Pisosterol Induces G2/M Cell Cycle Arrest and Apoptosis via the ATM/ATR Signaling Pathway in Human Glioma Cells

Author(s): Wallax A.S. Ferreira, Rommel R. Burbano, Claudia do Ó. Pessoa, Maria L. Harada, Bárbara do Nascimento Borges, Edivaldo H. Correa de Oliveira*

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

Volume 20 , Issue 6 , 2020


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Graphical Abstract:


Abstract:

Background: Pisosterol, a triterpene derived from Pisolithus tinctorius, exhibits potential antitumor activity in various malignancies. However, the molecular mechanisms that mediate the pisosterol-specific effects on glioma cells remain unknown.

Objective: This study aimed to evaluate the antitumoral effects of pisosterol on glioma cell lines.

Methods: The 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) and trypan blue exclusion assays were used to evaluate the effect of pisosterol on cell proliferation and viability in glioma cells. The effect of pisosterol on the distribution of the cells in the cell cycle was performed by flow cytometry. The expression and methylation pattern of the promoter region of MYC, ATM, BCL2, BMI1, CASP3, CDK1, CDKN1A, CDKN2A, CDKN2B, CHEK1, MDM2, p14ARF and TP53 was analyzed by RT-qPCR, western blotting and bisulfite sequencing PCR (BSP-PCR).

Results: Here, it has been reported that pisosterol markedly induced G2/M arrest and apoptosis and decreased the cell viability and proliferation potential of glioma cells in a dose-dependent manner by increasing the expression of ATM, CASP3, CDK1, CDKN1A, CDKN2A, CDKN2B, CHEK1, p14ARF and TP53 and decreasing the expression of MYC, BCL2, BMI1 and MDM2. Pisosterol also triggered both caspase-independent and caspase-dependent apoptotic pathways by regulating the expression of Bcl-2 and activating caspase-3 and p53.

Conclusion: It has been, for the first time, confirmed that the ATM/ATR signaling pathway is a critical mechanism for G2/M arrest in pisosterol-induced glioma cell cycle arrest and suggests that this compound might be a promising anticancer candidate for further investigation.

Keywords: Brain cancer, cell cycle, gliomas, methylation, triterpenes, DNA damage.

[1]
McNeill, K.A. Epidemiology of brain tumors. Neurol. Clin., 2016, 34(4), 981-998.
[http://dx.doi.org/10.1016/j.ncl.2016.06.014] [PMID: 27720005]
[2]
Jovčevska, I.; Kočevar, N.; Komel, R. Glioma and glioblastoma - how much do we (not) know? Mol. Clin. Oncol., 2013, 1(6), 935-941.
[http://dx.doi.org/10.3892/mco.2013.172] [PMID: 24649273]
[3]
Adamson, C.; Kanu, O.O.; Mehta, A.I.; Di, C.; Lin, N.; Mattox, A.K.; Bigner, D.D. Glioblastoma multiforme: a review of where we have been and where we are going. Expert Opin. Investig. Drugs, 2009, 18(8), 1061-1083.
[http://dx.doi.org/10.1517/13543780903052764] [PMID: 19555299]
[4]
Ferreira, W.A.; Pinheiro, Ddo.R.; Costa Junior, C.A.; Rodrigues-Antunes, S.; Araújo, M.D.; Leão Barros, M.B.; Teixeira, A.C.; Faro, T.A.; Burbano, R.R.; Oliveira, E.H.; Harada, M.L.; Borges, B.N. An update on the epigenetics of glioblastomas. Epigenomics, 2016, 8(9), 1289-1305.
[http://dx.doi.org/10.2217/epi-2016-0040] [PMID: 27585647]
[5]
Wen, P.Y.; Kesari, S. Malignant gliomas in adults. N. Engl. J. Med., 2008, 359(5), 492-507.
[http://dx.doi.org/10.1056/NEJMra0708126] [PMID: 18669428]
[6]
Bastien, J.I.; McNeill, K.A.; Fine, H.A. Molecular characterizations of glioblastoma, targeted therapy, and clinical results to date. Cancer, 2015, 121(4), 502-516.
[http://dx.doi.org/10.1002/cncr.28968] [PMID: 25250735]
[7]
Rankeillor, K.L.; Cairns, D.A.; Loughrey, C.; Short, S.C.; Chumas, P.; Ismail, A.; Chakrabarty, A.; Lawler, S.E.; Roberts, P. Methylation-specific multiplex ligation-dependent probe amplification identifies promoter methylation events associated with survival in glioblastoma. J. Neurooncol., 2014, 117(2), 243-251.
[http://dx.doi.org/10.1007/s11060-014-1372-y] [PMID: 24554053]
[8]
Stupp, R.; Taillibert, S.; Kanner, A.A.; Kesari, S.; Steinberg, D.M.; Toms, S.A.; Taylor, L.P.; Lieberman, F.; Silvani, A.; Fink, K.L.; Barnett, G.H.; Zhu, J.J.; Henson, J.W.; Engelhard, H.H.; Chen, T.C.; Tran, D.D.; Sroubek, J.; Tran, N.D.; Hottinger, A.F.; Landolfi, J.; Desai, R.; Caroli, M.; Kew, Y.; Honnorat, J.; Idbaih, A.; Kirson, E.D.; Weinberg, U.; Palti, Y.; Hegi, M.E.; Ram, Z. Maintenance therapy with tumor-treating fields plus temozolomide vs temozolomide alone for glioblastoma: A randomized clinical trial. JAMA, 2015, 314(23), 2535-2543.
[http://dx.doi.org/10.1001/jama.2015.16669] [PMID: 26670971]
[9]
Stupp, R.; Taillibert, S.; Kanner, A.; Read, W.; Steinberg, D.; Lhermitte, B.; Toms, S.; Idbaih, A.; Ahluwalia, M.S.; Fink, K.; Di Meco, F.; Lieberman, F.; Zhu, J.J.; Stragliotto, G.; Tran, D.; Brem, S.; Hottinger, A.; Kirson, E.D.; Lavy-Shahaf, G.; Weinberg, U.; Kim, C.Y.; Paek, S.H.; Nicholas, G.; Bruna, J.; Hirte, H.; Weller, M.; Palti, Y.; Hegi, M.E.; Ram, Z. Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: A randomized clinical trial. JAMA, 2017, 318(23), 2306-2316.
[http://dx.doi.org/10.1001/jama.2017.18718] [PMID: 29260225]
[10]
Stupp, R.; Mason, W.P.; van den Bent, M.J.; Weller, M.; Fisher, B.; Taphoorn, M.J.; Belanger, K.; Brandes, A.A.; Marosi, C.; Bogdahn, U.; Curschmann, J.; Janzer, R.C.; Ludwin, S.K.; Gorlia, T.; Allgeier, A.; Lacombe, D.; Cairncross, J.G.; Eisenhauer, E.; Mirimanoff, R.O. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med., 2005, 352(10), 987-996.
[http://dx.doi.org/10.1056/NEJMoa043330] [PMID: 15758009]
[11]
Vredenburgh, J.J.; Desjardins, A.; Herndon, J.E., II; Marcello, J.; Reardon, D.A.; Quinn, J.A.; Rich, J.N.; Sathornsumetee, S.; Gururangan, S.; Sampson, J.; Wagner, M.; Bailey, L.; Bigner, D.D.; Friedman, A.H.; Friedman, H.S. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J. Clin. Oncol., 2007, 25(30), 4722-4729.
[http://dx.doi.org/10.1200/JCO.2007.12.2440] [PMID: 17947719]
[12]
Fernández, A.; Sessel, S. Selective antagonism of anticancer drugs for side-effect removal. Trends Pharmacol. Sci., 2009, 30(8), 403-410.
[http://dx.doi.org/10.1016/j.tips.2009.06.001] [PMID: 19595465]
[13]
Perfetti, V.; Palladini, G.; Brunetti, L.; Sgarella, A.; Brugnatelli, S.; Gobbi, P.G.; Corazza, G.R. Bortezomib-induced paralytic ileus is a potential gastrointestinal side effect of this first-in-class anticancer proteasome inhibitor. Eur. J. Gastroenterol. Hepatol., 2007, 19(7), 599-601.
[http://dx.doi.org/10.1097/MEG.0b013e32811ebffe] [PMID: 17556909]
[14]
Valverde, M.E.; Hernández-Pérez, T.; Paredes-López, O. Edible mushrooms: improving human health and promoting quality life. Int. J. Microbiol., 2015, 2015,376387
[http://dx.doi.org/10.1155/2015/376387] [PMID: 25685150]
[15]
Marx, D.H. Tree host range and world distribution of the extomycorrhizal fungus Pisolithus tinctorius. Can. J. Microbiol., 1977, 23(3), 217-223.
[http://dx.doi.org/10.1139/m77-033] [PMID: 856419]
[16]
Martin, F.; Laurent, P.; de Carvalho, D.; Voiblet, C.; Balestrini, R.; Bonfante, P.; Tagu, D. Cell wall proteins of the ectomycorrhizal basidiomycete Pisolithus tinctorius: identification, function, and expression in symbiosis. Fungal Genet. Biol., 1999, 27(2-3), 161-174.
[http://dx.doi.org/10.1006/fgbi.1999.1138] [PMID: 10441442]
[17]
Martin, F.; Tommerup, C.; Tagu, D. Genetics of ectomycorrhizal fungi: Progress and prospects. Plant Soil, 1994, 159(1), 159-170.
[http://dx.doi.org/10.1007/BF00000105]
[18]
Ahn, M.Y.; Jee, S.D.; Lee, B.M. Antiobesity effects of Isaria sinclairii by repeated oral treatment in obese Zucker rats over a 4-month period. J. Toxicol. Environ. Health A, 2007, 70(15-16), 1395-1401.
[http://dx.doi.org/10.1080/15287390701428556] [PMID: 17654260]
[19]
Ameri, A.; Ghadge, C.; Vaidy, J.G.; Deokule, S.S. Anti-Staphylococcus aureus activity of Pisolithus albus from Pune, India. J. Med. Plants Res., 2011, 5(4), 527-532.
[20]
Tsantrizos, Y.S.; Kope, H.H.; Fortin, J.A.; Ogilvie, K.K. Antifungal antibiotics from Pisolithus tinctorius. Phytochemistry, 1991, 30, 1113-1118.
[http://dx.doi.org/10.1016/S0031-9422(00)95183-5]
[21]
Montenegro, R.C.; Jimenez, P.C.; Feio Farias, R.A.; Andrade-Neto, M.; Silva Bezerra, F.; Moraes, M.E.; de Moraes, M.O.; Pessoa, C.; Costa-Lotufo, L.V. Cytotoxic activity of pisosterol, a triterpene isolated from Pisolithus tinctorius (Mich.: Pers.) Coker Couch, 1928. Z. Natforsch. C J. Biosci., 2004, 59(7-8), 519-522.
[http://dx.doi.org/10.1515/znc-2004-7-812] [PMID: 15813372]
[22]
Burbano, R.R.; Lima, P.D.; Bahia, M.O.; Khayat, A.S.; Silva, T.C.; Bezerra, F.S.; Andrade Neto, M.; de Moraes, M.O.; Montenegro, R.C.; Costa-Lotufo, L.V.; Pessoa, C. Cell cycle arrest induced by pisosterol in HL60 cells with gene amplification. Cell Biol. Toxicol., 2009, 25(3), 245-251.
[http://dx.doi.org/10.1007/s10565-008-9074-x] [PMID: 18465199]
[23]
Carvalho Montenegro, R.; Feio Farias, R.A.; Pinho Pereira, M.R.; Negreiros Nunes Alves, A.P.; Silva Bezerra, F.; Andrade-Neto, M.; Pessoa, C.; de Moraes, M.O.; Veras Costa-Lotufo, L. Antitumor activity of pisosterol in mice bearing with S180 tumor. Biol. Pharm. Bull., 2008, 31(3), 454-457.
[http://dx.doi.org/10.1248/bpb.31.454] [PMID: 18310909]
[24]
Montenegro, R.C.; de Vasconcellos, M.C.; Silva Bezerra, F.; Andrade-Neto, M.; Pessoa, C.; de Moraes, M.O.; Costa-Lotufo, L.V. Pisosterol induces monocytic differentiation in HL-60 cells. Toxicol. In Vitro: In: Int. J. Publ. Assoc. BIBRA; , 2007; 21, pp. (5)795-800.
[25]
Pereira, E.L.; Lima, P.D.; Khayat, A.S.; Bahia, M.O.; Bezerra, F.S.; Andrade-Neto, M.; Montenegro, R.C.; Pessoa, C.; Costa-Lotufo, L.V.; Moraes, M.O.; Yoshioka, F.K.; Pinto, G.R.; Burbano, R.R. Inhibitory effect of pisosterol on human glioblastoma cell lines with C-MYC amplification. J. Appl. Toxicol., 2011, 31(6), 554-560.
[http://dx.doi.org/10.1002/jat.1596] [PMID: 21061448]
[26]
Silva, T.C.; Lima, P.D.; Bahia, M.O.; Khayat, A.S.; Bezerra, F.S.; Andrade-Neto, M.; Seabra, A.D.; Pontes, T.B.; Moraes, M.O.; Montenegro, R.C.; Costa-Lotufo, L.V.; Pessoa, C.; Pinto, G.R.; Burbano, R.R. Pisosterol induces interphase arrest in HL60 cells with c-MYC amplification. Hum. Exp. Toxicol., 2010, 29(3), 235-240.
[http://dx.doi.org/10.1177/0960327109359637] [PMID: 20071475]
[27]
Annovazzi, L.; Mellai, M.; Schiffer, D. Chemotherapeutic drugs: DNA damage and repair in glioblastoma. Cancers (Basel), 2017, 9(6), E57
[http://dx.doi.org/10.3390/cancers9060057] [PMID: 28587121]
[28]
Blackford, A.N.; Jackson, S.P. ATM, ATR, and DNA-PK: The trinity at the heart of the DNA damage response. Mol. Cell, 2017, 66(6), 801-817.
[http://dx.doi.org/10.1016/j.molcel.2017.05.015] [PMID: 28622525]
[29]
Shiloh, Y.; Ziv, Y. The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nat. Rev. Mol. Cell Biol., 2013, 14(4), 197-210.
[http://dx.doi.org/10.1038/nrm3546]
[30]
Bolderson, E.; Richard, D.J.; Zhou, B.B.; Khanna, K.K. Recent advances in cancer therapy targeting proteins involved in DNA double-strand break repair. Clin. Cancer Res.: Off. J. Am. Assoc. Cancer Res., 2009, 15(20), 6314-6320.
[31]
Kastan, M.B.; Bartek, J. Cell-cycle checkpoints and cancer. Nature, 2004, 432(7015), 316-323.
[http://dx.doi.org/10.1038/nature03097] [PMID: 15549093]
[32]
Golding, S.E.; Rosenberg, E.; Khalil, A.; McEwen, A.; Holmes, M.; Neill, S.; Povirk, L.F.; Valerie, K. Double strand break repair by homologous recombination is regulated by cell cycle-independent signaling via ATM in human glioma cells. J. Biol. Chem., 2004, 279(15), 15402-15410.
[http://dx.doi.org/10.1074/jbc.M314191200] [PMID: 14744854]
[33]
Mosmann, T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Methods, 1983, 65(1-2), 55-63.
[http://dx.doi.org/10.1016/0022-1759(83)90303-4] [PMID: 6606682]
[34]
Denizot, F.; Lang, R. Rapid colorimetric assay for cell growth and survival. Modifications to the tetrazolium dye procedure giving improved sensitivity and reliability. J. Immunol. Methods, 1986, 89(2), 271-277.
[http://dx.doi.org/10.1016/0022-1759(86)90368-6] [PMID: 3486233]
[35]
Zhou, J-J.; Yue, X-F.; Han, J-X.; Yang, W-Y. Improved MTT assay for activity of antitumor agents. Carol. J. Pharm., 1993, 24, 455-455.
[36]
Jordan, J.P.; Hand, C.M.; Markowitz, R.S.; Black, P. Test for chemotherapeutic sensitivity of cerebral gliomas: use of colorimetric MTT assay. J. Neurooncol., 1992, 14(1), 19-35.
[http://dx.doi.org/10.1007/BF00170942] [PMID: 1335043]
[37]
Tonn, J.C.; Nikkhah, G.; Darling, J.L.; Schachenmayr, W. Test for chemotherapeutic sensitivity of cerebral gliomas: use of the colorimetric MTT assay. J. Neurooncol., 1993, 16(2), 177-180.
[http://dx.doi.org/10.1007/BF01324706] [PMID: 8123170]
[38]
Kumar, A.; Bhatkar, D.; Jahagirdar, D.; Sharma, N.K. Non-homologous end joining inhibitor SCR-7 to exacerbate low-dose doxorubicin cytotoxicity in HeLa cells. J. Cancer Prev., 2017, 22(1), 47-54.
[http://dx.doi.org/10.15430/JCP.2017.22.1.47] [PMID: 28382286]
[39]
Leal, M.F.; Ribeiro, H.F.; Rey, J.A.; Pinto, G.R.; Smith, M.C.; Moreira-Nunes, C.A.; Assumpção, P.P.; Lamarão, L.M.; Calcagno, D.Q.; Montenegro, R.C.; Burbano, R.R. YWHAE silencing induces cell proliferation, invasion and migration through the up-regulation of CDC25B and MYC in gastric cancer cells: new insights about YWHAE role in the tumor development and metastasis process. Oncotarget, 2016, 7(51), 85393-85410.
[http://dx.doi.org/10.18632/oncotarget.13381] [PMID: 27863420]
[40]
Ferreira, W.A.; Araújo, M.D.; Anselmo, N.P.; de Oliveira, E.H.; Brito, J.R.; Burbano, R.R.; Harada, M.L.; Borges, Bdo.N. Expression analysis of genes involved in the RB/E2F pathway in astrocytic tumors. PLoS One, 2015, 10(8), e0137259
[http://dx.doi.org/10.1371/journal.pone.0137259] [PMID: 26317630]
[41]
Bustin, S.A.; Benes, V.; Garson, J.A.; Hellemans, J.; Huggett, J.; Kubista, M.; Mueller, R.; Nolan, T.; Pfaffl, M.W.; Shipley, G.L.; Vandesompele, J.; Wittwer, C.T. The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments. Clin. Chem., 2009, 55(4), 611-622.
[http://dx.doi.org/10.1373/clinchem.2008.112797] [PMID: 19246619]
[42]
Aithal, M.G.; Rajeswari, N. Validation of housekeeping genes for gene expression analysis in glioblastoma using quantitative real-time polymerase chain reaction. Brain Tumor Res. Treat., 2015, 3(1), 24-29.
[http://dx.doi.org/10.14791/btrt.2015.3.1.24] [PMID: 25977903]
[43]
Livak, K.J.; Schmittgen, T.D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods, 2001, 25(4), 402-408.
[http://dx.doi.org/10.1006/meth.2001.1262] [PMID: 11846609]
[44]
Kawamata, N.; Inagaki, N.; Mizumura, S.; Sugimoto, K.J.; Sakajiri, S.; Ohyanagi-Hara, M.; Oshimi, K. Methylation status analysis of cell cycle regulatory genes (p16INK4A, p15INK4B, p21Waf1/Cip1, p27Kip1 and p73) in natural killer cell disorders. Eur. J. Haematol., 2005, 74(5), 424-429.
[http://dx.doi.org/10.1111/j.1600-0609.2005.00417.x] [PMID: 15813917]
[45]
Araújo, M.D. Analysis of the methylation pattern and expression of genes involved in the p14 / mdm2 / p53 pathway in astrocytic tumors. Universidade Federal do Pará, Instituto de Ciências Biológicas, 2013.
[46]
Sanger, F.; Nicklen, S.; Coulson, A.R. DNA sequencing with chain-terminating inhibitors. Proc. Natl. Acad. Sci. USA, 1977, 74(12), 5463-5467.
[http://dx.doi.org/10.1073/pnas.74.12.5463] [PMID: 271968]
[47]
Hall, T.A. BioEdit: A user-friendly biological sequence alignment Editor and analysis program for Windows 95/98/NT. Nucleic Acids Symp. Ser., 1999, 41, 95-98.
[48]
Rohde, C.; Zhang, Y.; Jurkowski, T.P.; Stamerjohanns, H.; Reinhardt, R.; Jeltsch, A. Bisulfite sequencing Data Presentation and Compilation (BDPC) web server--a useful tool for DNA methylation analysis. Nucleic Acids Res., 2008, 36(5), e34
[http://dx.doi.org/10.1093/nar/gkn083] [PMID: 18296484]
[49]
Bock, C.; Reither, S.; Mikeska, T.; Paulsen, M.; Walter, J.; Lengauer, T. BiQ Analyzer: visualization and quality control for DNA methylation data from bisulfite sequencing. Bioinformatics, 2005, 21(21), 4067-4068.
[http://dx.doi.org/10.1093/bioinformatics/bti652] [PMID: 16141249]
[50]
Vandesompele, J.; De Preter, K.; Pattyn, F.; Poppe, B.; Van Roy, N.; De Paepe, A.; Speleman, F. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol., 2002, 3(7) , RESEARCH0034
[51]
Henry, C.M.; Hollville, E.; Martin, S.J. Measuring apoptosis by microscopy and flow cytometry. Methods, 2013, 61(2), 90-97.
[http://dx.doi.org/10.1016/j.ymeth.2013.01.008] [PMID: 23403105]
[52]
Nicoletti, I.; Migliorati, G.; Pagliacci, M.C.; Grignani, F.; Riccardi, C. A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry. J. Immunol. Methods, 1991, 139(2), 271-279.
[http://dx.doi.org/10.1016/0022-1759(91)90198-O] [PMID: 1710634]
[53]
Wasser, S.P. Medicinal mushroom science: Current perspectives, advances, evidences, and challenges. Biomed. J., 2014, 37(6), 345-356.
[http://dx.doi.org/10.4103/2319-4170.138318] [PMID: 25179726]
[54]
Hawksworth, D.L. Global species numbers of fungi: Are tropical studies and molecular approaches contributing to a more robust estimate? Biodivers. Conserv., 2012, 21(9), 2425-2433.
[http://dx.doi.org/10.1007/s10531-012-0335-x]
[55]
Chang, S.T.; Wasser, S.P. The role of culinary-medicinal mushrooms on human welfare with a pyramid model for human health. Int. J. Med. Mushrooms, 2012, 14(2), 95-134.
[http://dx.doi.org/10.1615/IntJMedMushr.v14.i2.10] [PMID: 22506573]
[56]
Finimundy, T.C.; Gambato, G.; Fontana, R.; Camassola, M.; Salvador, M.; Moura, S.; Hess, J.; Henriques, J.A.; Dillon, A.J.; Roesch-Ely, M. Aqueous extracts of Lentinula edodes and Pleurotus sajor-caju exhibit high antioxidant capability and promising in vitro antitumor activity. Nutr. Res., 2013, 33(1), 76-84.
[http://dx.doi.org/10.1016/j.nutres.2012.11.005] [PMID: 23351413]
[57]
Yu, S.; Weaver, V.; Martin, K.; Cantorna, M.T. The effects of whole mushrooms during inflammation. BMC Immunol., 2009, 10, 12.
[http://dx.doi.org/10.1186/1471-2172-10-12] [PMID: 19232107]
[58]
Zhang, L.; Fan, C.; Liu, S. Chemical composition and antitumor activity of polysaccharide from Inonotus obliquus. J. Med. Plants Res., 2011, 5, 1251-1260.
[59]
Alves, R.; Preto, M.; Vasconcelos, V.; Oliveira, R.S.; Martins, R. Cytotoxicity induced by extracts of Pisolithus tinctorius spores on human cancer and normal cell lines-evaluation of the anticancer potential. J. Toxicol. Environ. Health A, 2015, 78(13-14), 840-847.
[http://dx.doi.org/10.1080/15287394.2015.1051176] [PMID: 26167750]
[60]
Liu, J.; Zhang, Y.; Chen, L.; Yu, F.; Li, X.; Dan Tao, ; Zhao, J.; Zhou, S. Polyphyllin I induces G2/M phase arrest and apoptosis in U251 human glioma cells via mitochondrial dysfunction and the JNK signaling pathway. Acta Biochim. Biophys. Sin. (Shanghai), 2017, 49(6), 479-486.
[http://dx.doi.org/10.1093/abbs/gmx033] [PMID: 28449039]
[61]
Liu, L.; Zhao, J.L.; Wang, J.G. [Oleanolic acid induces G2/M phase arrest and apoptosis in human hepatocellular carcinoma Bel-7402 cells]. Zhongguo Zhongyao Zazhi, 2015, 40(24), 4897-4902.
[PMID: 27245040]
[62]
Borkova, L.; Adamek, R.; Kalina, P.; Drašar, P.; Dzubak, P.; Gurska, S.; Rehulka, J.; Hajduch, M.; Urban, M.; Sarek, J. Synthesis and cytotoxic activity of triterpenoid thiazoles derived from allobetulin, methyl betulonate, methyl oleanonate, and oleanonic acid. ChemMedChem, 2017, 12(5), 390-398.
[http://dx.doi.org/10.1002/cmdc.201600626] [PMID: 28084676]
[63]
Deng, C.; Zhang, B.; Zhang, S.; Duan, C.; Cao, Y.; Kang, W.; Yan, H.; Ding, X.; Zhou, F.; Wu, L.; Duan, G.; Shen, S.; Xu, G.; Zhang, W.; Chen, M.; Huang, S.; Zhang, X.; Lv, Y.; Ling, T.; Wang, L.; Zou, X. Low nanomolar concentrations of Cucurbitacin-I induces G2/M phase arrest and apoptosis by perturbing redox homeostasis in gastric cancer cells in vitro and in vivo. Cell Death Dis., 2016, 7, e2106
[http://dx.doi.org/10.1038/cddis.2016.13] [PMID: 26890145]
[64]
Jiang, Q.W.; Cheng, K.J.; Mei, X.L.; Qiu, J.G.; Zhang, W.J.; Xue, Y.Q.; Qin, W.M.; Yang, Y.; Zheng, D.W.; Chen, Y.; Wei, M.N.; Zhang, X.; Lv, M.; Chen, M.W.; Wei, X.; Shi, Z. Synergistic anticancer effects of triptolide and celastrol, two main compounds from thunder god vine. Oncotarget, 2015, 6(32), 32790-32804.
[http://dx.doi.org/10.18632/oncotarget.5411] [PMID: 26447544]
[65]
Marostica, L.L.; Silva, I.T.; Kratz, J.M.; Persich, L.; Geller, F.C.; Lang, K.L.; Caro, M.S.; Durán, F.J.; Schenkel, E.P.; Simões, C.M. Synergistic antiproliferative effects of a new cucurbitacin B derivative and chemotherapy drugs on lung cancer cell line A549. Chem. Res. Toxicol., 2015, 28(10), 1949-1960.
[http://dx.doi.org/10.1021/acs.chemrestox.5b00153] [PMID: 26372186]
[66]
Ku, J.M.; Kim, S.R.; Hong, S.H.; Choi, H.S.; Seo, H.S.; Shin, Y.C.; Ko, S.G. Cucurbitacin D induces cell cycle arrest and apoptosis by inhibiting STAT3 and NF-κB signaling in doxorubicin-resistant human breast carcinoma (MCF7/ADR) cells. Mol. Cell. Biochem., 2015, 409(1-2), 33-43.
[http://dx.doi.org/10.1007/s11010-015-2509-9] [PMID: 26169986]
[67]
Hsieh, Y.H.; Lee, C.H.; Chen, H.Y.; Hsieh, S.C.; Lin, C.L.; Tsai, J.P. Induction of cell cycle arrest, DNA damage, and apoptosis by nimbolide in human renal cell carcinoma cells. Tumour Biol., 2015, 36(10), 7539-7547.
[http://dx.doi.org/10.1007/s13277-015-3477-0] [PMID: 25916210]
[68]
Lohberger, B.; Kretschmer, N.; Bernhart, E.; Rinner, B.; Stuendl, N.; Kaltenegger, H.; Kahl, S.; Bauer, R.; Leithner, A. 25-O-acetyl-23,24-dihydro-cucurbitacin F induces cell cycle G2/M arrest and apoptosis in human soft tissue sarcoma cells. J. Ethnopharmacol., 2015, 164, 265-272.
[http://dx.doi.org/10.1016/j.jep.2015.02.023] [PMID: 25701753]
[69]
So, J.Y.; Lin, J.J.; Wahler, J.; Liby, K.T.; Sporn, M.B.; Suh, N. A synthetic triterpenoid CDDO-Im inhibits tumorsphere formation by regulating stem cell signaling pathways in triple-negative breast cancer. PLoS One, 2014, 9(9), e107616
[http://dx.doi.org/10.1371/journal.pone.0107616] [PMID: 25229616]
[70]
Piao, S.; Kang, M.; Lee, Y.J.; Choi, W.S.; Chun, Y.S.; Kwak, C.; Kim, H.H. Cytotoxic effects of escin on human castration-resistant prostate cancer cells through the induction of apoptosis and G2/M cell cycle arrest. Urology, 2014, 84(4), 982.
[71]
Kong, Y.; Chen, J.; Zhou, Z.; Xia, H.; Qiu, M.H.; Chen, C. Cucurbitacin E induces cell cycle G2/M phase arrest and apoptosis in triple negative breast cancer. PLoS One, 2014, 9(7), e103760
[http://dx.doi.org/10.1371/journal.pone.0103760] [PMID: 25072848]
[72]
Guo, J.; Zhao, W.; Hao, W.; Ren, G.; Lu, J.; Chen, X. Cucurbitacin B induces DNA damage, G2/M phase arrest, and apoptosis mediated by reactive oxygen species (ROS) in leukemia K562 cells. Anticancer. Agents Med. Chem., 2014, 14(8), 1146-1153.
[http://dx.doi.org/10.2174/1871520614666140601220915] [PMID: 24893803]
[73]
Zheng, Q.; Liu, Y.; Liu, W.; Ma, F.; Zhou, Y.; Chen, M.; Chang, J.; Wang, Y.; Yang, G.; He, G. Cucurbitacin B inhibits growth and induces apoptosis through the JAK2/STAT3 and MAPK pathways in SH‑SY5Y human neuroblastoma cells. Mol. Med. Rep., 2014, 10(1), 89-94.
[http://dx.doi.org/10.3892/mmr.2014.2175] [PMID: 24789581]
[74]
Hsu, Y.C.; Huang, T.Y.; Chen, M.J. Therapeutic ROS targeting of GADD45γ in the induction of G2/M arrest in primary human colorectal cancer cell lines by cucurbitacin E. Cell Death Dis., 2014, 5, e1198
[http://dx.doi.org/10.1038/cddis.2014.151] [PMID: 24763055]
[75]
Hsu, Y.C.; Chen, M.J.; Huang, T.Y. Inducement of mitosis delay by cucurbitacin E, a novel tetracyclic triterpene from climbing stem of Cucumis melo L., through GADD45γ in human brain malignant glioma (GBM) 8401 cells. Cell Death Dis., 2014, 5, e1087
[http://dx.doi.org/10.1038/cddis.2014.22] [PMID: 24577085]
[76]
Guo, J.; Wu, G.; Bao, J.; Hao, W.; Lu, J.; Chen, X. Cucurbitacin B induced ATM-mediated DNA damage causes G2/M cell cycle arrest in a ROS-dependent manner. PLoS One, 2014, 9(2), e88140
[http://dx.doi.org/10.1371/journal.pone.0088140] [PMID: 24505404]
[77]
Wang, L.; Xu, J.; Zhao, C.; Zhao, L.; Feng, B. Antiproliferative, cell-cycle dysregulation effects of novel asiatic acid derivatives on human non-small cell lung cancer cells. Chem. Pharm. Bull. (Tokyo), 2013, 61(10), 1015-1023.
[http://dx.doi.org/10.1248/cpb.c13-00328] [PMID: 23924616]
[78]
Wang, X.; Bai, H.; Zhang, X.; Liu, J.; Cao, P.; Liao, N.; Zhang, W.; Wang, Z.; Hai, C. Inhibitory effect of oleanolic acid on hepatocellular carcinoma via ERK-p53-mediated cell cycle arrest and mitochondrial-dependent apoptosis. Carcinogenesis, 2013, 34(6), 1323-1330.
[http://dx.doi.org/10.1093/carcin/bgt058] [PMID: 23404993]
[79]
Kausar, H.; Munagala, R.; Bansal, S.S.; Aqil, F.; Vadhanam, M.V.; Gupta, R.C. Cucurbitacin B potently suppresses non-small-cell lung cancer growth: identification of intracellular thiols as critical targets. Cancer Lett., 2013, 332(1), 35-45.
[http://dx.doi.org/10.1016/j.canlet.2013.01.008] [PMID: 23340170]
[80]
Ren, S.; Ouyang, D.Y.; Saltis, M.; Xu, L.H.; Zha, Q.B.; Cai, J.Y.; He, X.H. Anti-proliferative effect of 23,24-dihydrocucurbitacin F on human prostate cancer cells through induction of actin aggregation and cofilin-actin rod formation. Cancer Chemother. Pharmacol., 2012, 70(3), 415-424.
[http://dx.doi.org/10.1007/s00280-012-1921-z] [PMID: 22814677]
[81]
Chen, W.J.; Yu, C.; Yang, Z.; He, J.L.; Yin, J.; Liu, H.Z.; Liu, H.T.; Wang, Y.X. Tubeimoside-1 induces G2/M phase arrest and apoptosis in SKOV-3 cells through increase of intracellular Ca2+ and caspase-dependent signaling pathways. Int. J. Oncol., 2012, 40(2), 535-543.
[PMID: 21971569]
[82]
Shi, X.; Franko, B.; Frantz, C.; Amin, H.M.; Lai, R. JSI-124 (cucurbitacin I) inhibits Janus kinase-3/signal transducer and activator of transcription-3 signalling, downregulates nucleophosmin-anaplastic lymphoma kinase (ALK), and induces apoptosis in ALK-positive anaplastic large cell lymphoma cells. Br. J. Haematol., 2006, 135(1), 26-32.
[http://dx.doi.org/10.1111/j.1365-2141.2006.06259.x] [PMID: 16939498]
[83]
Blaskovich, M.A.; Sun, J.; Cantor, A.; Turkson, J.; Jove, R.; Sebti, S.M. Discovery of JSI-124 (cucurbitacin I), a selective Janus kinase/signal transducer and activator of transcription 3 signaling pathway inhibitor with potent antitumor activity against human and murine cancer cells in mice. Cancer Res., 2003, 63(6), 1270-1279.
[PMID: 12649187]
[84]
Kang, H.M.; Lee, S.K.; Shin, D.S.; Lee, M.Y.; Han, D.C.; Baek, N.I.; Son, K.H.; Kwon, B.M. Dehydrotrametenolic acid selectively inhibits the growth of H-ras transformed rat2 cells and induces apoptosis through caspase-3 pathway. Life Sci., 2006, 78(6), 607-613.
[http://dx.doi.org/10.1016/j.lfs.2005.05.066] [PMID: 16112686]
[85]
Yue, Q.X.; Cao, Z.W.; Guan, S.H.; Liu, X.H.; Tao, L.; Wu, W.Y.; Li, Y.X.; Yang, P.Y.; Liu, X.; Guo, D.A. Proteomics characterization of the cytotoxicity mechanism of ganoderic acid D and computer-automated estimation of the possible drug target network. Mol. Cell. Proteomics, 2008, 7(5), 949-961.
[http://dx.doi.org/10.1074/mcp.M700259-MCP200] [PMID: 18166740]
[86]
Su, Y.; Li, G.; Zhang, X.; Gu, J.; Zhang, C.; Tian, Z.; Zhang, J. JSI-124 inhibits glioblastoma multiforme cell proliferation through G(2)/M cell cycle arrest and apoptosis augment. Cancer Biol. Ther., 2008, 7(8), 1243-1249.
[http://dx.doi.org/10.4161/cbt.7.8.6263] [PMID: 18487947]
[87]
Sharma, A.; Singh, K.; Almasan, A. Histone H2AX phosphorylation: a marker for DNA damage. Methods Mol. Biol., 2012, 920, 613-626.
[http://dx.doi.org/10.1007/978-1-61779-998-3_40] [PMID: 22941631]
[88]
Andreassen, P.R.; Lacroix, F.B.; Lohez, O.D.; Margolis, R.L. Neither p21WAF1 nor 14-3-3sigma prevents G2 progression to mitotic catastrophe in human colon carcinoma cells after DNA damage, but p21WAF1 induces stable G1 arrest in resulting tetraploid cells. Cancer Res., 2001, 61(20), 7660-7668.
[PMID: 11606409]
[89]
Dai, Y.; Grant, S. New insights into checkpoint kinase 1 in the DNA damage response signaling network. Clin. Cancer Res.: Off. J. Am. Assoc. Cancer Res., 2010, 16(2), 376-383.
[90]
Abraham, R.T. Cell cycle checkpoint signaling through the ATM and ATR kinases. Genes Dev., 2001, 15(17), 2177-2196.
[http://dx.doi.org/10.1101/gad.914401] [PMID: 11544175]
[91]
Huang, M.; Miao, Z.H.; Zhu, H.; Cai, Y.J.; Lu, W.; Ding, J. Chk1 and Chk2 are differentially involved in homologous recombination repair and cell cycle arrest in response to DNA double-strand breaks induced by camptothecins. Mol. Cancer Ther., 2008, 7(6), 1440-1449.
[http://dx.doi.org/10.1158/1535-7163.MCT-07-2116] [PMID: 18566216]
[92]
Lukas, C.; Bartkova, J.; Latella, L.; Falck, J.; Mailand, N.; Schroeder, T.; Sehested, M.; Lukas, J.; Bartek, J. DNA damage-activated kinase Chk2 is independent of proliferation or differentiation yet correlates with tissue biology. Cancer Res., 2001, 61(13), 4990-4993.
[PMID: 11431331]
[93]
Molinari, M. Cell cycle checkpoints and their inactivation in human cancer. Cell Prolif., 2000, 33(5), 261-274.
[http://dx.doi.org/10.1046/j.1365-2184.2000.00191.x] [PMID: 11063129]
[94]
Chen, C.Y.; Hsu, Y.L.; Tsai, Y.C.; Kuo, P.L. Kotomolide A arrests cell cycle progression and induces apoptosis through the induction of ATM/p53 and the initiation of mitochondrial system in human non-small cell lung cancer A549 cells. Food Chem. Toxicol.: Int. J.Publ. Brit. Industrial Biol. Res. Assoc., 2008, 46(7), 2476-2484.
[95]
Sahu, R.P.; Batra, S.; Srivastava, S.K. Activation of ATM/Chk1 by curcumin causes cell cycle arrest and apoptosis in human pancreatic cancer cells. Br. J. Cancer, 2009, 100(9), 1425-1433.
[http://dx.doi.org/10.1038/sj.bjc.6605039] [PMID: 19401701]
[96]
Wei, F.; Ojo, D.; Lin, X.; Wong, N.; He, L.; Yan, J.; Xu, S.; Major, P.; Tang, D. BMI1 attenuates etoposide-induced G2/M checkpoints via reducing ATM activation. Oncogene, 2015, 34(23), 3063-3075.
[http://dx.doi.org/10.1038/onc.2014.235] [PMID: 25088203]
[97]
Lin, X.; Ojo, D.; Wei, F.; Wong, N.; Gu, Y.; Tang, D. A novel aspect of tumorigenesis-BMI1 functions in regulating DNA damage response. Biomolecules, 2015, 5(4), 3396-3415.
[http://dx.doi.org/10.3390/biom5043396] [PMID: 26633535]
[98]
Pan, M.R.; Peng, G.; Hung, W.C.; Lin, S.Y. Monoubiquitination of H2AX protein regulates DNA damage response signaling. J. Biol. Chem., 2011, 286(32), 28599-28607.
[http://dx.doi.org/10.1074/jbc.M111.256297] [PMID: 21676867]
[99]
Chagraoui, J.; Hébert, J.; Girard, S.; Sauvageau, G. An anticlastogenic function for the Polycomb Group gene Bmi1. Proc. Natl. Acad. Sci. USA, 2011, 108(13), 5284-5289.
[http://dx.doi.org/10.1073/pnas.1014263108] [PMID: 21402923]
[100]
Aylon, Y.; Oren, M. New plays in the p53 theater. Curr. Opin. Genet. Dev., 2011, 21(1), 86-92.
[http://dx.doi.org/10.1016/j.gde.2010.10.002] [PMID: 21317061]
[101]
Speidel, D. Transcription-independent p53 apoptosis: an alternative route to death. Trends Cell Biol., 2010, 20(1), 14-24.
[http://dx.doi.org/10.1016/j.tcb.2009.10.002] [PMID: 19879762]
[102]
Vousden, K.H.; Prives, C. Blinded by the light: The growing complexity of p53. Cell, 2009, 137(3), 413-431.
[http://dx.doi.org/10.1016/j.cell.2009.04.037] [PMID: 19410540]
[103]
Abbas, T.; Dutta, A. p21 in cancer: intricate networks and multiple activities. Nat. Rev. Cancer, 2009, 9(6), 400-414.
[http://dx.doi.org/10.1038/nrc2657] [PMID: 19440234]
[104]
Peng, C.Y.; Graves, P.R.; Thoma, R.S.; Wu, Z.; Shaw, A.S.; Piwnica-Worms, H. Mitotic and G2 checkpoint control: regulation of 14-3-3 protein binding by phosphorylation of Cdc25C on serine-216. Science, 1997, 277(5331), 1501-1505.
[http://dx.doi.org/10.1126/science.277.5331.1501] [PMID: 9278512]
[105]
Singh, S.V.; Herman-Antosiewicz, A.; Singh, A.V.; Lew, K.L.; Srivastava, S.K.; Kamath, R.; Brown, K.D.; Zhang, L.; Baskaran, R. Sulforaphane-induced G2/M phase cell cycle arrest involves checkpoint kinase 2-mediated phosphorylation of cell division cycle 25C. J. Biol. Chem., 2004, 279(24), 25813-25822.
[http://dx.doi.org/10.1074/jbc.M313538200] [PMID: 15073169]
[106]
Pollack, M.; Phaneuf, S.; Dirks, A.; Leeuwenburgh, C. The role of apoptosis in the normal aging brain, skeletal muscle, and heart. Ann. N. Y. Acad. Sci., 2002, 959, 93-107.
[http://dx.doi.org/10.1111/j.1749-6632.2002.tb02086.x] [PMID: 11976189]
[107]
Shangguan, W.J.; Li, H.; Zhang, Y.H. Induction of G2/M phase cell cycle arrest and apoptosis by ginsenoside Rf in human osteosarcoma MG‑63 cells through the mitochondrial pathway. Oncol. Rep., 2014, 31(1), 305-313.
[http://dx.doi.org/10.3892/or.2013.2815] [PMID: 24173574]
[108]
Luo, X.; Budihardjo, I.; Zou, H.; Slaughter, C.; Wang, X. Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell, 1998, 94(4), 481-490.
[http://dx.doi.org/10.1016/S0092-8674(00)81589-5] [PMID: 9727491]
[109]
Gosslau, A.; Chen, K.Y. Nutraceuticals, apoptosis, and disease prevention. Nutrition, 2004, 20(1), 95-102.
[http://dx.doi.org/10.1016/j.nut.2003.09.017] [PMID: 14698022]


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VOLUME: 20
ISSUE: 6
Year: 2020
Published on: 14 June, 2020
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DOI: 10.2174/1871520620666200203160117
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