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Anti-Cancer Agents in Medicinal Chemistry


ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Research Article

3, 3′-Dimethylquercetin Inhibits the Proliferation of Human Colon Cancer RKO Cells through Inducing G2/M Cell Cycle Arrest and Apoptosis

Author(s): Jianguo Wu, Jun Yi, Yanbin Wu, Xuzheng Chen, Jianwei Zeng, Jinzhong Wu* and Wei Peng*

Volume 19 , Issue 3 , 2019

Page: [402 - 409] Pages: 8

DOI: 10.2174/1871520618666181106120718

Price: $65


Background: Our previous study successfully identified that 3,3′-Dimethylquercetin (DMQ) acted as a potent anticancer agent against human colon cancer cell lines RKO. Thus, this study was conducted to investigate the underlying mechanism by which DMQ displayed inhibitory activity in RKO cells.

Methods: Flow cytometry was used to evaluate the effect of DMQ on the cell cycle arrest, as well as the mitochondrial membrane potential in RKO cells. DAPI staining and DNA fragmentation ladder assays were performed to assess the apoptosis inducing activity of DMQ. Furthermore, western blot analysis was conducted to examine the expression of related proteins responsible for the cell cycle arrest and apoptosis.

Results: Treatment with DMQ caused a significant increase in the fraction of G2/M cells, and induced remarkable apoptosis. Furthermore, western blot analysis showed that DMQ arrested cells at G2/M checkpoint by down-regulation of cyclin B1, cdc2 and cdc25c and up-regulation of p21, and induced cell apoptosis via affecting the ratio of Bax/Bcl-2, causing loss of the mitochondrial membrane potential and enhancing the expression of cleaved caspase-9 (C-caspase-9) and cleaved caspase-3 (C-caspase-3).

Conclusion: These data showed that DMQ could suppress RKO cell growth by arresting RKO cells at G2/M checkpoint and inducing mitochondria-dependent cell apoptosis. Our findings shed light on the potential use of DMQ as a chemotherapeutic agent for CRC.

Keywords: Colorectal cancer, RKO cells, 3, 3′-dimethylquercetin, apoptosis, cell cycle arrest, mitochondrial membrane potential.

Graphical Abstract
Losurdo, G.; Principi, M.; Girardi, B.; Pricci, M.; Barone, M.; Ierardi, E.; Di-Leo, A. Histamine and histaminergic receptors in colorectal cancer: from basic science to evidence-based medicine. Anticancer. Agents Med. Chem., 2018, 18(1), 15-20.
Jiang, B.; Zhao, W.; Shi, M.; Zhang, J.; Chen, A.; Ma, H.; Suleman, M.; Lin, F.; Zhou, L.; Wang, J.; Zhang, Y.; Liu, M.; Wen, S.; Ouyang, C.; Wang, H.; Huang, X.; Zhou, H.; Li, Q. IDH1 Arg-132 mutant promotes tumor formation through down-regulating p53. J. Biol. Chem., 2018, 293(25), 9747-9758.
Zhu, X.; Wang, K.; Zhang, K.; Pan, Y.; Zhou, F.F.; Zhu, L. Polyphyllin I induces cell cycle arrest and cell apoptosis in human retinoblastoma Y-79 cells through Targeting p53. Anticancer. Agents Med. Chem., 2018, 18, 875-881.
Li, C.F.; Wu, W.R.; Chan, T.C.; Wang, Y.H.; Chen, L.R.; Wu, W.J.; Yeh, B.W.; Liang, S.S.; Shiue, Y.L. Transmembrane and coiled-coil domain 1 impairs the akt signaling pathway in urinary bladder urothelial carcinoma: A characterization of a tumor suppressor. Clin. Cancer Res., 2017, 23(24), 7650-7663.
Ratsima, H.; Serrano, D.; Pascariu, M.; D’Amours, D. Centrosome-dependent bypass of the DNA damage checkpoint by the polo kinase Cdc5. Cell Rep., 2016, 14(6), 1422-1434.
Meng, X.; Bi, J.; Li, Y.; Yang, S.; Zhang, Y.; Li, M.; Liu, H.; Li, Y.; Mcdonald, M.E.; Thiel, K.W.; Wen, K.K.; Wang, X.; Wu, M.; Leslie, K.K. AZD1775 increases sensitivity to olaparib and gemcitabine in cancer cells with p53 mutations. Cancers , 2018, 10(5), 149.
Chang, Y.T.; Wu, C.Y.; Tang, J.Y.; Huang, C.Y.; Liaw, C.C.; Wu, S.H.; Sheu, J.H.; Chang, H.W. Sinularin induces oxidative stress-mediated G2/M arrest and apoptosis in oral cancer cells. Environ. Toxicol., 2017, 2(9), 2124-2132.
Song, M.; Wu, X.; Charoensinphon, N.; Wang, M.; Zheng, J.; Gao, Z.; Xu, F.; Li, Z.; Li, F.; Zhou, J.; Xiao, H. Dietary 5-demethylnobiletin inhibits cigarette carcinogen NNK-induced lung tumorigenesis in mice. Food Funct., 2017, 8(3), 954-963.
Lin, Y.T.; Lin, C.C.; Wang, H.C.; Hsu, Y.C. Induction of mitotic delay in pharyngeal and nasopharyngeal carcinoma cells using an aqueous extract of Ajuga bracteosa. Int. J. Med. Sci., 2017, 14(5), 462-469.
Elkady, A.I. Anethole inhibits the proliferation of human prostate cancer cells via induction of cell cycle arrest and apoptosis. Anticancer. Agents Med. Chem., 2018, 18(2), 216-236.
Yang, H.; Qiu, L.; Zhang, L.; Lv, G.C.; Li, K.; Yu, H.X.; Xie, M.H.; Lin, J.G. Platinum-zoledronate complex blocks gastric cancer cell proliferation by inducing cell cycle arrest and apoptosis. Tumour Biol., 2016, 37(8), 10981-10992.
Bishayee, A.; Sethi, G. Bioactive natural products in cancer prevention and therapy: Progress and promise. Semin. Cancer Biol., 2016, 40-41, 1-3.
Bratkov, V.M.; Shkondrov, A.M.; Zdraveva, P.K.; Krasteva, I.N. Flavonoids from the genus Astragalus: Phytochemistry and biological activity. Pharmacogn. Rev., 2016, 10(19), 11-32.
Theodoratou, E.; Kyle, J.; Cetnarskyj, R.; Farrington, S.M.; Tenesa, A.; Barnetson, R.; Porteous, M.; Dunlop, M.; Campbell, H. Dietary flavonoids and the risk of colorectal cancer. Cancer Epidemiol. Biomarkers Prev., 2007, 16(4), 684-693.
Jiang, C.H.; Sun, T.L.; Xiang, D.X.; Wei, S.S.; Li, W.Q. Anticancer activity and mechanism of xanthohumol: A prenylated flavonoid from hops (Humulus lupulus L.). Front. Pharmacol., 2018, 9, 530.
Hoensch, H.; Groh, B.; Edler, L.; Kirch, W. Prospective cohort comparison of flavonoid treatment in patients with resected colorectal cancer to prevent recurrence. World J. Gastroenterol., 2008, 14(14), 2187-2193.
Alvarez, A.; Pomar, F.; Sevilla, M.A.; Montero, M.J. Gastric antisecretory and antiulcer activities of an ethanolic extract of Bidens pilosa L. var. radiata Schult. Bip. J. Ethnopharmacol., 1999, 67(3), 333-340.
Yang, H.L.; Chen, S.C.; Chang, N.W.; Chang, J.M.; Lee, M.L.; Tsai, P.C.; Fu, H.H.; Kao, W.W.; Chiang, H.C.; Wang, H.H.; Hseu, Y.C. Protection from oxidative damage using Bidens pilosa extracts in normal human erythrocytes. Food Chem. Toxicol., 2006, 44(9), 1513-1521.
Wu, J.G.; Wan, Z.X.; Yi, J.; Wu, Y.B.; Peng, W.; Wu, J.Z. Investigation of the extracts from Bidens pilosa Linn. var. radiata Sch. Bip. for antioxidant activities and cytotoxicity against human tumor cells. J. Nat. Med., 2013, 67(1), 17-26.
Al-Dabbas, M.M.; Al-Ismail, K.; Abu-Taleb, R.; Hashimoto, F.; Rabah, I.O.; Kitahara, K.; Fujita, K.; Suganuma, T. Chemistry and antiproliferative activities of 3-methoxyflavones isolated from Varthemia iphionoides. Chem. Nat. Comp., 2011, 47(1), 17-21.
Talib, W.H.; Zarga, M.H.; Mahasneh, A.M. Antiproliferative, antimicrobial and apoptosis inducing effects of compounds isolated from Inula viscosa. Molecules, 2012, 17(3), 3291-3303.
Howells, L.M.; Britton, R.G.; Mazzoletti, M.; Greaves, P.; Broggini, M.; Brown, K.; Steward, W.P.; Gescher, A.J.; Sale, S. Preclinical colorectal cancer chemopreventive efficacy and p53-modulating activity of 3′,4′,5′-trimethoxyflavonol, a quercetin analogue. Cancer Prev. Res., 2010, 3(8), 929-239.
de-Oliveira, M.R.; Nabavi, S.M.; Braidy, N.; Setzer, W.N.; Ahmed, T.; Nabavi, S.F. Quercetin and the mitochondria: A mechanistic view. Biotechnol. Adv., 2016, 34(5), 532-549.
Stevens, J.J.; Graham, B.; Dugo, E.; Berhaneselassie-Sumner, B.; Ndebele, K.; Tchounwou, P.B. Arsenic trioxide induces apoptosis via specific signaling pathways in HT-29 colon cancer cells. J. Cancer Sci. Ther., 2017, 9(1), 298-306.
Lee, S.Y.; Ahn, S.M.; Wang, Z.; Choi, Y.W.; Shin, H.K.; Choi, B.T. Neuroprotective effects of 2,3,5,4′-tetrahydoxystilbene-2-O-β-D-glucoside from Polygonum multiflorum against glutamate-induced oxidative toxicity in HT22 cells. J. Ethnopharmacol., 2017, 195, 64-70.
Yang, Y.; Zong, M.; Xu, W.; Zhang, Y.; Wang, B.; Yang, M.; Tao, L. Natural pyrethrins induces apoptosis in human hepatocyte cells via Bax- and Bcl-2-mediated mitochondrial pathway. Chem. Biol. Interact., 2017, 26, 38-45.
Fadda, L.M.; Attia, H.A.; Al-Rasheed, N.M.; Ali, H.M.; Al-Rasheed, N.M. Roles of some antioxidants in modulation of cardiac myopathy induced by sodium nitrite via down-regulation of mRNA expression of NF-κB, Bax, and flt-1 and suppressing DNA damage. Saudi Pharm. J., 2018, 26(2), 217-223.
Peng, W.; Wu, J.G.; Jiang, Y.B.; Liu, Y.J.; Sun, T.; Wu, N.; Wu, C.J. Antitumor activity of 4-O-(2-O-acetyl-6-O-p-coumaroyl-β-D-glucopyranosyl)-p-coumaric acid against lung cancers via mitochondrial-mediated apoptosis. Chem. Biol. Interact., 2015, 233, 8-13.
Yang, J.L.; Lien, J.C.; Chen, Y.Y.; Hsu, S.C.; Chang, S.J.; Huang, A.C.; Amagaya, S.; Funayana, S.; Wood, W.G.; Kuo, C.L.; Chung, J.G. Crude extract of Euphorbia formosana induces apoptosis of DU145 human prostate cancer cells act through the caspase-dependent and independent signaling pathway. Environ. Toxicol., 2016, 31(11), 1600-1611.
Husain, I.; Sharma, A.; Kumar, S.; Malik, F. Purification and characterization of glutaminase free asparaginase from Enterobacter cloacae: In-vitro evaluation of cytotoxic potential against human myeloid leukemia HL-60 cells. PLoS One, 2016, 11(2)e0148877
Vijayaraghavan, S.; Moulder, S.; Keyomarsi, K.; Layman, R.M. Inhibiting CDK in cancer therapy: Current evidence and future directions. Target. Oncol., 2018, 13(1), 21-38.
Rao, Y.K.; Fang, S.H.; Tzeng, Y.M. Synthesis, growth inhibition, and cell cycle evaluations of novel flavonoid derivatives. Bioorg. Med. Chem., 2005, 13(24), 6850-6855.
Lien, L.M.; Wang, M.J.; Chen, R.J.; Chiu, H.C.; Wu, J.L.; Shen, M.Y.; Chou, D.S.; Sheu, J.R.; Lin, K.H.; Lu, W.J. Nobiletin, a polymethoxylated flavone, inhibits glioma cell growth and migration via arresting cell cycle and suppressing MAPK and Akt pathways. Phytother. Res., 2016, 30(2), 214-221.
Block, K.I.; Gyllenhaal, C.; Lowe, L.; Amedei, A.; Amin, A.R.; Amin, A.; Aquilano, K.; Arbiser, J.; Arreola, A.; Arzumanyan, A.; Ashraf, S.S. Designing a broad-spectrum integrative approach for cancer prevention and treatment. Semin. Cancer Biol., 2015, 35, S276-S304.

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