Phenolic Alkaloids from Menispermum Dauricum Inhibits BxPC-3 Pancreatic Cancer Cells by Blocking of Hedgehog Signaling Pathway

Overview

Journal Pharmacogn Mag

Publisher Sage Publications

Date 2015 Nov 25

PMID 26600712

Citations 4

Authors

Zhong-Guang Zhou

Chao-Ying Zhang

Hong-Xin Fei

Li-Li Zhong

Yun Bai

Affiliations

Soon will be listed here.

Abstract

Background: The Hedgehog (Hh) signaling pathway plays an important role in pancreatic cancer (PC) cells. Phenolic alkaloids from Menispermum dauricum (PAMD), a traditional Chinese medicine used for the treatment of immune disorders, have been reported to have antitumor activity recently.

Objective: To investigate the efficacy and mechanism of PAMD against PC cell BxPC-3.

Materials And Methods: F assay was used to assess cell proliferation inhibition of PAMD; the apoptotic induction and cell cycle arrest was detected by flow cytometry; the BxPC-3 xenograft was established to evaluate the tumor growth inhibition of PAMD; hematoxylin-eosin staining was applied to analyze the pathological morphology of tumor tissues; immunohistochemistry (IHC) and Western blot was adopted to detect the protein levels; quantitative real-time polymerase chain reaction was used to determine the mRNA expressions.

Results: PAMD shows time-and dose-dependent proliferation inhibition on the BxPC-3 cell, induced G0/G1 phase arrest and cell apoptosis in vitro. PAMD also showed better inhibition of tumor growth and a preferable safety profile compared with chemotherapeutic regimen 5-fluoro-2, 4 (1 H, 3 H) pyrimidinedione in BxPC-3 xenograft in vivo. Furthermore, PAMD directly decreases the protein and mRNA levels of Sonic Hedgehog (Shh) and its downstream transcription factor Gli-1 in the BxPC-3 tumor tissues.

Conclusion: The treatment of PAMD displayed Hh signaling pathway blockade through decreasing the protein and mRNA levels of Shh and its downstream transcription factor Gli-1, suggesting a promising strategy in treating human PC.

Citing Articles

Advances in the treatment of pancreatic cancer with traditional Chinese medicine.

Zhang Y, Xu H, Li Y, Sun Y, Peng X Front Pharmacol. 2023; 14:1089245.

PMID: 37608897 PMC: 10440824. DOI: 10.3389/fphar.2023.1089245.

Mining Therapeutic Efficacy from Treasure Chest of Biodiversity and Chemodiversity: Pharmacophylogeny of Ranunculales Medicinal Plants.

Hao D, Xu L, Zheng Y, Lyu H, Xiao P Chin J Integr Med. 2022; 28(12):1111-1126.

PMID: 35809180 PMC: 9282152. DOI: 10.1007/s11655-022-3576-x.

Dauricine suppresses the growth of pancreatic cancer by modulating the Hedgehog signaling pathway.

Zhang Y, Fei H, Guo J, Zhang X, Wu S, Zhong L Oncol Lett. 2019; 18(5):4403-4414.

PMID: 31611949 PMC: 6781764. DOI: 10.3892/ol.2019.10790.

Different Survival Benefits of Chinese Medicine for Pancreatic Cancer: How to Choose?.

Li M, Wang M, Guo X, Wu C, Li D, Zhang X Chin J Integr Med. 2017; 24(3):178-184.

PMID: 29063468 DOI: 10.1007/s11655-017-2971-1.

References

Kayed H, Kleeff J, Keleg S, Guo J, Ketterer K, Berberat P . Indian hedgehog signaling pathway: expression and regulation in pancreatic cancer. Int J Cancer. 2004; 110(5):668-76. DOI: 10.1002/ijc.20194. View

Xu L, Wang X, Wan J, Li T, Gong X, Zhang K . Sonic Hedgehog pathway is essential for neuroblastoma cell proliferation and tumor growth. Mol Cell Biochem. 2012; 364(1-2):235-41. DOI: 10.1007/s11010-011-1222-6. View

Ingham P, Nakano Y, Seger C . Mechanisms and functions of Hedgehog signalling across the metazoa. Nat Rev Genet. 2011; 12(6):393-406. DOI: 10.1038/nrg2984. View

Zhao B, Chen Y, Sun X, Zhou M, Ding J, Zhan J . Phenolic alkaloids from Menispermum dauricum rhizome protect against brain ischemia injury via regulation of GLT-1, EAAC1 and ROS generation. Molecules. 2012; 17(3):2725-37. PMC: 6268705. DOI: 10.3390/molecules17032725. View

Morton J, Mongeau M, Klimstra D, Morris J, Lee Y, Kawaguchi Y . Sonic hedgehog acts at multiple stages during pancreatic tumorigenesis. Proc Natl Acad Sci U S A. 2007; 104(12):5103-8. PMC: 1828712. DOI: 10.1073/pnas.0701158104. View

Berman D, Karhadkar S, Maitra A, Montes de Oca R, Gerstenblith M, Briggs K . Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature. 2003; 425(6960):846-51. DOI: 10.1038/nature01972. View

McMahon A . More surprises in the Hedgehog signaling pathway. Cell. 2000; 100(2):185-8. DOI: 10.1016/s0092-8674(00)81555-x. View

Jemal A, Siegel R, Xu J, Ward E . Cancer statistics, 2010. CA Cancer J Clin. 2010; 60(5):277-300. DOI: 10.3322/caac.20073. View

Ling C, Yue X, Ling C . Three advantages of using traditional Chinese medicine to prevent and treat tumor. J Integr Med. 2014; 12(4):331-5. DOI: 10.1016/S2095-4964(14)60038-8. View

10.

Adolphe C, Narang M, Ellis T, Wicking C, Kaur P, Wainwright B . An in vivo comparative study of sonic, desert and Indian hedgehog reveals that hedgehog pathway activity regulates epidermal stem cell homeostasis. Development. 2004; 131(20):5009-19. DOI: 10.1242/dev.01367. View

11.

Feldmann G, Dhara S, Fendrich V, Bedja D, Beaty R, Mullendore M . Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases: a new paradigm for combination therapy in solid cancers. Cancer Res. 2007; 67(5):2187-96. PMC: 3073370. DOI: 10.1158/0008-5472.CAN-06-3281. View

12.

Ingham P, McMahon A . Hedgehog signaling in animal development: paradigms and principles. Genes Dev. 2001; 15(23):3059-87. DOI: 10.1101/gad.938601. View

13.

Xu Y, An Y, Wang X, Zha W, Li X . Inhibition of the Hedgehog pathway induces autophagy in pancreatic ductal adenocarcinoma cells. Oncol Rep. 2013; 31(2):707-12. DOI: 10.3892/or.2013.2881. View

14.

Onishi H, Katano M . Hedgehog signaling pathway as a new therapeutic target in pancreatic cancer. World J Gastroenterol. 2014; 20(9):2335-42. PMC: 3942836. DOI: 10.3748/wjg.v20.i9.2335. View

15.

Vincent A, Herman J, Schulick R, Hruban R, Goggins M . Pancreatic cancer. Lancet. 2011; 378(9791):607-20. PMC: 3062508. DOI: 10.1016/S0140-6736(10)62307-0. View

16.

Jiang J, Hui C . Hedgehog signaling in development and cancer. Dev Cell. 2008; 15(6):801-12. PMC: 6443374. DOI: 10.1016/j.devcel.2008.11.010. View

17.

Thayer S, Pasca di Magliano M, Heiser P, Nielsen C, Roberts D, Lauwers G . Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature. 2003; 425(6960):851-6. PMC: 3688051. DOI: 10.1038/nature02009. View

18.

Wang J, Li Y, Zu X, Chen M, Qi L . Dauricine can inhibit the activity of proliferation of urinary tract tumor cells. Asian Pac J Trop Med. 2012; 5(12):973-6. DOI: 10.1016/S1995-7645(12)60185-0. View

19.

Siegel R, Naishadham D, Jemal A . Cancer statistics, 2013. CA Cancer J Clin. 2013; 63(1):11-30. DOI: 10.3322/caac.21166. View

20.

Yang Z, Li C, Wang X, Zhai C, Yi Z, Wang L . Dauricine induces apoptosis, inhibits proliferation and invasion through inhibiting NF-kappaB signaling pathway in colon cancer cells. J Cell Physiol. 2010; 225(1):266-75. DOI: 10.1002/jcp.22261. View