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Anti-Cancer Agents in Medicinal Chemistry

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

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Research Article

Synergistic Effect of α-Solanine and Cisplatin Induces Apoptosis and Enhances Cell Cycle Arrest in Human Hepatocellular Carcinoma Cells

Author(s): Sherien M. El-Daly*, Shaimaa A. Gouhar, Amira M. Gamal-Eldeen, Fatma F. Abdel Hamid, Magdi N. Ashour and Nahla S. Hassan

Volume 19, Issue 18, 2019

Page: [2197 - 2210] Pages: 14

DOI: 10.2174/1871520619666190930123520

Price: $65

Abstract

Aim: The clinical application of cisplatin is limited by severe side effects associated with high applied doses. The synergistic effect of a combination treatment of a low dose of cisplatin with the natural alkaloid α-solanine on human hepatocellular carcinoma cells was evaluated.

Methods: HepG2 cells were exposed to low doses of α-solanine and cisplatin, either independently or in combination. The efficiency of this treatment modality was evaluated by investigating cell growth inhibition, cell cycle arrest, and apoptosis enhancement.

Results: α-solanine synergistically potentiated the effect of cisplatin on cell growth inhibition and significantly induced apoptosis. This synergistic effect was mediated by inducing cell cycle arrest at the G2/M phase, enhancing DNA fragmentation and increasing apoptosis through the activation of caspase 3/7 and/or elevating the expression of the death receptors DR4 and DR5. The induced apoptosis from this combination treatment was also mediated by reducing the expression of the anti-apoptotic mediators Bcl-2 and survivin, as well as by modulating the miR-21 expression.

Conclusion: Our study provides strong evidence that a combination treatment of low doses of α-solanine and cisplatin exerts a synergistic anticancer effect and provides an effective treatment strategy against hepatocellular carcinoma.

Keywords: α-solanine, cisplatin, hepatocellular carcinoma, apoptosis, cell cycle arrest, synergistic effect.

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[1]
Lombardi, A.; Grimaldi, A.; Zappavigna, S.; Misso, G.; Caraglia, M. Hepatocarcinoma: Genetic and epigenetic features. Minerva Gastroenterol. Dietol., 2018, 64(1), 14-27.
[PMID: 28398025]
[2]
Management, C. Type 2 Diabetes mellitus increases the risk of hepatocellular carcinoma in subjects with chronic hepatitis B virus infection : A meta-analysis and systematic review. Cancer Manag. Res., 2019, 11, 705-713.
[3]
Chow, P.K.H.; Gandhi, M.; Tan, S.B.; Khin, M.W.; Khasbazar, A.; Ong, J.; Choo, S.P.; Cheow, P.C.; Chotipanich, C.; Lim, K.; Lesmana, L.A.; Manuaba, T.W.; Yoong, B.K.; Raj, A.; Law, C.S.; Cua, I.H.Y.; Lobo, R.R.; Teh, C.S.C.; Kim, Y.H.; Jong, Y.W.; Han, H.S.; Bae, S.H.; Yoon, H.K.; Lee, R.C.; Hung, C.F.; Peng, C.Y.; Liang, P.C.; Bartlett, A.; Kok, K.Y.Y.; Thng, C.H.; Low, A.S.C.; Goh, A.S.W.; Tay, K.H.; Lo, R.H.G.; Goh, B.K.P.; Ng, D.C.E.; Lekurwale, G.; Liew, W.M.; Gebski, V.; Mak, K.S.W.; Soo, K.C. SIRveNIB: Selective internal radiation therapy versus sorafenib in asia-pacific patients with hepatocellular carcinoma. J. Clin. Oncol., 2018, 36(19), 1913-1921.
[http://dx.doi.org/10.1200/JCO.2017.76.0892] [PMID: 29498924]
[4]
Le Grazie, M.; Biagini, M.R.; Tarocchi, M.; Polvani, S.; Galli, A. Chemotherapy for hepatocellular carcinoma: The present and the future. World J. Hepatol., 2017, 9(21), 907-920.
[http://dx.doi.org/10.4254/wjh.v9.i21.907] [PMID: 28824742]
[5]
Go, R.S.; Adjei, A.A. Review of the comparative pharmacology and clinical activity of cisplatin and carboplatin. J. Clin. Oncol., 1999, 17(1), 409-422.
[http://dx.doi.org/10.1200/JCO.1999.17.1.409] [PMID: 10458260]
[6]
Beppu, T.; Sugimoto, K.; Shiraki, K.; Tameda, M.; Inagaki, Y.; Ogura, S.; Kasai, C.; Kusagawa, S.; Nojiri, K.; Yoneda, M.; Fuke, H.; Yamamoto, N.; Takei, Y.; Fujimori, M.; Hasegawa, T.; Yamanaka, T.; Uraki, J.; Kashima, M.; Takaki, H.; Nakatsuka, A.; Yamakado, K.; Takeda, K. Clinical utility of transarterial infusion chemotherapy using cisplatin-lipiodol emulsion for unresectable hepatocellular carcinoma. Anticancer Res., 2012, 32(11), 4923-4930.
[PMID: 23155261]
[7]
Bayat Mokhtari, R.; Homayouni, T.S.; Baluch, N.; Morgatskaya, E.; Kumar, S.; Das, B.; Yeger, H. Combination therapy in combating cancer. Oncotarget, 2017, 8(23), 38022-38043.
[PMID: 28410237]
[8]
Mangla, B.; Kohli, K. Combination of natural agent with synthetic drug for the breast cancer therapy. Int. J. Drug Dev. Res., 2009, 10, 22-26.
[9]
Nair, S.; Boczkowski, D.; Moeller, B.; Dewhirst, M.; Vieweg, J.; Gilboa, E. Synergy between tumor immunotherapy and antiangiogenic therapy. Blood, 2003, 102(3), 964-971.
[http://dx.doi.org/10.1182/blood-2002-12-3738] [PMID: 12689940]
[10]
Langner, E.; Rzeski, W. Dietary derived compounds in cancer chemoprevention. Contemp. Oncol. (Pozn.), 2012, 16(5), 394-400.
[http://dx.doi.org/10.5114/wo.2012.31767] [PMID: 23788916]
[11]
Huang, X.; Kojima-Yuasa, A.; Xu, S.; Kennedy, D.O.; Hasuma, T.; Matsui-Yuasa, I. Combination of Zizyphus jujuba and green tea extracts exerts excellent cytotoxic activity in HepG2 cells via reducing the expression of APRIL. Am. J. Chin. Med., 2009, 37(1), 169-179.
[http://dx.doi.org/10.1142/S0192415X09006758] [PMID: 19222120]
[12]
Kojima-Yuasa, A.; Huang, X.; Matsui-Yuasa, I. Synergistic anticancer activities of natural substances in human hepatocellular carcinoma. Diseases, 2015, 3(4), 260-281.
[http://dx.doi.org/10.3390/diseases3040260] [PMID: 28943624]
[13]
Friedman, M. Potato glycoalkaloids and metabolites: Roles in the plant and in the diet. J. Agric. Food Chem., 2006, 54(23), 8655-8681.
[http://dx.doi.org/10.1021/jf061471t] [PMID: 17090106]
[14]
Lv, C.; Kong, H.; Dong, G.; Liu, L.; Tong, K.; Sun, H.; Chen, B.; Zhang, C.; Zhou, M. Antitumor efficacy of a-solanine against pancreatic cancer pancreatic cancer in vitro and in vivo. PLoS One, 2014, 9(2)e87868
[http://dx.doi.org/10.1371/journal.pone.0087868] [PMID: 24505326]
[15]
Zhang, F.; Yang, R.; Zhang, G.; Cheng, R.; Bai, Y.; Zhao, H.; Lu, X.; Li, H.; Chen, S.; Li, J.; Wu, S.; Li, P.; Chen, X.; Sun, Q.; Zhao, G. Anticancer function of α-solanine in lung adenocarcinoma cells by inducing microRNA-138 expression. Tumour Biol., 2016, 37(5), 6437-6446.
[http://dx.doi.org/10.1007/s13277-015-4528-2] [PMID: 26631041]
[16]
Wang, L.; Sun, Q.Q.; Zhang, S.J.; Du, Y.W.; Wang, Y.Y.; Zang, W.Q.; Chen, X.N.; Zhao, G.Q. Inhibitory effect of α-solanine on esophageal carcinoma in vitro. Exp. Ther. Med., 2016, 12(3), 1525-1530.
[http://dx.doi.org/10.3892/etm.2016.3500] [PMID: 27588073]
[17]
Lu, M-K.; Shih, Y-W.; Chang, Chien, T.T.; Fang, L.H.; Huang, H.C.; Chen, P.S. α-Solanine inhibits human melanoma cell migration and invasion by reducing matrix metalloproteinase-2/9 activities. Biol. Pharm. Bull., 2010, 33(10), 1685-1691.
[http://dx.doi.org/10.1248/bpb.33.1685] [PMID: 20930376]
[18]
Ji, Y.B.; Gao, S.Y.; Ji, C.F.; Zou, X. Induction of apoptosis in HepG2 cells by solanine and Bcl-2 protein. J. Ethnopharmacol., 2008, 115(2), 194-202.
[http://dx.doi.org/10.1016/j.jep.2007.09.023] [PMID: 18022776]
[19]
Sun, H.; Lv, C.; Yang, L.; Wang, Y.; Zhang, Q.; Yu, S.; Kong, H.; Wang, M.; Xie, J.; Zhang, C.; Zhou, M. Solanine induces mitochondria-mediated apoptosis in human pancreatic cancer cells. BioMed Res. Int., 2014, 2014805926
[http://dx.doi.org/10.1155/2014/805926] [PMID: 24949471]
[20]
Hansen, M.B.; Nielsen, S.E.; Berg, K. Re-examination and further development of a precise and rapid dye method for measuring cell growth/cell kill. J. Immunol. Methods, 1989, 119(2), 203-210.
[http://dx.doi.org/10.1016/0022-1759(89)90397-9] [PMID: 2470825]
[21]
Yan, Z.; Caldwell, G.W. Evaluation of cytochrome P450 inhibition in human liver microsomes. In: Optimization in Drug Discovery; Humana Press; New Jersey: USA, 2004; pp. 231-244.
[http://dx.doi.org/10.1385/1-59259-800-5:231]
[22]
Chou, T.C.; Talalay, P. Quantitative analysis of dose-effect relationships: The combined effects of multiple drugs or enzyme inhibitors. Adv. Enzyme Regul., 1984, 22, 27-55.
[http://dx.doi.org/10.1016/0065-2571(84)90007-4] [PMID: 6382953]
[23]
Kasibhatla, S.; Amarante-Mendes, G.P.; Finucane, D.; Brunner, T.; Bossy-Wetzel, E.; Green, D.R. Acridine Orange/Ethidium Bromide (AO/EB) staining to detect apoptosis. CSH Protoc., 2006, 2006(3), pdb.prot4493.
[http://dx.doi.org/10.1101/pdb.prot4493] [PMID: 22485874]
[24]
Smith, S.M.; Ribble, D.; Goldstein, N.B.; Norris, D.A.; Shellman, Y.G. A simple technique for quantifying apoptosis in 96-well plates. Methods Cell Biol., 2012, 5, 12.
[http://dx.doi.org/10.1016/B978-0-12-405914-6.00020-2]
[25]
Gibb, R.K.; Gercel-Taylor, C. Use of diphenylamine in the detection of apoptosis. Methods Mol. Med., 2001, 39, 679-680.
[PMID: 21340829]
[26]
Gamal-Eldeen, A.M.; Moustafa, D.; El-Daly, S.M.; El-Hussieny, E.A.; Saleh, S.; Khoobchandani, M.; Bacon, K.L.; Gupta, S.; Katti, K.; Shukla, R.; Katti, K.V. Photothermal therapy mediated by gum Arabic-conjugated gold nanoparticles suppresses liver preneoplastic lesions in mice. J. Photochem. Photobiol. B, 2016, 163, 47-56.
[http://dx.doi.org/10.1016/j.jphotobiol.2016.08.009] [PMID: 27533849]
[27]
Gamal-Eldeen, A.M.; El-Daly, S.M.; Borai, I.H.; Wafay, H.A.; Abdel-Ghaffar, A.R.B. Photodynamic therapeutic effect of indocyanine green entrapped in polymeric nanoparticles and their anti-EGFR-conjugate in skin cancer in CD1 mice. Photodiagn. Photodyn. Ther., 2013, 10(4), 446-459.
[http://dx.doi.org/10.1016/j.pdpdt.2013.03.013] [PMID: 24284098]
[28]
Kotowski, U.; Heiduschka, G.; Brunner, M.; Erovic, B.M.; Martinek, H.; Thurnher, D. Arsenic trioxide enhances the cytotoxic effect of cisplatin in head and neck squamous cell carcinoma cell lines. Oncol. Lett., 2012, 3(6), 1326-1330.
[http://dx.doi.org/10.3892/ol.2012.643] [PMID: 22783443]
[29]
Yildirim, H.; Kockar, F.; Nakiboglu, C. Antiproliferative activity of some novel platinum complexes on C6 glioma and MCF-7 breast cancer cells. Afr. J. Biotechnol., 2012, 11(60), 12422-12428.
[30]
Tekin, E.; Beppler, C.; White, C.; Mao, Z.; Savage, V.M.; Yeh, P.J. Enhanced identification of synergistic and antagonistic emergent interactions among three or more drugs. J. R. Soc. Interface, 2016, 13(119)20160332
[http://dx.doi.org/10.1098/rsif.2016.0332] [PMID: 27278366]
[31]
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]
[32]
DiPaola, R.S. To arrest or not to G(2)-M Cell-cycle arrest: Commentary re: A.K. Tyagi et al., Silibinin strongly synergizes human prostate carcinoma DU145 cells to doxorubicin-induced growth inhibition, G(2)-M arrest, and apoptosis. Clin. Cancer Res., 2002, 8(11), 3311-3314.
[PMID: 12429616]
[33]
Wang, H.; Zhang, T.; Sun, W.; Wang, Z.; Zuo, D.; Zhou, Z.; Li, S.; Xu, J.; Yin, F.; Hua, Y.; Cai, Z. Erianin induces G2/M-phase arrest, apoptosis, and autophagy via the ROS/JNK signaling pathway in human osteosarcoma cells in vitro and in vivo. Cell Death Dis., 2016, 7(6)e2247
[http://dx.doi.org/10.1038/cddis.2016.138] [PMID: 27253411]
[34]
Chung, T.W.; Lin, S.C.; Su, J.H.; Chen, Y.K.; Lin, C.C.; Chan, H.L. Sinularin induces DNA damage, G2/M phase arrest, and apoptosis in human hepatocellular carcinoma cells. BMC Complement. Altern. Med., 2017, 17(1), 62.
[http://dx.doi.org/10.1186/s12906-017-1583-9] [PMID: 28103869]
[35]
Davidovich, P.; Kearney, C.J.; Martin, S.J. Inflammatory outcomes of apoptosis, necrosis and necroptosis. Biol. Chem., 2014, 395(10), 1163-1171.
[http://dx.doi.org/10.1515/hsz-2014-0164] [PMID: 25153241]
[36]
Friedman, M.; Lee, K.R.; Kim, H.J.; Lee, I.S.; Kozukue, N. Anticarcinogenic effects of glycoalkaloids from potatoes against human cervical, liver, lymphoma, and stomach cancer cells. J. Agric. Food Chem., 2005, 53(15), 6162-6169.
[http://dx.doi.org/10.1021/jf050620p] [PMID: 16029012]
[37]
Pan, B.; Zhong, W.; Deng, Z.; Lai, C.; Chu, J.; Jiao, G.; Liu, J.; Zhou, Q. Inhibition of prostate cancer growth by solanine requires the suppression of cell cycle proteins and the activation of ROS/P38 signaling pathway. Cancer Med., 2016, 5(11), 3214-3222.
[http://dx.doi.org/10.1002/cam4.916] [PMID: 27726305]
[38]
Fichtinger-Schepman, A.M.J.; van der Veer, J.L.; den Hartog, J.H.; Lohman, P.H.; Reedijk, J. Adducts of the antitumor drug cis-diamminedichloroplatinum(II) with DNA: Formation, identification, and quantitation. Biochemistry, 1985, 24(3), 707-713.
[http://dx.doi.org/10.1021/bi00324a025] [PMID: 4039603]
[39]
Vaisman, A.; Varchenko, M.; Said, I.; Chaney, S.G. Cell cycle changes associated with formation of Pt-DNA adducts in human ovarian carcinoma cells with different cisplatin sensitivity. Cytometry, 1997, 27(1), 54-64.
[http://dx.doi.org/10.1002/(SICI)1097-0320 (19970101)27:1<54:AID-CYTO7>3.0.CO;2-L] [PMID: 9000585]
[40]
Collins, J.A.; Schandi, C.A.; Young, K.K.; Vesely, J.; Willingham, M.C. Major DNA fragmentation is a late event in apoptosis. J. Histochem. Cytochem., 1997, 45(7), 923-934.
[http://dx.doi.org/10.1177/002215549704500702] [PMID: 9212818]
[41]
Zhao, X.; Ogunwobi, O.O.; Liu, C. Survivin inhibition is critical for Bcl-2 inhibitor-induced apoptosis in hepatocellular carcinoma cells. PLoS One, 2011, 6(8)e21980
[http://dx.doi.org/10.1371/journal.pone.0021980] [PMID: 21829603]
[42]
Kita, A.; Nakahara, T.; Takeuchi, M.; Kinoyama, I.; Yamanaka, K.; Minematsu, T.; Mitsuoka, K.; Fushiki, H.; Miyoshi, S.; Sasamata, M.; Miyata, K. Survivin supressant: A promising target for cancer therapy and pharmacological profiles of YM155. Nippon Yakurigaku Zasshi, 2010, 136(4), 198-203.
[http://dx.doi.org/10.1254/fpj.136.198] [PMID: 20948154]
[43]
Soifer, H.S.; Rossi, J.J.; Saetrom, P. MicroRNAs in disease and potential therapeutic applications. Mol. Ther., 2007, 15(12), 2070-2079.
[http://dx.doi.org/10.1038/sj.mt.6300311] [PMID: 17878899]
[44]
Buscaglia, L.E.B.; Li, Y. Apoptosis and the target genes of microRNA-21. Chin. J. Cancer, 2011, 30(6), 371-380.
[http://dx.doi.org/10.5732/cjc.30.0371] [PMID: 21627859]
[45]
Sims, E.K.; Lakhter, A.J.; Anderson-Baucum, E.; Kono, T.; Tong, X.; Evans-Molina, C. MicroRNA 21 targets BCL2 mRNA to increase apoptosis in rat and human beta cells. Diabetologia, 2017, 60(6), 1057-1065.
[http://dx.doi.org/10.1007/s00125-017-4237-z] [PMID: 28280903]
[46]
Dong, J.; Zhao, Y.P.; Zhou, L.; Zhang, T.P.; Chen, G. Bcl-2 upregulation induced by miR-21 via a direct interaction is associated with apoptosis and chemoresistance in MIA PaCa-2 pancreatic cancer cells. Arch. Med. Res., 2011, 42(1), 8-14.
[http://dx.doi.org/10.1016/j.arcmed.2011.01.006] [PMID: 21376256]
[47]
Du, G.; Cao, D.; Meng, L. miR-21 inhibitor suppresses cell proliferation and colony formation through regulating the PTEN/AKT pathway and improves paclitaxel sensitivity in cervical cancer cells. Mol. Med. Rep., 2017, 15(5), 2713-2719.
[http://dx.doi.org/10.3892/mmr.2017.6340] [PMID: 28447761]
[48]
Yu, X.; Chen, Y.; Tian, R.; Li, J.; Li, H.; Lv, T.; Yao, Q. miRNA-21 enhances chemoresistance to cisplatin in epithelial ovarian cancer by negatively regulating PTEN. Oncol. Lett., 2017, 14(2), 1807-1810.
[http://dx.doi.org/10.3892/ol.2017.6324] [PMID: 28789414]
[49]
Yu, X.; Zheng, H.; Chan, M.T.V.; Wu, W.K.K. Modulation of chemoresponsiveness to platinum-based agents by microRNAs in cancer. Am. J. Cancer Res., 2017, 7(9), 1769-1778.
[PMID: 28979802]
[50]
Shen, K.H.; Liao, A.C.H.; Hung, J.H.; Lee, W.J.; Hu, K.C.; Lin, P.T.; Liao, R.F.; Chen, P.S. α-Solanine inhibits invasion of human prostate cancer cell by suppressing epithelial-mesenchymal transition and MMPs expression. Molecules, 2014, 19(8), 11896-11914.
[http://dx.doi.org/10.3390/molecules190811896] [PMID: 25116803]
[51]
Bröker, L.E.; Kruyt, F.A.E.; Giaccone, G. Cell death independent of caspases: A review. Clin. Cancer Res., 2005, 11(9), 3155-3162.
[http://dx.doi.org/10.1158/1078-0432.CCR-04-2223] [PMID: 15867207]
[52]
Chen, L.; Jiang, J.; Cheng, C.; Yang, A.; He, Q.; Li, D.; Wang, Z. P53 dependent and independent apoptosis induced by lidamycin in human colorectal cancer cells. Cancer Biol. Ther., 2007, 6(6), 965-973.
[http://dx.doi.org/10.4161/cbt.6.6.4193] [PMID: 17534142]
[53]
Bruni, E.; Reichle, A.; Scimeca, M.; Bonanno, E.; Ghibelli, L. Lowering etoposide doses shifts cell demise from caspase-dependent to differentiation and Caspase-3-independent apoptosis via DNA damage response, inducing AML culture extinction. Front. Pharmacol., 2018, 9, 1307.
[http://dx.doi.org/10.3389/fphar.2018.01307] [PMID: 30483138]
[54]
Richardson, G.D.; Robson, C.N.; Lang, S.H.; Neal, D.E.; Maitland, N.J.; Collins, A.T. CD133, a novel marker for human prostatic epithelial stem cells. J. Cell Sci., 2004, 117(Pt 16), 3539-3545.
[http://dx.doi.org/10.1242/jcs.01222] [PMID: 15226377]
[55]
Song, W.; Li, H.; Tao, K.; Li, R.; Song, Z.; Zhao, Q.; Zhang, F.; Dou, K. Expression and clinical significance of the stem cell marker CD133 in hepatocellular carcinoma. Int. J. Clin. Pract., 2008, 62(8), 1212-1218.
[http://dx.doi.org/10.1111/j.1742-1241.2008.01777.x] [PMID: 18479363]
[56]
Ma, S.; Chan, K.W.; Hu, L.; Lee, T.K.W.; Wo, J.Y.H.; Ng, I.O.L.; Zheng, B.J.; Guan, X.Y. Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology, 2007, 132(7), 2542-2556.
[http://dx.doi.org/10.1053/j.gastro.2007.04.025] [PMID: 17570225]
[57]
Piao, L.S.; Hur, W.; Kim, T.K.; Hong, S.W.; Kim, S.W.; Choi, J.E.; Sung, P.S.; Song, M.J.; Lee, B.C.; Hwang, D.; Yoon, S.K. CD133+ liver cancer stem cells modulate radioresistance in human hepatocellular carcinoma. Cancer Lett., 2012, 315(2), 129-137.
[http://dx.doi.org/10.1016/j.canlet.2011.10.012] [PMID: 22079466]
[58]
Lan, X.; Wu, Y.Z.; Wang, Y.; Wu, F.R.; Zang, C.B.; Tang, C.; Cao, S.; Li, S.L. CD133 silencing inhibits stemness properties and enhances chemoradiosensitivity in CD133-positive liver cancer stem cells. Int. J. Mol. Med., 2013, 31(2), 315-324.
[http://dx.doi.org/10.3892/ijmm.2012.1208] [PMID: 23233126]
[59]
Korkaya, H.; Wicha, M.S. Selective targeting of cancer stem cells: A new concept in cancer therapeutics. BioDrugs, 2007, 21(5), 299-310.
[http://dx.doi.org/10.2165/00063030-200721050-00002] [PMID: 17896836]

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