Synergistic Effects of Ethanol Extract of Allium sativum (Garlic) with DAPT and ATRA on Notch Signaling Targeted Molecular Action on Lung Cancer Cell line (A549)

Ragavi      Ravichandran; D.   David   Wilson; S.      Viswanathan; Siddikuzzaman; Lucia      Bonati; Selvamani      Rajendran; V.   Berlin   Grace

doi:10.2174/1570180820666230831095954

Abstract

Background: The activated oncogenic Notch signalling is an emerging target to treat cancer progression and recurrence. Synthetic inhibitors of Notch receptors are in pre-clinical studies. However, the overexpression of Notch signalling molecules at the gene level needs to be regulated to control cancer progression.

Objective: We propose that this can be achieved by gene-regulatory drugs in combination with natural phytochemical compounds.

Methods: The ethanol extract of Allium sativum alone and in combination with DAPT and ATRA were evaluated for cytotoxicity on A549 cells by MTT and Trypan blue assays. Their effects on Notch 1, Hes 1 and p53 gene expressions were studied by RT-PCR and qPCR. Their inhibition on metastatic invasion of A549 cells was analyzed by in vitro wound scratch assay. The phytochemicals of the extract were identified by GC-MS analysis.

Results: Many organosulfur compounds having anti-cancer potency were identified in GC-MS. The combination treatment with 50μg (IC₅₀) of garlic extract exhibited a highly significant (P≤0.01) synergistic inhibitory effect on A549 cell growth and migration. It has also significantly reduced the expression of Notch 1 and Hes 1 oncogenes and enhanced p53 gene expression, compared with the individual treatments. This indicates the synergistic action of the extract on the downregulation of Notch signalling at the mRNA level.

Conclusion: Our study results imply that the combination therapies have potent molecular treatment action via down-regulating Notch signaling target genes and upregulating p53 gene expression as an underlying mechanism of inhibitory action on A549 lung cancer cells.

Keywords: Combination treatment, notch signaling, A549 cells, p53, RT-PCR, GC-MS analysis.

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[1]
Jemal, A.; Siegel, R.; Xu, J.; Ward, E. Cancer statistics, 2010. CA Cancer J. Clin.,  2010, 60(5), 277-300.
 [http://dx.doi.org/10.3322/caac.20073] [PMID:  20610543]

[2]
Siegel, R.; Naishadham, D.; Jemal, A. Cancer statistics for hispanics/latinos. CA Cancer J. Clin.,  2012, 62(5), 283-298.
 [http://dx.doi.org/10.3322/caac.21153] [PMID:  22987332]

[3]
Jemal, A.; Bray, F.; Center, M.M.; Ferlay, J.; Ward, E.; Forman, D. Global cancer statistics. CA Cancer J. Clin.,  2011, 61(2), 69-90.
 [http://dx.doi.org/10.3322/caac.20107] [PMID:  21296855]

[4]
Chabner, B.A.; Roberts, T.G., Jr Chemotherapy and the war on cancer. Nat. Rev. Cancer,  2005, 5(1), 65-72.
 [http://dx.doi.org/10.1038/nrc1529] [PMID:  15630416]

[5]
Velasco-Velázquez, M.A.; Yu, Z.; Jiao, X.; Pestell, R.G. Cancer stem cells and the cell cycle: Targeting the drive behind breast cancer. Expert Rev. Anticancer Ther.,  2009, 9(3), 275-279.
 [http://dx.doi.org/10.1586/14737140.9.3.275] [PMID:  19275505]

[6]
Wang, Y.; Jiang, M.; Du, C.; Yu, Y.; Liu, Y.; Li, M.; Luo, F. Utilization of lung cancer cell lines for the study of lung cancer stem cells Review).. Oncol. Lett.,  2018, 15(5), 6791-6798.
 [http://dx.doi.org/10.3892/ol.2018.8265] [PMID:  29731860]

[7]
Medema, J.P. Cancer stem cells: The challenges ahead. Nat. Cell Biol.,  2013, 15(4), 338-344.
 [http://dx.doi.org/10.1038/ncb2717] [PMID:  23548926]

[8]
Halim, N.H.A.; Zakaria, N.; Satar, N.A.; Yahaya, B.H. Isolation and characterization of cancer stem cells of the non-small-cell lung cancer (A549) cell line, in Stem Cell Heterogeneity. Methods Mol. Biol.,  2016, 1516, 371-388.
 [http://dx.doi.org/10.1007/7651_2016_326] [PMID:  27032945]

[9]
Sharif, A.; Shaji, A.; Chammaa, M.; Pawlik, E.; Fernandez-Valdivia, R. Notch transduction in non-small cell lung cancer. Int. J. Mol. Sci.,  2020, 21(16), 5691.
 [http://dx.doi.org/10.3390/ijms21165691] [PMID:  32784481]

[10]
Meng, X.; Wang, X.; Wang, Y. More than 45% of A549 and H446 cells are cancer initiating cells: evidence from cloning and tumorigenic analyses. Oncol. Rep.,  2009, 21(4), 995-1000.
 [PMID:  19287999]

[11]
Reya, T.; Clevers, H. Wnt signalling in stem cells and cancer. Nature,  2005, 434(7035), 843-850.
 [http://dx.doi.org/10.1038/nature03319] [PMID:  15829953]

[12]
Artavanis-Tsakonas, S.; Rand, M.D.; Lake, R.J. Notch signaling: Cell fate control and signal integration in development. Science,  1999, 284(5415), 770-776.
 [http://dx.doi.org/10.1126/science.284.5415.770] [PMID:  10221902]

[13]
Wang, Z.; Li, Y.; Ahmad, A.; Azmi, A.S.; Banerjee, S.; Kong, D.; Sarkar, F.H. Targeting Notch signaling pathway to overcome drug resistance for cancer therapy. Biochim. Biophys. Acta,  2010, 1806(2), 258-267.
 [PMID:  20600632]

[14]
Espinoza, I.; Miele, L. Notch inhibitors for cancer treatment. Pharmacol. Ther.,  2013, 139(2), 95-110.
 [http://dx.doi.org/10.1016/j.pharmthera.2013.02.003] [PMID:  23458608]

[15]
Li, X.; Cao, Y.; Li, M.; Jin, F. Upregulation of HES1 promotes cell proliferation and invasion in breast cancer as a prognosis marker and therapy target via the AKT Pathway and EMT Process. J. Cancer,  2018, 9(4), 757-766.
 [http://dx.doi.org/10.7150/jca.22319] [PMID:  29556333]

[16]
Li, B.; Gao, M.H.; Chu, X.M.; Teng, L.; Lv, C.Y.; Yang, P.; Yin, Q.F. The synergistic antitumor effects of all-trans retinoic acid and C-phycocyanin on the lung cancer A549 cells in vitro and in vivo. Eur. J. Pharmacol.,  2015, 749, 107-114.
 [http://dx.doi.org/10.1016/j.ejphar.2015.01.009] [PMID:  25617793]

[17]
Shih, I.M.; Wang, T.L. Notch signaling, γ-secretase inhibitors, and cancer therapy. Cancer Res.,  2007, 67(5), 1879-1882.
 [http://dx.doi.org/10.1158/0008-5472.CAN-06-3958] [PMID:  17332312]

[18]
Olsauskas-Kuprys, R.; Zlobin, A.; Osipo, C. Gamma secretase inhibitors of notch signaling. OncoTargets Ther.,  2013, 6, 943-955.
 [PMID:  23901284]

[19]
Feng, J. Jianpeng, Wang; Qian, Liu; Jiye, Li; Zhang, Qi; Zhuang, Zhengping; Xiaohui, Yao; Chunhui, Liu; Yangfang, Li; Cao, Lei; Chuzhong, Li; Gong, Lei; Li, Dan; Yazhuo, Zhang; Gao, Hua DAPT, a γ-Secretase Inhibitor, Suppresses Tumorigenesis, and Progression of Growth Hormone-Producing Adenomas by Targeting Notch Signaling; Oncol, 2019, p. 27.

[20]
Borghese, L.; Dolezalova, D.; Thoralf, O.; Simone, H.; Anke, L.; Barbara, S.; Philipp, K.; Frank, E.; Ales, H.; Oliver, B. Inhibition of notch signaling in human embryonic stem cell derived neural stem cells delays G1/S Phase transition and accelerates neuronal differentiation. Stem Cells,  2010, 28, 955-964.
 [http://dx.doi.org/10.1002/stem.408] [PMID:  20235098]

[21]
Dai, G.; Deng, S.; Guo, W.; Yu, L.; Yang, J.; Zhou, S.; Gao, T. Notch pathway inhibition using DAPT, a γ‐secretase inhibitor (GSI), enhances the antitumor effect of cisplatin in resistant osteosarcoma. Mol. Carcinog.,  2019, 58(1), 3-18.
 [http://dx.doi.org/10.1002/mc.22873] [PMID:  29964327]

[22]
Ghanbari-Movahed, M.; Ghanbari-Movahed, Z.; Momtaz, S.; Kilpatrick, K.L.; Farzaei, M.H.; Bishayee, A. Unlocking the secrets of cancer stem cells with γ-Secretase inhibitors: A novel anticancer strategy. Molecules,  2021, 26(4), 972.
 [http://dx.doi.org/10.3390/molecules26040972] [PMID:  33673088]

[23]
Ghanbari-Movahed, M.; Shiri Varnamkhasti, B.; Shourian, M. Inhibiting Notch activity in breast cancer stem cells by functionalized gold nanoparticles with gamma-secretase inhibitor DAPT and vitamin C. Chem. Zvesti,  2022, 76(2), 1157-1170.
 [http://dx.doi.org/10.1007/s11696-021-01936-w]

[24]
Poulain, S.; Lacomme, S.; Battaglia-Hsu, S.F.; du Manoir, S.; Brochin, L.; Vignaud, J.M.; Martinet, N. Signalling with retinoids in the human lung: validation of new tools for the expression study of retinoid receptors. BMC Cancer,  2009, 9(1), 423.
 [http://dx.doi.org/10.1186/1471-2407-9-423] [PMID:  19961602]

[25]
Zhou, G.; Zhang, Ji. Zhen-YI, W.; Sai-Juan, C.; Zhu, C. Treatment of acute promyelocytic leukaemia with all-trans retinoic acid and arsenic trioxide: a paradigm of synergistic molecular targeting therapy. Philos. Trans. R. Soc. Lond. B Biol. Sci.,  2007, 362(1482), 959-971.

[26]
Nguyen, P.H.; Giraud, J.; Staedel, C.; Chambonnier, L.; Dubus, P.; Chevret, E.; Boeuf, H.; Gauthereau, X.; Rousseau, B.; Fevre, M.; Soubeyran, I.; Belleannée, G.; Evrard, S.; Collet, D.; Mégraud, F.; Varon, C. All-trans retinoic acid targets gastric cancer stem cells and inhibits patient-derived gastric carcinoma tumor growth. Oncogene,  2016, 35(43), 5619-5628.
 [http://dx.doi.org/10.1038/onc.2016.87] [PMID:  27157616]

[27]
Brown, G. Targeting the retinoic acid pathway to eradicate cancer stem cells. Int. J. Mol. Sci.,  2023, 24(3), 2373.
 [http://dx.doi.org/10.3390/ijms24032373] [PMID:  36768694]

[28]
Thomson, M.; Ali, M. Garlic [Allium sativum]: A review of its potential use as an anti-cancer agent. Curr. Cancer Drug Targets,  2003, 3(1), 67-81.
 [http://dx.doi.org/10.2174/1568009033333736] [PMID:  12570662]

[29]
Lawson, L. Bioactive organosulfur compounds of garlic and garlic products. In: Role in Reducing Blood Lipids;  ACS symposium seriesUSA, 1993; 534, pp. 306-330.
 [http://dx.doi.org/10.1021/bk-1993-0534.ch021]

[30]
Lawson, L.; Wang, Z. Pre-hepatic fate of the organosulfur compounds derived from garlic (Allium sativum). Planta Med.,  1993, 59(S1), 688-689.

[31]
Ziegler, S.; Sticher, O. HPLC of S-alk (en) yl-L-cysteine derivatives in garlic including quantitative determination of (+)-S-allyl-L-cysteine sulfoxide (alliin). Planta Med.,  1989, 55(4), 372-378.
 [http://dx.doi.org/10.1055/s-2006-962031] [PMID:  17262437]

[32]
Lawson, L.D. The composition and chemistry of garlic cloves and processed garlic. In: Garlic: the science and therapeutic application of Allium sativum L. and related species; Koch, H.P.; Lawson, L.D., Eds.; Williams & Wilkins: Baltimore, 1996; pp. 37-108.

[33]
Singh, V.K.; Singh, D.K. Pharmacological Effects of Garlic (Allium sativum L.); Annu. Rev. Biomed, 2008, p. 10.

[34]
Lau, B.H.S.; Tadi, P.P.; Tosk, J.M. Allium sativum (Garlic) and cancer prevention. Nutr. Res.,  1990, 10(8), 937-948.
 [http://dx.doi.org/10.1016/S0271-5317(05)80057-0]

[35]
Suluvoy, J.K.; Berlin Grace, V. M.  Phytochemical profile and free radical nitric oxide (NO) scavenging activity of Averrhoa bilimbi L. fruit extract. 3 Biotech,  2017, 7(1), 85.

[36]
Morohashi, Y.; Kan, T.; Tominari, Y.; Fuwa, H.; Okamura, Y.; Watanabe, N.; Sato, C.; Natsugari, H.; Fukuyama, T.; Iwatsubo, T.; Tomita, T. C-terminal fragment of presenilin is the molecular target of a dipeptidic γ-secretase-specific inhibitor DAPT (N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester). J. Biol. Chem.,  2006, 281(21), 14670-14676.
 [http://dx.doi.org/10.1074/jbc.M513012200] [PMID:  16569643]

[37]
Cai, L.; Luo, L.; Tang, Z.; Meng, X. Combined antitumor effects of 1,25dihydroxy vitamin D3 and Notch inhibitor in liver cancer. Oncol. Rep.,  2018, 40(3), 1515-1524. Epub 2018 Jul 5.
 [http://dx.doi.org/10.3892/or.2018.6549] [PMID:  30015939]

[38]
van Meerloo, J.; Kaspers, G.J.L.; Cloos, J. Cell sensitivity assays: The MTT assay, in Cancer cell culture. Methods Mol. Biol.,  2011, 731, 237-245.
 [http://dx.doi.org/10.1007/978-1-61779-080-5_20]

[39]
Strober, W. Trypan blue exclusion test of cell viability. Curr. Protoc. Immunol.,  1997, 21(1), 1-2.

[40]
Jiang, L.; Zhang, X.; Du, P.; Zheng, J. γ-Secretase inhibitor, DAPT inhibits self-renewal and stemness maintenance of ovarian cancer stem-like cells in vitro. Chin. J. Cancer Res.,  2011, 23(2), 140-146.
 [http://dx.doi.org/10.1007/s11670-011-0140-1] [PMID:  23482909]

[41]
Liang, C.C.; Park, A.Y.; Guan, J.L. In vitro scratch assay: A convenient and inexpensive method for analysis of cell migration in vitro. Nat. Protoc.,  2007, 2(2), 329-333.
 [http://dx.doi.org/10.1038/nprot.2007.30] [PMID:  17406593]

[42]
Enders, D.; Balensiefer, T. Nucleophilic carbenes in asymmetric organocatalysis. Acc. Chem. Res.,  2004, 37(8), 534-541.
 [http://dx.doi.org/10.1021/ar030050j] [PMID:  15311952]

[43]
Sakamoto, K.; Lavvson, L.D.; Milner, J.A. Allyl sulfides from garlic suppress the in vitro proliferation of human a549 lung tumor cells. Nutr. Cancer,  1997, 29(2), 152-156.
 [http://dx.doi.org/10.1080/01635589709514617] [PMID:  9427979]

[44]
Leung, E.L.H.; Fiscus, R.R.; Tung, J.W.; Tin, V.P.C.; Cheng, L.C.; Sihoe, A.D.L.; Fink, L.M.; Ma, Y.; Wong, M.P. Non-small cell lung cancer cells expressing CD44 are enriched for stem cell-like properties. PLoS One,  2010, 5(11), e14062.
 [http://dx.doi.org/10.1371/journal.pone.0014062] [PMID:  21124918]

[45]
Sundaram, S.G.; Milner, J.A. Diallyl disulfide inhibits the proliferation of human tumor cells in culture. Biochim. Biophys. Acta Mol. Basis Dis.,  1996, 1315(1), 15-20.
 [http://dx.doi.org/10.1016/0925-4439(95)00088-7] [PMID:  8611641]

[46]
Sen, S.; D’Incalci, M. Apoptosis biochemical events and relevance to cancer chemotherapy. FEBS Lett.,  1992, 307(1), 122-127.
 [http://dx.doi.org/10.1016/0014-5793(92)80914-3] [PMID:  1639187]

[47]
Foucquier, J.; Guedj, M. Analysis of drug combinations: Current methodological landscape. Pharmacol. Res. Perspect.,  2015, 3(3), e00149.
 [http://dx.doi.org/10.1002/prp2.149] [PMID:  26171228]

[48]
Wang, Z.; Li, Y.; Sarkar, F.H. Notch signaling proteins: Legitimate targets for cancer therapy. Curr. Protein Pept. Sci.,  2010, 11(6), 398-408.
 [http://dx.doi.org/10.2174/138920310791824039] [PMID:  20491628]

[49]
Ferrari-Toninelli, G.; Bonini, S.A.; Uberti, D.; Buizza, L.; Bettinsoli, P.; Poliani, P.L.; Facchetti, F.; Memo, M. Targeting notch pathway induces growth inhibition and differentiation of neuroblastoma cells. Neuro-oncol.,  2010, 12(12), 1231-1243.
 [http://dx.doi.org/10.1093/neuonc/noq101] [PMID:  20716592]

[50]
Lee, H.W.; Kim, S.J.; Choi, I.J.; Song, J.; Chun, K.H. Targeting notch signaling by γ-secretase inhibitor I enhances the cytotoxic effect of 5-FU in gastric cancer. Clin. Exp. Metastasis,  2015, 32(6), 593-603.
 [http://dx.doi.org/10.1007/s10585-015-9730-5] [PMID:  26134677]

[51]
Li, P.; Lin, X.; Zhang, J.R.; Li, Y.; Lu, J.; Huang, F.C.; Zheng, C.H.; Xie, J.W.; Wang, J.B.; Huang, C.M. The expression of presenilin 1 enhances carcinogenesis and metastasis in gastric cancer. Oncotarget,  2016, 7(9), 10650-10662.
 [http://dx.doi.org/10.18632/oncotarget.7298] [PMID:  26872378]

[52]
Geling, A.; Steiner, H.; Willem, M.; Bally-Cuif, L.; Haass, C. A γ‐secretase inhibitor blocks Notch signaling in vivo and causes a severe neurogenic phenotype in zebrafish. EMBO Rep.,  2002, 3(7), 688-694.
 [http://dx.doi.org/10.1093/embo-reports/kvf124] [PMID:  12101103]

[53]
Miao, R.; Xu, T.; Liu, L.; Wang, M.; Jiang, Y.; Li, J.; Guo, R. Rosiglitazone and retinoic acid inhibit proliferation and induce apoptosis in the HCT-15 human colorectal cancer cell line. Exp. Ther. Med.,  2011, 2(3), 413-417.
 [http://dx.doi.org/10.3892/etm.2011.227] [PMID:  22977519]

[54]
Grieselhuber, N.R.; Klco, J.M.; Verdoni, A.M.; Lamprecht, T.; Sarkaria, S.M.; Wartman, L.D.; Ley, T.J. Notch signaling in acute promyelocytic leukemia. Leukemia,  2013, 27(7), 1548-1557.
 [http://dx.doi.org/10.1038/leu.2013.68] [PMID:  23455394]

[55]
Aster, J.C.; Pear, W.S.; Blacklow, S.C. The varied roles of notch in cancer. Annu. Rev. Pathol.,  2017, 12(1), 245-275.
 [http://dx.doi.org/10.1146/annurev-pathol-052016-100127] [PMID:  27959635]

[56]
Brzozowa-Zasada, M.; Piecuch, A.; Michalski, M.; Segiet, O.; Kurek, J.; Harabin-Słowińska, M.; Wojnicz, R. Notch and its oncogenic activity in human malignancies. Eur. Surg.,  2017, 49(5), 199-209.
 [http://dx.doi.org/10.1007/s10353-017-0491-z] [PMID:  29104587]

[57]
Piazzi, G.; Fini, L.; Selgrad, M.; Garcia, M.; Daoud, Y.; Wex, T.; Malfertheiner, P.; Gasbarrini, A.; Romano, M.; Meyer, R.L.; Genta, R.M.; Fox, J.G.; Boland, C.R.; Bazzoli, F.; Ricciardiello, L. Epigenetic regulation of Delta-Like1 controls Notch1 activation in gastric cancer. Oncotarget,  2011, 2(12), 1291-1301.
 [http://dx.doi.org/10.18632/oncotarget.414] [PMID:  22249198]

[58]
Yan, B.; Liu, L.; Zhao, Y.; Xiu, L.J.; Sun, D.Z.; Liu, X.; Lu, Y.; Shi, J.; Zhang, Y.C.; Li, Y.J.; Wang, X.W.; Zhou, Y.Q.; Feng, S.H.; Lv, C.; Wei, P.K.; Qin, Z.F. Xiaotan Sanjie decoction attenuates tumor angiogenesis by manipulating Notch-1-regulated proliferation of gastric cancer stem-like cells. World J. Gastroenterol.,  2014, 20(36), 13105-13118.
 [http://dx.doi.org/10.3748/wjg.v20.i36.13105] [PMID:  25278704]

[59]
Li, L.C.; Peng, Y.; Liu, Y.M.; Wang, L.L.; Wu, X.L. Gastric cancer cell growth and epithelial-mesenchymal transition are inhibited by γ-secretase inhibitor DAPT. Oncol. Lett.,  2014, 7(6), 2160-2164.
 [http://dx.doi.org/10.3892/ol.2014.1980] [PMID:  24932308]

[60]
Dedhia, P.H.; Bertaux-Skeirik, N.; Zavros, Y.; Spence, J.R. Organoid models of human gastrointestinal development and disease. Gastroenterology,  2016, 150(5), 1098-1112.
 [http://dx.doi.org/10.1053/j.gastro.2015.12.042]

[61]
Nair, V.; Rajesh, C.; Vinod, A.U.; Bindu, S.; Sreekanth, A.R.; Mathen, J.S.; Balagopal, L. Strategies for heterocyclic construction via novel multicomponent reactions based on isocyanides and nucleophilic carbenes. Acc. Chem. Res.,  2003, 36(12), 899-907.
 [http://dx.doi.org/10.1021/ar020258p] [PMID:  14674781]

[62]
Mori, M.; Miyamoto, T.; Yakushiji, H.; Ohno, S.; Miyake, Y.; Sakaguchi, T.; Hattori, M.; Hongo, A.; Nakaizumi, A.; Ueda, M.; Ohno, E. Effects of N-[N-(3, 5-difluorophenacetyl-l-alanyl)]-S-phenylglycine t-butyl ester (DAPT) on cell proliferation and apoptosis in Ishikawa endometrial cancer cells. Hum. Cell,  2012, 25(1), 9-15.
 [http://dx.doi.org/10.1007/s13577-011-0038-8] [PMID:  22189483]

[63]
Chen, Q.; Deng, B.; Luo, Q.; Song, G. Deep tumor‐penetrated nanosystem eliminates cancer stem cell for highly efficient liver cancer therapy. Chem. Eng. J.,  2021, 421(2), 127874.
 [http://dx.doi.org/10.1016/j.cej.2020.127874]

[64]
Yao, W.; Wang, L.; Huang, H.; Li, X.; Wang, P.; Mi, K.; Cheng, J.; Liu, H.; Gu, C.; Huang, L.; Huang, J. All-trans retinoic acid reduces cancer stem cell-like cell-mediated resistance to gefitinib in NSCLC adenocarcinoma cells. BMC Cancer,  2020, 20(1), 315.
 [http://dx.doi.org/10.1186/s12885-020-06818-0] [PMID:  32293355]

[65]
Berardi, D.E.; Ariza Bareño, L.; Amigo, N.; Cañonero, L.; Pelagatti, M.N.; Motter, A.N.; Taruselli, M.A.; Díaz Bessone, M.I.; Cirigliano, S.M.; Edelstein, A.; Peters, M.G.; Diament, M.; Urtreger, A.J.; Todaro, L.B. All-trans retinoic acid and protein kinase C α/β1 inhibitor combined treatment targets cancer stem cells and impairs breast tumor progression. Sci. Rep.,  2021, 11(1), 6044.
 [http://dx.doi.org/10.1038/s41598-021-85344-w] [PMID:  33723318]

[66]
Yang, X.; Klein, R.; Tian, X.; Cheng, H.T.; Kopan, R.; Shen, J. Notch activation induces apoptosis in neural progenitor cells through a p53-dependent pathway. Dev. Biol.,  2004, 269(1), 81-94.
 [http://dx.doi.org/10.1016/j.ydbio.2004.01.014] [PMID:  15081359]

[67]
Hong, Y.S.; Ham, Y.A.; Choi, J.H.; Kim, J. Effects of allyl sulfur compounds and garlic extract on the expression of Bcl-2, Bax, and p53 in non small cell lung cancer cell lines. Exp. Mol. Med.,  2000, 32(3), 127-134.
 [http://dx.doi.org/10.1038/emm.2000.22] [PMID:  11048643]

[68]
Oommen, S.; Anto, R.J.; Srinivas, G.; Karunagaran, D. Allicin (from garlic) induces caspase-mediated apoptosis in cancer cells. Eur. J. Pharmacol.,  2004, 485(1-3), 97-103.
 [http://dx.doi.org/10.1016/j.ejphar.2003.11.059] [PMID:  14757128]

[69]
Justus, C.R.; Leffler, N.; Ruiz-Echevarria, M.; Yang, L.V. In vitro cell migration and invasion assays. J. Vis. Exp.,  2014, 88(88), 51046.
 [PMID:  24962652]

[70]
Friedl, P.; Hegerfeldt, Y.; Tusch, M. Collective cell migration in morphogenesis and cancer. Int. J. Dev. Biol.,  2004, 48(5-6), 441-449.
 [http://dx.doi.org/10.1387/ijdb.041821pf] [PMID:  15349818]

[71]
Albini, A.; Iwamoto, Y.; Kleinman, H.K.; Martin, G.R.; Aaronson, S.A.; Kozlowski, J.M.; McEwan, R.N. A rapid in vitro assay for quantitating the invasive potential of tumor cells. Cancer Res.,  1987, 47(12), 3239-3245.
 [PMID:  2438036]

[72]
Xie, M.; Liu, M.; He, C.S. SIRT1 regulates endothelial Notch signaling in lung cancer. PLoS One,  2012, 7(9), e45331.
 [http://dx.doi.org/10.1371/journal.pone.0045331] [PMID:  23028940]

[73]
Liu, Y.; Wen, Q.; Chen, X.; Yang, S.; Gao, L.; Gao, L.; Zhang, C.; Li, J.; Xiang, X.; Wan, K.; Chen, X.; Zhang, X.; Zhong, J. All-trans retinoic acid arrests cell cycle in leukemic bone marrow stromal cells by increasing intercellular communication through connexin 43-mediated gap junction. J. Hematol. Oncol.,  2015, 8(1), 110.
 [http://dx.doi.org/10.1186/s13045-015-0212-7] [PMID:  26446715]

[74]
Alhasan, L.; Addai, Z.R. Allicin-induced modulation of angiogenesis in lung cancer cells (A549). Trop. J. Pharm. Res.,  2019, 17(11), 2129-2134.
 [http://dx.doi.org/10.4314/tjpr.v17i11.3]

[75]
Sriuranpong, V.; Borges, M.W.; Ravi, R.K.; Arnold, D.R.; Nelkin, B.D.; Baylin, S.B.; Ball, D.W. Notch signaling induces cell cycle arrest in small cell lung cancer cells. Cancer Res.,  2001, 61(7), 3200-3205.
 [PMID:  11306509]

[76]
Liu, Z.H.; Dai, X.M.; Du, B. Hes1: A key role in stemness, metastasis and multidrug resistance. Cancer Biol. Ther.,  2015, 16(3), 353-359.
 [http://dx.doi.org/10.1080/15384047.2015.1016662] [PMID:  25781910]

[77]
Lotan, R. Retinoids and apoptosis: Implications for cancer chemoprevention and therapy. J. Natl. Cancer Inst.,  1995, 87(22), 1655-1657.
 [http://dx.doi.org/10.1093/jnci/87.22.1655] [PMID:  7473809]

[78]
Kopan, R.; Ilagan, M.X.G. The canonical notch signaling pathway: Unfolding the activation mechanism. Cell,  2009, 137(2), 216-233.
 [http://dx.doi.org/10.1016/j.cell.2009.03.045] [PMID:  19379690]

[79]
Abdelaziz, T.E. El- Borai, N.B.; Khalifa Hanem, K.; El- Gendy, H. Contribution of garlic for improving the cytoprotective effect of mesna against cyclophosphamide toxicity in rats. GSC Biol. Pharm. Sci.,  2019, 07(03), 008-020.

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DOI https://dx.doi.org/10.2174/1570180820666230831095954	Print ISSN 1570-1808
Publisher Name Bentham Science Publisher	Online ISSN 1875-628X

Letters in Drug Design & Discovery

Synergistic Effects of Ethanol Extract of Allium sativum (Garlic) with DAPT and ATRA on Notch Signaling Targeted Molecular Action on Lung Cancer Cell line (A549)

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