Metabolites of Lycium barbarum L. from Lactobacillus acidophilus as Anti-hepatocellular carcinoma agents: induce apoptosis

Volume 5, Issue 2, April 2020     |     PP. 30-46      |     PDF (957 K)    |     Pub. Date: May 10, 2020
DOI:    206 Downloads     6231 Views  

Author(s)

Jie Liu, The Third Affiliated Hospital of Shenzhen University, Shenzhen University, Shenzhen 518020, China; School of Medicine, Shenzhen University, Shenzhen 518060, China.
Huailing Wang, The Third Affiliated Hospital of Shenzhen University, Shenzhen University, Shenzhen 518020, China.
Zhendan He, Department of Pharmacy, Health Science Center, Shenzhen University, Shenzhen 518060, China.
Xiaowei Zeng, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China.
Lin Mei, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China.
Anjin Tao, Hybio Pharmaceutical Co., Ltd. , Shenzhen 518057, China.
Zhigang Liu, The Third Affiliated Hospital of Shenzhen University, Shenzhen University, Shenzhen 518020, China; School of Medicine, Shenzhen University, Shenzhen 518060, China.
Xizhuo Sun, The Third Affiliated Hospital of Shenzhen University, Shenzhen University, Shenzhen 518020, China.
Xiaoyu Liu, School of Medicine, Shenzhen University, Shenzhen 518060, China.

Abstract
The fruit of Lycium barbarum L., also known as Gouqi, is a well-known Chinese herbal medicine with various biological activities. Gouqi has a long history of consumption in fermented milk products. In current study, five novel Gouqi metabolites by Lactobacillus acidophilus (GMLs) were structural identified and anti-neoplastic potency against hepatocellular carcinoma (HCC) was further explored. Mechanistic study revealed that GML-4 (methyl 2-(benzyloxy)-2-(2-(2,4-dimethoxybenzamido)acetamido)acetate) blocked the HepG2 cells in G0/G1-phase, as indicated by the decreased expressions of Cyclins and CDKs, and increased expressions of p21 and p27. Further, GML-4-induced cell apoptosis, as indicated by Caspases activation and phosphorylation of AKT/mTOR/S6K1/4E-BP1 signaling pathways. Of note, these findings suggest that GML-4 might be a potential lead compound candidate for the management of anti-HCC.

Keywords
Lactobacillus acidophilus; Lycium barbarum L.; Liver cancer; AKT/mTOR/S6K1/4E-BP1

Cite this paper
Jie Liu, Huailing Wang, Zhendan He, Xiaowei Zeng, Lin Mei, Anjin Tao, Zhigang Liu, Xizhuo Sun, Xiaoyu Liu, Metabolites of Lycium barbarum L. from Lactobacillus acidophilus as Anti-hepatocellular carcinoma agents: induce apoptosis , SCIREA Journal of Chemistry. Volume 5, Issue 2, April 2020 | PP. 30-46.

References

[ 1 ] Dutta, R. and R.I. Mahato, Recent advances in hepatocellular carcinoma therapy. Pharmacology & Therapeutics. 173: p. 106-117.
[ 2 ] Eggert, T. and T.F. Greten, Current Standard and Future Perspectives in Non-Surgical Therapy for Hepatocellular Carcinoma. Digestion: p. 1-4.
[ 3 ] Lu, T., et al., Prevention of hepatocellular carcinoma in chronic viral hepatitis B and C infection. World Journal of Gastroenterology, 2013. 19(47): p. 8887-8894.
[ 4 ] CXCR4 inhibition in tumor microenvironment facilitates anti-PD-1 immunotherapy in sorafenib-treated HCC in mice. 2014. 61(5): p. 1591.
[ 5 ] S.M.K., et al., Brassinin Induces Apoptosis in PC-3 Human Prostate Cancer Cells through the Suppression of PI3K/Akt/mTOR/S6K1 Signaling Cascades. Phytotherapy Research Ptr, 2014. 28(3): p. 423.
[ 6 ] Xu, Y., et al., Activation of AMPK and inactivation of Akt result in suppression of mTOR-mediated S6K1 and 4E-BP1 pathways leading to neuronal cell death in in vitro models of Parkinson\"s disease. Cellular Signalling. 26(8): p. 1680-1689.
[ 7 ] Tsai, B.P., et al., A novel Bcr-Abl-mTOR-eIF4A axis regulates IRES-mediated translation of LEF-1. Open Biology. 4(11): p. 140180-140180.
[ 8 ] Dreyer, H.C., et al., Chronic paraplegia-induced muscle atrophy downregulates the mTOR/S6K1 signaling pathway. Journal of Applied Physiology. 104(1): p. 27-33.
[ 9 ] Lin, D.C., Probiotics As Functional Foods. Nutrition in Clinical Practice, 2004. 18(6): p. 497-506.
[ 10 ] Wasilewski, A., et al., Beneficial Effects of Probiotics, Prebiotics, Synbiotics, and Psychobiotics in Inflammatory Bowel Disease. Inflammatory Bowel Diseases. 21(7): p. 1674-1682.
[ 11 ] Haller, D., et al., Guidance for Substantiating the Evidence for Beneficial Effects of Probiotics: Probiotics in Chronic Inflammatory Bowel Disease and the Functional Disorder Irritable Bowel Syndrome. Journal of Nutrition. 140(3): p. 690S-697S.
[ 12 ] Moayyedi, P., et al., The efficacy of probiotics in the therapy of irritable bowel syndrome (IBS): A systematic review. 2008. 28(11): p. 2202-2212.
[ 13 ] Chen, C.-C., et al., Probiotics Have Clinical, Microbiologic, and Immunologic Efficacy in Acute Infectious Diarrhea. The Pediatric Infectious Disease Journal. 29(2): p. 135-138.
[ 14 ] M.D, P.D.J.V., Probiotics: Intestinal gatekeeping, immunomodulation, and hepatic injury. Hepatology, 2007. 46(3): p. 618-621.
[ 15 ] Wang, X.-Y., et al., Effects of ginsenoside and Lycium barbarum polysaccharide on UVB irradiation-induced premature senescence of skin fibroblasts. 2010.
[ 16 ] Hu, C.-K., et al., The protective effects of Lycium barbarum and Chrysanthemum morifolum on diabetic retinopathies in rats. 15(Supplement s2): p. 0-0.
[ 17 ] Magiera, S. and M. Zar?ba, Chromatographic Determination of Phenolic Acids and Flavonoids inLycium barbarumL. and Evaluation of Antioxidant Activity. Food Analytical Methods. 8(10): p. 2665-2674.
[ 18 ] Lin, C.-F., et al., Phenolic derivatives from Aster indicus. Phytochemistry (Amsterdam). 68(19): p. 2450-2454.
[ 19 ] Sakagami, H., et al., Protection of Differentiating Neuronal Cells from Amyloid β Peptide-induced Injury by Alkaline Extract of Leaves of Sasa senanensis Rehder. 2018. 32(2): p. 231.
[ 20 ] Liu, J., et al., DMXAA-pyranoxanthone hybrids enhance inhibition activities against human cancer cells with multi-target functions. European Journal of Medicinal Chemistry, 2017. 143: p. 1768.
[ 21 ] Liu, J., et al., Synthesis of xanthone derivatives and studies on the inhibition against cancer cells growth and synergistic combinations of them. European Journal of Medicinal Chemistry. 133: p. 50-61.
[ 22 ] Incorporation of nitric oxide donor into 1,3-dioxyxanthones leads to synergistic anticancer activity. 2018. 151: p. 158-172.
[ 23 ] Moubarak, R.S., et al., Sequential Activation of Poly(ADP-Ribose) Polymerase 1, Calpains, and Bax Is Essential in Apoptosis-Inducing Factor-Mediated Programmed Necrosis. Molecular & Cellular Biology. 27(13): p. 4844-4862.
[ 24 ] Janicke and R. U., Caspase-3 Is Required for DNA Fragmentation and Morphological Changes Associated with Apoptosis. Journal of Biological Chemistry. 273(16): p. 9357-9360.
[ 25 ] Tsapras, P. and I.P. Nezis, Caspase involvement in autophagy. Cell Death & Differentiation, 2017. 24(8).
[ 26 ] Kong, A.N.T., et al., Signal transduction events elicited by natural products: role of MAPK and caspase pathways in homeostatic response and induction of apoptosis. Archives of Pharmacal Research, 2000. 23(1): p. 1-16.
[ 27 ] Kavitha, N., et al., Phaleria macrocarpa (Boerl.) fruit induce G0/G1 and G2/M cell cycle arrest and apoptosis through mitochondria-mediated pathway in MDA-MB-231 human breast cancer cell. Journal of Ethnopharmacology, 2017. 201(Complete): p. 42-55.
[ 28 ] Rana, B., et al., The DNA Binding Activity of C/EBP Transcription Factors Is Regulated in the G Phase of the Hepatocyte Cell Cycle. Journal of Biological Chemistry, 1995. 270(30): p. 18123-32.
[ 29 ] Zhang, X.J., et al., Strophalloside Induces Apoptosis of SGC-7901 Cells through the Mitochondrion-Dependent Caspase-3 Pathway. Molecules, 2015. 20(4): p. 5714-28.
[ 30 ] Borutaite, V., et al., Inhibition of mitochondrial permeability transition prevents mitochondrial dysfunction, cytochrome c release and apoptosis induced by heart ischemia. Journal of Molecular & Cellular Cardiology, 2003. 35(4): p. 0-366.
[ 31 ] Melittin exerts antitumorigenic effects in human MM1.S multiple myeloma cells through the suppression of AKT/mTOR/S6K1/4E-BP1 signaling cascades. Oriental Pharmacy & Experimental Medicine. 15(1): p. 33-44.
[ 32 ] Hu, Z., et al., Brain-expressed X-linked 2 Is Pivotal for Hyperactive Mechanistic Target of Rapamycin (mTOR)-mediated Tumorigenesis. Journal of Biological Chemistry. 290(42): p. 25756-25765.
[ 33 ] Pichiorri, et al., Downregulation of p53-inducible microRNAs 192, 194, and 215 Impairs the p53/MDM2 Autoregulatory Loop in Multiple Myeloma Development. Cancer Cell, 2016. 18(4): p. 367-381.