Antitumour Activity of Muricatacin Isomers and its Derivatives in Human Colorectal Carcinoma Cell HCT116

Author(s): Wencong Wang, Rui Zhang, Jinxing Wang, Jun Tang, Mingan Wang, Yu Kuang*

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 20 , Issue 2 , 2020

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background and Purpose: Colorectal cancer is one of the leading causes of cancer-related death in elderly people. The natural product muricatacin is an important member of the γ-lactone family, and it has exhibited antitumour activity in multiple cancer cell lines; however, the antitumour activities of muricatacin stereoisomers and their derivatives in colorectal cancer cells have not yet been systematically explored.

Methods: The colorectal carcinoma cell line HCT116 was investigated in this study. Cell proliferation was assessed by MTT assay or crystal violet staining. Cell cycle arrest and cell apoptosis were evaluated by flow cytometry assay. The expression levels of p53, p21, cyclin E, cyclin D1, caspase-3, cleaved caspase-3, caspase-9, cleaved caspase-9 and LC3B were measured using western blot analysis. Autophagy induced by M2 was monitored by immunofluorescence assay with an antibody against LC3B.

Results: Cell proliferation assays showed that both naturally occurring muricatacin (M4) and its synthetic stereoisomer (M2) are potent cell growth inhibitors in HCT116 cells, with IC50 values of 79.43 and 83.17μM, respectively; these values are much lower than those of the other two isomers, M1 and M3, and those of the sixmembered lactone analogues. The flow cytometry analysis revealed that M2 and M4 induced significant cell cycle arrest during G0/G1 phase and caused relatively low apoptosis rates in HCT116 cells. Further analysis indicated that M2 caused p53-independent p21 induction and cyclin E/cyclin D1 downregulation. In addition, M2 also markedly induced autophagy in the early stage of administration.

Conclusion: Our results suggested that muricatacins possess potent antitumour activity against the colorectal carcinoma cell line HCT116 through inducing G0/G1 phase cell cycle arrest and autophagy in the early stage of administration.

Keywords: Muricatacin, antitumour activity, colorectal carcinoma cell line HCT116, cell cycle arrest, apoptosis, autophagy.

[1]
Ferlay, J.; Shin, H.R.; Bray, F.; Forman, D.; Mathers, C.; Parkin, D.M. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int. J. Cancer, 2010, 127(12), 2893-2917.
[http://dx.doi.org/10.1002/ijc.25516] [PMID: 21351269]
[2]
Ando, K.; Heymann, M.F.; Stresing, V.; Mori, K.; Rédini, F.; Heymann, D. Current therapeutic strategies and novel approaches in osteosarcoma. Cancers (Basel), 2013, 5(2), 591-616.
[http://dx.doi.org/10.3390/cancers5020591] [PMID: 24216993]
[3]
Asghar, U.; Witkiewicz, A.K.; Turner, N.C.; Knudsen, E.S. The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat. Rev. Drug Discov., 2015, 14(2), 130-146.
[http://dx.doi.org/10.1038/nrd4504] [PMID: 25633797]
[4]
Lane, D.P.; Cheok, C.F.; Lain, S. p53-based cancer therapy. Cold Spring Harb. Perspect. Biol., 2010, 2(9)a001222
[http://dx.doi.org/10.1101/cshperspect.a001222] [PMID: 20463003]
[5]
Rebucci, M.; Michiels, C. Molecular aspects of cancer cell resistance to chemotherapy. Biochem. Pharmacol., 2013, 85(9), 1219-1226.
[http://dx.doi.org/10.1016/j.bcp.2013.02.017] [PMID: 23435357]
[6]
Liang, X.J.; Chen, C.; Zhao, Y.; Wang, P.C. Circumventing tumor resistance to chemotherapy by nanotechnology. Methods Mol. Biol., 2010, 596, 467-488.
[http://dx.doi.org/10.1007/978-1-60761-416-6_21] [PMID: 19949937]
[7]
Natarajan, B.; Gaur, R.; Hemmingsson, O.; Kao, G.; Naredi, P. Depletion of the ER chaperone ENPL-1 sensitizes C. elegans to the anticancer drug cisplatin. Worm, 2013, 2(1)e24059
[http://dx.doi.org/10.4161/worm.24059] [PMID: 24058864]
[8]
Murcia, M.C.; Navarro, C.; Moreno, A.; Csaky, A.G. Naturally occurring delta-hydroxy-gamma-lactones: Muricatacins and related compounds. Curr. Org. Chem., 2010, 14, 15-47.
[http://dx.doi.org/10.2174/138527210790226410]
[9]
Chaudhari, D.A.; Ingle, A.B.; Fernandes, R.A. A concise synthesis of (4R,5R)-(-)-muricatacin and (4R,5R)-L-(-)-factor from D-glucono-delta-lactone. Tetrahedron Asymmetry, 2016, 27, 114-117.
[http://dx.doi.org/10.1016/j.tetasy.2016.01.003]
[10]
Alali, F.Q.; Liu, X.X.; McLaughlin, J.L. Annonaceous acetogenins: recent progress. J. Nat. Prod., 1999, 62(3), 504-540.
[http://dx.doi.org/10.1021/np980406d] [PMID: 10096871]
[11]
Liaw, C.C.; Liou, J.R.; Wu, T.Y.; Chang, F.R.; Wu, Y.C. Acetogenins from Annonaceae. Prog. Chem. Org. Nat. Prod., 2016, 101, 113-230.
[http://dx.doi.org/10.1007/978-3-319-22692-7_2] [PMID: 26659109]
[12]
Makabe, H.; Konno, H.; Miyoshi, H. Current topics of organic and biological chemistry of annonaceous acetogenins and their synthetic mimics. Curr. Drug Discov. Technol., 2008, 5(3), 213-229.
[http://dx.doi.org/10.2174/157016308785739820] [PMID: 18690890]
[13]
Cooze, C.; Manchoju, A.; Pansare, S.V. Synthesis of (-)-muricatacin and (-)-(R,R)-L-factor involving an organocatalytic direct vinylogous aldol reaction. Synlett, 2017, 28, 2928-2932.
[http://dx.doi.org/10.1055/s-0036-1590858]
[14]
Dong, H.B.; Yang, M.Y.; Liu, B.; Wang, M.A. Concise stereoselective total synthesis of (+)-muricatacin and (+)-epi-muricatacin. J. Asian Nat. Prod. Res., 2014, 16(8), 847-853.
[http://dx.doi.org/10.1080/10286020.2014.916695] [PMID: 24899519]
[15]
Dong, H.B.; Yang, M.Y.; Zhang, X.T.; Wang, M.A. Synthesis of muricatacin and 6-acetoxy-5-hexadecanolide isomers from pent-4-ynoic acid and Hex-5-ynoic acid. Youji Huaxue, 2015, 35, 152-158.
[http://dx.doi.org/10.6023/cjoc201408035]
[16]
Zhang, R.; Xu, A.; Qin, C.; Zhang, Q.; Chen, S.; Lang, Y.; Wang, M.; Li, C.; Feng, W.; Zhang, R.; Jiang, Z.; Tang, J. Pseudorabies virus dUTPase UL50 induces lysosomal degradation of Type I interferon receptor 1 and antagonizes the alpha interferon response. J. Virol., 2017, 91(21), 91.
[http://dx.doi.org/10.1128/JVI.01148-17] [PMID: 28794045]
[17]
Geng, Y.; Wang, X.; Yang, L.; Sun, H.; Wang, Y.; Zhao, Y.; She, R.; Wang, M.X.; Wang, D.X.; Tang, J. Antitumor activity of a 5-hydroxy-1H-pyrrol-2-(5H)-one-based synthetic small molecule in vitro and in vivo. PLoS One, 2015, 10(6)e0128928
[http://dx.doi.org/10.1371/journal.pone.0128928] [PMID: 26042776]
[18]
Agarwal, M.L.; Agarwal, A.; Taylor, W.R.; Stark, G.R. p53 controls both the G2/M and the G1 cell cycle checkpoints and mediates reversible growth arrest in human fibroblasts. Proc. Natl. Acad. Sci. USA, 1995, 92(18), 8493-8497.
[http://dx.doi.org/10.1073/pnas.92.18.8493] [PMID: 7667317]
[19]
Römer, L.; Klein, C.; Dehner, A.; Kessler, H.; Buchner, J. p53--a natural cancer killer: structural insights and therapeutic concepts. Angew. Chem. Int. Ed. Engl., 2006, 45(39), 6440-6460.
[http://dx.doi.org/10.1002/anie.200600611] [PMID: 16983711]
[20]
Wei, J.; Zaika, E.; Zaika, A. p53 Family: Role of protein isoforms in human cancer. J. Nucleic Acids, 2012, 2012687359
[http://dx.doi.org/10.1155/2012/687359] [PMID: 22007292]
[21]
Amaral, J.D.; Xavier, J.M.; Steer, C.J.; Rodrigues, C.M. The role of p53 in apoptosis. Discov. Med., 2010, 9(45), 145-152.
[PMID: 20193641]
[22]
Freed-Pastor, W.A.; Prives, C. Mutant p53: one name, many proteins. Genes Dev., 2012, 26(12), 1268-1286.
[http://dx.doi.org/10.1101/gad.190678.112] [PMID: 22713868]
[23]
Sherr, C.J. Cancer cell cycles. Science, 1996, 274(5293), 1672-1677.
[http://dx.doi.org/10.1126/science.274.5293.1672] [PMID: 8939849]
[24]
Dong, H.B.; Yang, M.Y.; Zhang, X.T.; Wang, M.A. Asymmetric total synthesis of all four isomers of 6-acetoxy-5-hexadecanolide: the major component of mosquito oviposition attractant pheromones. Tetrahedron Asymmetry, 2014, 25, 610-616.
[http://dx.doi.org/10.1016/j.tetasy.2014.03.006]
[25]
Chikara, S.; Lindsey, K.; Dhillon, H.; Mamidi, S.; Kittilson, J.; Christofidou-Solomidou, M.; Reindl, K.M. Enterolactone induces G1-phase cell cycle arrest in nonsmall cell lung cancer cells by downregulating cyclins and cyclin-dependent kinases. Nutr. Cancer, 2017, 69(4), 652-662.
[http://dx.doi.org/10.1080/01635581.2017.1296169] [PMID: 28323486]
[26]
Martin, L.A.; Farmer, I.; Johnston, S.R.; Ali, S.; Marshall, C.; Dowsett, M. Enhanced estrogen receptor (ER) alpha, ERBB2, and MAPK signal transduction pathways operate during the adaptation of MCF-7 cells to long term estrogen deprivation. J. Biol. Chem., 2003, 278(33), 30458-30468.
[http://dx.doi.org/10.1074/jbc.M305226200] [PMID: 12775708]
[27]
Bonni, A.; Brunet, A.; West, A.E.; Datta, S.R.; Takasu, M.A.; Greenberg, M.E. Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science, 1999, 286(5443), 1358-1362.
[http://dx.doi.org/10.1126/science.286.5443.1358] [PMID: 10558990]
[28]
Santarpia, L.; Lippman, S.M.; El-Naggar, A.K. Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy. Expert Opin. Ther. Targets, 2012, 16(1), 103-119.
[http://dx.doi.org/10.1517/14728222.2011.645805] [PMID: 22239440]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 20
ISSUE: 2
Year: 2020
Published on: 24 April, 2020
Page: [254 - 263]
Pages: 10
DOI: 10.2174/1871520619666191115111032
Price: $65

Article Metrics

PDF: 23
HTML: 4