference Dutta D, Chakraborty B, Sarkar A, Chowdhury C, Das P. A potent betulinic acid analogue ascertains an antagonistic mechanism between autophagy and proteasomal degradation pathway in HT-29 cells. BMC Cancer. 2016;16(1):23.CrossRef Dutta D, Chakraborty B, Sarkar A, Chowdhury C, Das P. A potent betulinic acid analogue ascertains an antagonistic mechanism between autophagy and proteasomal degradation pathway in HT-29 cells. BMC Cancer. 2016;16(1):23.CrossRef
5.
go back to reference Steele JC, Warhurst DC, Kirby GC, Simmonds MS. In vitro and in vivo evaluation of betulinic acid as an antimalarial. Phytother Res. 1999;13(2):115–9.CrossRef Steele JC, Warhurst DC, Kirby GC, Simmonds MS. In vitro and in vivo evaluation of betulinic acid as an antimalarial. Phytother Res. 1999;13(2):115–9.CrossRef
6.
go back to reference Jingbo W, Aimin C, Qi W, Xin L, Huaining L. Betulinic acid inhibits IL-1β-induced inflammation by activating PPAR-γ in human osteoarthritis chondrocytes. Int Immunopharmacol. 2015;29(2):687–92.CrossRef Jingbo W, Aimin C, Qi W, Xin L, Huaining L. Betulinic acid inhibits IL-1β-induced inflammation by activating PPAR-γ in human osteoarthritis chondrocytes. Int Immunopharmacol. 2015;29(2):687–92.CrossRef
7.
go back to reference Aiken C, Chen CH. Betulinic acid derivatives as HIV-1 antivirals. Trends Mol Med. 2005;11(1):31–6.CrossRef Aiken C, Chen CH. Betulinic acid derivatives as HIV-1 antivirals. Trends Mol Med. 2005;11(1):31–6.CrossRef
8.
go back to reference Wang Z, Mudalal M, Sun Y, et al. The effects of leukocyte-platelet rich fibrin (L-PRF) on suppression of the expressions of the pro-inflammatory cytokines, and proliferation of schwann cell, and neurotrophic factors.[J]. Sci Rep. 2020;10:2421.CrossRef Wang Z, Mudalal M, Sun Y, et al. The effects of leukocyte-platelet rich fibrin (L-PRF) on suppression of the expressions of the pro-inflammatory cytokines, and proliferation of schwann cell, and neurotrophic factors.[J]. Sci Rep. 2020;10:2421.CrossRef
9.
go back to reference Wang W, Wang Y, Liu M, et al. Betulinic acid induces apoptosis and suppresses metastasis in hepatocellular carcinoma cell lines in vitro and in vivo.[J]. J Cell Mol Med. 2019;23:586–95.CrossRef Wang W, Wang Y, Liu M, et al. Betulinic acid induces apoptosis and suppresses metastasis in hepatocellular carcinoma cell lines in vitro and in vivo.[J]. J Cell Mol Med. 2019;23:586–95.CrossRef
10.
go back to reference Yu S, Zhang Y, Li Q, et al. CLDN6 promotes tumor progression through the YAP1-snail1 axis in gastric cancer.[J]. Cell Death Dis. 2019;10:949.CrossRef Yu S, Zhang Y, Li Q, et al. CLDN6 promotes tumor progression through the YAP1-snail1 axis in gastric cancer.[J]. Cell Death Dis. 2019;10:949.CrossRef
11.
go back to reference Zhang G, Feng W, Wu J. Down-regulation of SEPT9 inhibits glioma progression through suppressing TGF-β-induced epithelial-mesenchymal transition (EMT).[J]. Biomed Pharmacother. 2020;125:109768.CrossRef Zhang G, Feng W, Wu J. Down-regulation of SEPT9 inhibits glioma progression through suppressing TGF-β-induced epithelial-mesenchymal transition (EMT).[J]. Biomed Pharmacother. 2020;125:109768.CrossRef
12.
go back to reference Wolfgang CL, Herman JM, Laheru D, Klein AP, Erdek MA, Fishman EK, Hruban RH. Recent progress in pancreatic cancer. CA Cancer J Clin. 2013;63(5):318–48.CrossRef Wolfgang CL, Herman JM, Laheru D, Klein AP, Erdek MA, Fishman EK, Hruban RH. Recent progress in pancreatic cancer. CA Cancer J Clin. 2013;63(5):318–48.CrossRef
13.
go back to reference Heinemann V. Gemcitabine: progress in the treatment of pancreatic cancer. Oncology. 2001;60(1):8–18.CrossRef Heinemann V. Gemcitabine: progress in the treatment of pancreatic cancer. Oncology. 2001;60(1):8–18.CrossRef
14.
go back to reference George S, Bhalerao SV, Lidstone EA, Ahmad IS, Abbasi A, Cunningham BT, Watkin KL. Cytotoxicity screening of Bangladeshi medicinal plant extracts on pancreatic cancer cells. BMC Complement Altern Med. 2010;10(1):52.CrossRef George S, Bhalerao SV, Lidstone EA, Ahmad IS, Abbasi A, Cunningham BT, Watkin KL. Cytotoxicity screening of Bangladeshi medicinal plant extracts on pancreatic cancer cells. BMC Complement Altern Med. 2010;10(1):52.CrossRef
15.
go back to reference Wang J, Wang Z, Wang X, et al. Combination of Alprazolam and Bailemian capsule improves the sleep quality in patients with post-stroke insomnia: a retrospective study. Front Psychiatry. 2019;10:411.CrossRef Wang J, Wang Z, Wang X, et al. Combination of Alprazolam and Bailemian capsule improves the sleep quality in patients with post-stroke insomnia: a retrospective study. Front Psychiatry. 2019;10:411.CrossRef
16.
go back to reference Yogeeswari P, Sriram D. Betulinic acid and its derivatives: a review on their biological properties. Curr Med Chem. 2005;12(6):657–66.CrossRef Yogeeswari P, Sriram D. Betulinic acid and its derivatives: a review on their biological properties. Curr Med Chem. 2005;12(6):657–66.CrossRef
17.
go back to reference Cloer EW, Goldfarb D, Schrank TP, Weissman BE, Major MB. NRF2 activation in cancer: from DNA to protein. Cancer Res. 2019;79(5):889–98.CrossRef Cloer EW, Goldfarb D, Schrank TP, Weissman BE, Major MB. NRF2 activation in cancer: from DNA to protein. Cancer Res. 2019;79(5):889–98.CrossRef
18.
go back to reference Towers CG, Fitzwalter BE, Regan DP, Goodspeed A, Morgan MJ, Liu C, et al. Cancer cells upregulate NRF2 signaling to adapt to autophagy inhibition. Dev Cell. 2019;50(6):690–703.CrossRef Towers CG, Fitzwalter BE, Regan DP, Goodspeed A, Morgan MJ, Liu C, et al. Cancer cells upregulate NRF2 signaling to adapt to autophagy inhibition. Dev Cell. 2019;50(6):690–703.CrossRef
19.
go back to reference Slattery ML, Lundgreen A, Kadlubar S, Bondurant KL, Wolff RK. JAK/STAT/SOCS-signaling pathway and colon and rectal cancer. Mol Carcinog. 2013;52(2):155–66.CrossRef Slattery ML, Lundgreen A, Kadlubar S, Bondurant KL, Wolff RK. JAK/STAT/SOCS-signaling pathway and colon and rectal cancer. Mol Carcinog. 2013;52(2):155–66.CrossRef
20.
go back to reference Passamonti F, Maffioli M, Caramazza D, Cazzola M. Myeloproliferative neoplasms: from JAK2 mutations discovery to JAK2 inhibitor therapies. Oncotarget. 2011;2(6):485–90.CrossRef Passamonti F, Maffioli M, Caramazza D, Cazzola M. Myeloproliferative neoplasms: from JAK2 mutations discovery to JAK2 inhibitor therapies. Oncotarget. 2011;2(6):485–90.CrossRef
21.
go back to reference Thomas S, Snowden JA, Zeidler MP, Danson S. The role of JAK/STAT signalling in the pathogenesis, prognosis and treatment of solid tumours. Br J Cancer. 2015;113(3):365–71.CrossRef Thomas S, Snowden JA, Zeidler MP, Danson S. The role of JAK/STAT signalling in the pathogenesis, prognosis and treatment of solid tumours. Br J Cancer. 2015;113(3):365–71.CrossRef
22.
go back to reference Guertin DA, Sabatini DM. Defining the role of mTOR in cancer. Cancer Cell. 2007;12(1):9–22.CrossRef Guertin DA, Sabatini DM. Defining the role of mTOR in cancer. Cancer Cell. 2007;12(1):9–22.CrossRef
23.
go back to reference Skeen J, Bhaskar PT, Chen CC, Chen WS, Peng XD, Nogueira V, et al. Akt deficiency impairs normal cell proliferation and suppresses oncogenesis in a p53-independent and mTORC1-dependent manner. Cancer Cell. 2006;10(4):269–80.CrossRef Skeen J, Bhaskar PT, Chen CC, Chen WS, Peng XD, Nogueira V, et al. Akt deficiency impairs normal cell proliferation and suppresses oncogenesis in a p53-independent and mTORC1-dependent manner. Cancer Cell. 2006;10(4):269–80.CrossRef
24.
go back to reference Easton J, Houghton PJ. mTOR and cancer therapy. Oncogene. 2006;25(48):6436–46.CrossRef Easton J, Houghton PJ. mTOR and cancer therapy. Oncogene. 2006;25(48):6436–46.CrossRef
25.
go back to reference Kuo CJ, Huang CC, Chou SY, Lo YC, Kao TJ, Huang NK, et al. Potential therapeutic effect of curcumin, a natural mTOR inhibitor, in tuberous sclerosis complex. Phytomedicine. 2019;54:132–9.CrossRef Kuo CJ, Huang CC, Chou SY, Lo YC, Kao TJ, Huang NK, et al. Potential therapeutic effect of curcumin, a natural mTOR inhibitor, in tuberous sclerosis complex. Phytomedicine. 2019;54:132–9.CrossRef
26.
go back to reference Liu X, Jiang Q, Liu H, Luo S. Vitexin induces apoptosis through mitochondrial pathway and PI3K/Akt/mTOR signaling in human non-small cell lung cancer A549 cells. Biol Res. 2019;52(1):1–7.CrossRef Liu X, Jiang Q, Liu H, Luo S. Vitexin induces apoptosis through mitochondrial pathway and PI3K/Akt/mTOR signaling in human non-small cell lung cancer A549 cells. Biol Res. 2019;52(1):1–7.CrossRef
27.
go back to reference Paquette M, Elhoujeiri L, Pause A. mTOR pathways in cancer and autophagy. Cancers. 2018;10(1):18.CrossRef Paquette M, Elhoujeiri L, Pause A. mTOR pathways in cancer and autophagy. Cancers. 2018;10(1):18.CrossRef
28.
go back to reference Morselli E, Galluzzi L, Kepp O, Vicencio J, Criollo A, Maiuri MC, Kroemer G. Anti- and pro-tumor functions of autophagy. Biochim Biophys Acta. 2009;1793(9):1524–32.CrossRef Morselli E, Galluzzi L, Kepp O, Vicencio J, Criollo A, Maiuri MC, Kroemer G. Anti- and pro-tumor functions of autophagy. Biochim Biophys Acta. 2009;1793(9):1524–32.CrossRef
29.
go back to reference Jiang J, Pi J, Jin H, Cai J. Oridonin-induced mitochondria-dependent apoptosis in esophageal cancer cells by inhibiting PI3K/AKT/mTOR and Ras/Raf pathways. J Cell Biochem. 2019;120(3):3736–46.CrossRef Jiang J, Pi J, Jin H, Cai J. Oridonin-induced mitochondria-dependent apoptosis in esophageal cancer cells by inhibiting PI3K/AKT/mTOR and Ras/Raf pathways. J Cell Biochem. 2019;120(3):3736–46.CrossRef
30.
go back to reference Tian Y, Jia S, Shi J, Gong G, Yu J, Niu Y, et al. Polyphyllin I induces apoptosis and autophagy via modulating JNK and mTOR pathways in human acute myeloid leukemia cells. Chem Biol Interact. 2019;311:108793.CrossRef Tian Y, Jia S, Shi J, Gong G, Yu J, Niu Y, et al. Polyphyllin I induces apoptosis and autophagy via modulating JNK and mTOR pathways in human acute myeloid leukemia cells. Chem Biol Interact. 2019;311:108793.CrossRef
Metadata
Title
Chemopreventive effect of Betulinic acid via mTOR -Caspases/Bcl2/Bax apoptotic signaling in pancreatic cancer
Authors
Yangyang Guo
Hengyue Zhu
Min Weng
Cheng Wang
Linxiao Sun
Publication date
01-12-2020
Publisher
BioMed Central
Published in
BMC Complementary Medicine and Therapies / Issue 1/2020
Electronic ISSN: 2662-7671
DOI
https://doi.org/10.1186/s12906-020-02976-7

Other articles of this Issue 1/2020

BMC Complementary Medicine and Therapies 1/2020 Go to the issue