Paris Saponin VII Induces Apoptosis and Cell Cycle Arrest in Erythroleukemia Cells by a Mitochondrial Membrane Signaling Pathway

Xin       Lin; Babu       Gajendran; Krishnapriya    M.    Varier; Wuling       Liu; Jingrui       Song; Qing       Rao; Chunlin       Wang; Jianfei       Qiu; Wei       Ni; XuJie       Qin; Min       Wen; Haiyang       Liu; Yanmei      Li

doi:10.2174/1871520620666200615134039

Abstract

Background and Purpose: Leukemia is considered a top-listed ailment, according to WHO, which contributes to the death of a major population of the world every year. Paris Saponin VII (PS), a saponin which was isolated from the roots of Trillium kamtschaticum, from our group, was reported to provide hemostatic, cytotoxic and antimicrobial activities. However, its molecular mechanism underlying the anti-proliferative effects remains unclear. Thus, this study hypothesized to assess that mechanism in PS treated HEL cells.

Methods: The MTT assay was used to analyze the PS inhibited cell viability in the HEL cells. We further found that PS could induce S phase cell cycle arrest through flow cytometry as well as the western blot analysis of intrinsic and extrinsic apoptotic molecules.

Results: The MTT assay showed the IC50 concentration of PS as 0.667μM. The study revealed that PS treatment inhibits cell proliferation dose-dependently. It further caused mitochondrial membrane potential changes by PS treatment. Mechanistic protein expression revealed a dose-dependent upsurge for Bid and Bim molecules, while Bcl2 and PARP expression levels were significantly (P<0.05) down-regulated in PS treated HEL cells resulting in caspase -3 release and increased the Bim levels upon 24h of incubation.

Conclusion: These findings indicate that PS possesses an excellent anti-leukemic activity via the regulation of the mitochondrial pathway, leading to S phase cell cycle arrest and caspase-dependent apoptosis, suggesting it as a potential alternative chemotherapeutic agent for leukemia patients.

Keywords: Leukemia, Paris Saponin VII, HEL, cell cycle, apoptosis, membrane signaling pathway.

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[1] 
Davis, A.S.; Viera, A.J.; Mead, M.D. Leukemia: An overview for primary care. Am. Fam. Physician,  2014, 89(9), 731-738.
[PMID:  24784336] 
[2] 
Siegel, R.; Ma, J.; Zou, Z.; Jemal, A. Cancer statistics, 2014. CA Cancer J. Clin.,  2014, 64(1), 9-29.
[http://dx.doi.org/10.3322/caac.21208] [PMID:  24399786] 
[3] 
Govaerts, R.H.A.; Trillium, L.; Sp, P. World checklist of selected plant families published update; Facilitated by the Trustees of the Royal Botanic Gardens: Kew, 2011, p. 339.
[4] 
Gawler, K. Bot. Trillium camschatcense; Flo Chi, 1985, p. 95.
[5] 
Zhao, Y.; Du, X.; Fu, H. New research progress of Trillium tschonoskii maxim. Anhui agricul. Sci. Bull.,  2017, 16(5), 133-145.
[6] 
Yu, L.; Zou, K.; Wang, J.; Zhu, L.; Zhou, Y.; Yang, J. Study on the anti-inflammatory, analgesic and thrombosis effects of extract of Trillium tschonoskii Maxim. Lishizhen Med. Res.,  2008, 285, 1178-1180.
[7] 
Yokosuka, A.; Mimaki, Y. Steroidal glycosides from the underground parts of Trillium erectum and their cytotoxic activity.Phytochemistry, 2008, 69(15), 2724-2730., 
[http://dx.doi.org/10.1016/j.phytochem.2008.08.004] [PMID: 18822438] 
[8] 
Chen, Y.; Ni, W.; Yan, H.; Qin, X.J.; Khan, A.; Liu, H.; Shu, T.; Jin, L.Y.; Liu, H.Y. Spirostanol glycosides with hemostatic and antimicrobial activities from Trillium kamtschaticum. Phytochemistry,  2016, 131, 165-173.
[http://dx.doi.org/10.1016/j.phytochem.2016.09.006] [PMID:  27665149] 
[9] 
Jung, H.K.; Kim, S.; Park, R.W.; Park, J.Y.; Kim, I.S.; Lee, B. Bladder tumor-targeted delivery of pro-apoptotic peptide for cancer therapy. J. Control. Release,  2016, 235, 259-267.http://dx.doi.org/
[http://dx.doi.org/10.1016/j.jconrel.2016.06.008] [PMID:  27282414] 
[10] 
Wei, G.; Wang, Y.; Huang, X.; Yang, G.; Zhao, J.; Zhou, S. Induction of mitochondrial apoptosis for cancer therapy via dual-targeted cascade-responsive multifunctional micelles. J. Mater. Chem. B Mater. Biol. Med.,  2018, 6(48), 8137-8147.
[http://dx.doi.org/10.1039/C8TB02159G] [PMID:  32254933] 
[11] 
Pfeffer, C.M.; Singh, A.T.K. Apoptosis: A target for anticancer therapy. Int. J. Mol. Sci.,  2018, 19(2), 448.
[http://dx.doi.org/10.3390/ijms19020448] [PMID:  29393886] 
[12] 
Lopez, J.; Tait, S.W.G. Mitochondrial apoptosis: Killing cancer using the enemy within. Br. J. Cancer,  2015, 112(6), 957-962.
[http://dx.doi.org/10.1038/bjc.2015.85] [PMID:  25742467] 
[13] 
Cui, J.W.; Vecchiarelli-Federico, L.M.; Li, Y.J.; Wang, G.J.; Ben-David, Y. Continuous Fli-1 expression plays an essential role in the proliferation and survival of F-MuLV-induced erythroleukemia and human erythroleukemia. Leukemia,  2009, 23(7), 1311-1319.
[http://dx.doi.org/10.1038/leu.2009.20 ] [PMID:  19282832] 
[14] 
Liu, M.; Zhao, X.; Xiao, L.; Liu, G.; Liu, H.; Wang, X.; Feng, X.; Lin, X. Cytotoxicity of the compounds isolated from Pulsatilla chinensis saponins and apoptosis induced by 23-hydroxybetulinic acid. Pharm. Biol.,  2015, 53(1), 1-9.
[http://dx.doi.org/10.3109/13880209.2014.907323] [PMID:  25026337] 
[15] 
Wang, N.; Fan, Y.; Yuan, C.M.; Song, J.; Yao, Y.; Liu, W.; Gajendran, B.; Zacksenhaus, E.; Li, Y.; Liu, J.; Hao, X.J.; Ben-David, Y. Selective ERK1/2 agonists isolated from Melia azedarach with potent anti-leukemic activity. BMC Cancer, 2019, 19(1), 764., 
[http://dx.doi.org/10.1186/s12885-019-5914-8] [PMID: 31375085] 
[16] 
Gajendran, B.; Chinnasamy, A.; Durai, P.; Raman, J.; Ramar, M. Biosynthesis and characterization of silver nanoparticles from Datura inoxia and its apoptotic effect on human breast cancer cell line MCF7. Mater. Lett.,  2014, 122, 98-102.
[http://dx.doi.org/10.1016/j.matlet.2014.02.003] 
[17] 
Gajendran, B.; Durai, P.; Varier, K.M.; Liu, W.; Li, Y.; Rajendran, S.; Nagarathnam, R.; Chinnasamy, A. Green synthesis of silver nanoparticle from Datura inoxia flower extract and its cytotoxic activity. Bionanoscience,  2019, 9(3), 564-572.
[http://dx.doi.org/10.1007/s12668-019-00645-9] 
[18] 
Song, J.; Yuan, C.; Yang, J.; Liu, T.; Yao, Y.; Xiao, X.; Gajendran, B.; Xu, D.; Li, Y.J.; Wang, C.; Liu, W.; Wen, M.; Spaner, D.; Filmus, J.; Zacksenhaus, E.; Zhang, Y.; Hao, X.; Ben-David, Y. Novel flavagline-like compounds with potent Fli-1 inhibitory activity suppress diverse types of leukemia. FEBS J.,  2018, 285(24), 4631-4645.
[http://dx.doi.org/10.1111/febs.14690] [PMID:  30387554] 
[19] 
Liu, T.; Yao, Y.; Zhang, G.; Wang, Y.; Deng, B.; Song, J.; Li, X.; Han, F.; Xiao, X.; Yang, J.; Xia, L.; Li, Y.J.; Plachynta, M.; Zhang, M.; Yan, C.; Mu, S.; Luo, H.; Zacksenhaus, E.; Hao, X.; Ben-David, Y. A screen for Fli-1 transcriptional modulators identifies PKC agonists that induce erythroid to megakaryocytic differentiation and suppress leukemogenesis. Oncotarget,  2017, 8(10), 16728-16743.
[http://dx.doi.org/10.18632/oncotarget.14377] [PMID:  28052010] 
[20] 
Kannan, K.; Jain, S.K. Oxidative stress and apoptosis. Pathophysiology,  2000, 7(3), 153-163.
[http://dx.doi.org/10.1016/S0928-4680(00)00053-5] [PMID:  10996508] 
[21] 
Blagosklonny, M.V. Carcinogenesis, cancer therapy and chemoprevention. Cell Death Differ.,  2005, 12(6), 592-602.
[http://dx.doi.org/10.1038/sj.cdd.4401610] [PMID:  15818400] 
[22] 
Zhang, Y.; Chen, S.; Wei, C.; Rankin, G.O.; Ye, X.; Chen, Y.C. Flavonoids from Chinese bayberry leaves induced apoptosis and G1 cell cycle arrest via Erk pathway in ovarian cancer cells. Eur. J. Med. Chem.,  2018, 147, 218-226.
[http://dx.doi.org/10.1016/j.ejmech.2018.01.084] [PMID:  29438890] 
[23] 
Haghighi, F.; Matin, M.M.; Bahrami, A.R.; Iranshahi, M.; Rassouli, F.B.; Haghighitalab, A. The cytotoxic activities of 7-isopentenyloxycoumarin on 5637 cells via induction of apoptosis and cell cycle arrest in G2/M stage. Daru,  2014, 22(1), 3.
[http://dx.doi.org/10.1186/2008-2231-22-3] [PMID:  24393601] 
[24] 
Wei, Y.L.; Xu, L.; Liang, Y.; Xu, X.H.; Zhao, X.Y. Berbamine exhibits potent antitumor effects on imatinib-resistant CML cells in vitro and in vivo. Acta Pharmacol. Sin.,  2009, 30(4), 451-457.
[http://dx.doi.org/10.1038/aps.2009.19] [PMID:  19270722] 
[25] 
Ju, D.S.; Kim, M.J.; Bae, J.H.; Song, H.S.; Chung, B.S.; Lee, M.K.; Kang, C.D.; Lee, H.S.; Kim, D.W.; Kim, S.H. Camptothecin acts synergistically with imatinib and overcomes imatinib resistance through Bcr-Abl independence in human K562 cells. Cancer Lett.,  2007, 252(1), 75-85.http://dx.doi.org/
[http://dx.doi.org/10.1016/j.canlet.2006.12.013] [PMID:  17223257] 
[26] 
Tong, H.; Ren, Y.; Zhang, F.; Jin, J. Homoharringtonine affects the JAK2-STAT5 signal pathway through alteration of protein tyrosine kinase phosphorylation in acute myeloid leukemia cells. Eur. J. Haematol.,  2008, 81(4), 259-266.
[http://dx.doi.org/10.1111/j.1600-0609.2008.01116.x] [PMID:  18616510] 
[27] 
Ye, L.L.; Cao, W.K.; Shi, Y.Y.; Deng, Z.K.; Tao, S.D.; Ji, P.; Fu, X.H.; Zong, M.Z.; Li, Y.F. Effect of homoharringtonine on expression of NF-κB and BCL-2 proteins in K562 cells. Zhongguo Shi Yan Xue Ye Xue Za Zhi,  2013, 21(1), 78-81.
[PMID:  23484696] 
[28] 
Shi, D.X.; Ma, L.M.; Lu, Y.J.; Bai, B. Apoptosis-inducing effect of tetrandrine and imatinib on K562/G01 cells and its related mechanism. Zhongguo Shi Yan Xue Ye Xue Za Zhi, 2014, 22(3), 723-728., 
[PMID: 24989284] 
[29] 
Zhang, W.; Zhang, D.; Ma, X.; Liu, Z.; Li, F.; Wu, D. Paris saponin VII suppressed the growth of human cervical cancer Hela cells.Eur. J. Med. Res.,,  2014, 19(1), 41.
[http://dx.doi.org/10.1186/2047-783X-19-41] [PMID: 25128382] 
[30] 
Zhou, H.; Sun, Y.; Zheng, H.; Fan, L.; Mei, Q.; Tang, Y.; Duan, X.; Li, Y. Paris saponin VII extracted from trillium tschonoskii suppresses proliferation and induces apoptosis of human colorectal cancer cells. J. Ethnopharmacol.,  2019, 239111903
[http://dx.doi.org/10.1016/j.jep.2019.111903] [PMID:  31047966] 
[31] 
Yan, T.; Hu, G.; Wang, A.; Sun, X.; Yu, X.; Jia, J. Paris saponin VII induces cell cycle arrest and apoptosis by regulating Akt/MAPK pathway and inhibition of P-glycoprotein in K562/ADR cells. Phytother. Res.,  2018, 32(5), 898-907.
[http://dx.doi.org/10.1002/ptr.6029] [PMID:  29377384] 
[32] 
Fulda, S. Targeting apoptosis signaling pathways for anticancer therapy. Front. Oncol.,  2011, 1(1), 23.
[http://dx.doi.org/10.3389/fonc.2011.00023] [PMID:  22655234] 
[33] 
Green, D.R.; Llambi, F. Cell death signaling. Cold Spring Harb. Perspect. Biol.,  2015, 7(12)a006080
[http://dx.doi.org/10.1101/cshperspect.a006080] [PMID:  26626938] 
[34] 
Liu, L.; Yim, H.; Choi, J.H.; Kim, S.T.; Jin, Y.; Lee, S.K. ATM kinase promotes both caspase-8 and caspase-9 activation during TNF-α-induced apoptosis of HeLa cells. FEBS Lett.,  2014, 588(6), 929-935.
[http://dx.doi.org/10.1016/j.febslet.2014.01.050] [PMID:  24530529] 
[35] 
Schug, Z.T.; Gonzalvez, F.; Houtkooper, R.H.; Vaz, F.M.; Gottlieb, E. BID is cleaved by caspase-8 within a native complex on the mitochondrial membrane. Cell Death Differ.,  2011, 18(3), 538-548.
[http://dx.doi.org/10.1038/cdd.2010.135] [PMID:  21072056] 
[36] 
Fan, Y.; Guo, D.Y.; Song, Q.; Li, T. Effect of total saponin of aralia taibaiensis on proliferation of leukemia cells. Zhong Yao Cai,  2013, 36(4), 604-607.
[PMID:  24134011] 
[37] 
Yuan, J.; Lovejoy, D.B.; Richardson, D.R. Novel di-2-pyridyl-derived iron chelators with marked and selective antitumor activity: In vitro and in vivo assessment. Blood,  2004, 104(5), 1450-1458.
[http://dx.doi.org/10.1182/blood-2004-03-0868] [PMID:  15150082] 
[38] 
Qi, J.; Liang, S.; Gou, Y.; Zhang, Z.; Zhou, Z.; Yang, F.; Liang, H. Synthesis of four binuclear copper(II) complexes: Structure, anticancer properties and anticancer mechanism. Eur. J. Med. Chem.,  2015, 96(2), 360-368.
[http://dx.doi.org/10.1016/j.ejmech.2015.04.031] [PMID:  25899339] 
[39] 
Tao, H.; Qian, P.; Lu, J.; Guo, Y.; Zhu, H.; Wang, F. Autophagy inhibition enhances radiosensitivity of Eca 109 cells via the mitochondrial apoptosis pathway. Int. J. Oncol.,  2018, 52(6), 1853-1862.
[http://dx.doi.org/10.3892/ijo.2018.4349] [PMID:  29620258] 
[40] 
Adams, J.M. Ways of dying: Multiple pathways to apoptosis. Genes Dev.,  2003, 17(20), 2481-2495.
[http://dx.doi.org/10.1101/gad.1126903] [PMID:  14561771] 
[41] 
Lan, J.; Huang, L.; Lou, H.; Chen, C.; Liu, T.; Hu, S.; Yao, Y.; Song, J.; Luo, J.; Liu, Y.; Xia, B.; Xia, L.; Zeng, X.; Ben-David, Y.; Pan, W. Design and synthesis of novel C14-urea-tetrandrine derivatives with potent anti-cancer activity. Eur. J. Med. Chem.,  2018, 143, 1968-1980.
[http://dx.doi.org/10.1016/j.ejmech.2017.11.007] [PMID:  29133049] 
[42] 
Zaman, S.; Wang, R.; Gandhi, V. Targeting the apoptosis pathway in hematologic malignancies. Leuk. Lymphoma,  2014, 55(9), 1980-1992.
[http://dx.doi.org/10.3109/10428194.2013.855307] [PMID:  24295132] 
[43] 
Pustylnikov, S.; Costabile, F.; Beghi, S.; Facciabene, A. Targeting mitochondria in cancer: Current concepts and immunotherapy approaches. Transl. Res.,  2018, 202, 35-51.http://dx.doi.org/
[http://dx.doi.org/10.1016/j.trsl.2018.07.013] [PMID:  30144423] 
[44] 
Xu, W.; Mi, Y.; He, P.; He, S.; Niu, L. γ-tocotrienol inhibits proliferation and induces apoptosis via the mitochondrial pathway in human cervical cancer HeLa cells. Molecules,  2017, 22(8), 1299.
[http://dx.doi.org/10.3390/molecules22081299] [PMID:  28777347] 
[45] 
Soriano, M.E.; Scorrano, L. The interplay between BCL-2 family proteins and mitochondrial morphology in the regulation of apoptosis.In: BCL-2 Protein Family. Advances in Experimental Medicine and Biology; Hetz, C., Ed.; Springer: New York, 2010, Vol. 687, . 
[http://dx.doi.org/10.1007/978-1-4419-6706-0_6] 
[46] 
Chow, L.M.; Chui, C.H.; Tang, J.C.; Teo, I.T.; Lau, F.Y.; Cheng, G.Y.; Wong, R.S.; Leung, T.W.; Lai, K.B.; Yau, M.Y.; Gou, D.; Chan, A.S. Gleditsia sinensis fruit extract is a potential chemotherapeutic agent in chronic and acute myelogenous leukemia. Oncol. Rep.,  2003, 10(5), 1601-1607.
[http://dx.doi.org/10.3892/or.10.5.1601] [PMID:  12883747] 
[47] 
Bhujade, A.; Gupta, G.; Talmale, S.; Das, S.K.; Patil, M.B. Induction of apoptosis in A431 skin cancer cells by Cissus quadrangularis Linn stem extract by altering Bax-Bcl-2 ratio, release of cytochrome c from mitochondria and PARP cleavage. Food Funct.,  2013, 4(2), 338-346.http://dx.doi.org/
[http://dx.doi.org/10.1039/C2FO30167A] [PMID:  23175101] 

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DOI https://dx.doi.org/10.2174/1871520620666200615134039	Print ISSN 1871-5206
Publisher Name Bentham Science Publisher	Online ISSN 1875-5992

Anti-Cancer Agents in Medicinal Chemistry

Paris Saponin VII Induces Apoptosis and Cell Cycle Arrest in Erythroleukemia Cells by a Mitochondrial Membrane Signaling Pathway

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