Pulsatilla saponin A Inhibits Proliferation and Induces Apoptosis in Diffuse Large Bcell Lymphoma Cells through the JAK2/STAT3 Signaling Pathway

Page: [2035 - 2041] Pages: 7

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Abstract

Objectives: This study aimed to investigate the performance of Pulsatilla saponin A (PsA) in diffuse large B-cell lymphoma (DLBCL) cells.

Methods: Proliferation, ELISA, apoptosis, cell cycle analysis, and assays were carried out to detect the growth and apoptosis in DLBCL cells. Western blotting was used to identify the change in the protein.

Results: In cell assays, PsA significantly inhibited the growth and apoptosis in DLBCL cells. The IL-10 and TNF-α of OCI-LY10 and U2932 cells were reduced after 24 h PsA treatment. Bax, cleaved PARP, and cleaved Caspase-3 were increased, while Bcl-2 and C-Myc decreased after PsA treatment. IL-10 may regulate the expression of C-Myc protein in cells by activating the JAK2/STAT3 signaling pathway. PsA can inhibit the overexpression of p-JAK2 and p- STAT3 signaling pathways induced by IL-10 stimulants. The proliferation and apoptosis induced by PsA were confirmed in DLBCL cells.

Conclusion: Our findings revealed that PsA may exert its antitumor effect by causing G1 arrest and apoptosis in DLBCL cells. The mechanism of PsA regulating apoptosis in DLBCL cells is probably through the JAK2/STAT3 signaling pathway in vitro.

Graphical Abstract

[1]
Ames, A.; Lee, D. Updates in the diffuse large B-Cell lymphoma treatment landscape. J. Adv. Pract. Oncol., 2022, 13(3), 341-344.
[http://dx.doi.org/10.6004/jadpro.2022.13.3.33] [PMID: 35663173]
[2]
Ding, W.; Zhao, S.; Wang, J.; Yang, Q.; Sun, H.; Yan, J.; Gao, L.; Yao, W.; Zhang, W.; Liu, W. Gastrointestinal lymphoma in southwest China: Subtype distribution of 1,010 cases using the WHO (2008) classification in a single institution. Acta Haematol., 2016, 135(1), 21-28.
[http://dx.doi.org/10.1159/000437130] [PMID: 26303279]
[3]
Bobillo, S.; Joffe, E.; Lavery, J.A.; Sermer, D.; Ghione, P.; Noy, A.; Caron, P.C.; Hamilton, A.; Hamlin, P.A.; Horwitz, S.M.; Kumar, A.; Matasar, M.J.; Moskowitz, A.; Owens, C.N.; Palomba, M.L.; Batlevi, C.L.; Straus, D.; von Keudell, G.; Zelenetz, A.D.; Yahalom, J.; Dogan, A.; Seshan, V.E.; Younes, A. Clinical characteristics and outcomes of extranodal stage I diffuse large B-cell lymphoma in the rituximab era. Blood, 2021, 137(1), 39-48.
[http://dx.doi.org/10.1182/blood.2020005112] [PMID: 32730585]
[4]
Ollila, T.A.; Olszewski, A.J. Extranodal diffuse large B cell lymphoma: Molecular features, prognosis, and risk of central nervous system recurrence. Curr. Treat. Options Oncol., 2018, 19(8), 38.
[http://dx.doi.org/10.1007/s11864-018-0555-8] [PMID: 29931605]
[5]
Tamma, R.; Ingravallo, G.; Gaudio, F.; Annese, T.; Albano, F.; Ruggieri, S.; Dicataldo, M.; Maiorano, E.; Specchia, G.; Ribatti, D. STAT3, tumor microenvironment, and microvessel density in diffuse large B cell lymphomas. Leuk. Lymphoma, 2020, 61(3), 567-574.
[http://dx.doi.org/10.1080/10428194.2019.1678154] [PMID: 31623480]
[6]
Schmitt, A.; Xu, W.; Bucher, P.; Grimm, M.; Konantz, M.; Horn, H.; Zapukhlyak, M.; Berning, P.; Brändle, M.; Jarboui, M.A.; Schönfeld, C.; Boldt, K.; Rosenwald, A.; Ott, G.; Grau, M.; Klener, P.; Vockova, P.; Lengerke, C.; Lenz, G.; Schulze-Osthoff, K.; Hailfinger, S. Dimethyl fumarate induces ferroptosis and impairs NF-κB/STAT3 signaling in DLBCL. Blood, 2021, 138(10), 871-884.
[http://dx.doi.org/10.1182/blood.2020009404] [PMID: 33876201]
[7]
Al-Khatib, S.M.; Abdo, N. AL-Eitan, L.N.; Al-Mistarehi, A.H.; Zahran, D.J.; Kewan, T.Z. The impact of IL-6 and IL-10 gene polymorphisms in diffuse large B-Cell lymphoma risk and overall survival in an arab population: A case-control study. Cancers, 2020, 12(2), 382.
[http://dx.doi.org/10.3390/cancers12020382] [PMID: 32046104]
[8]
Li, P.; Chai, J.; Chen, Z.; Liu, Y.; Wei, J.; Liu, Y.; Zhao, D.; Ma, J.; Wang, K.; Li, X.; Shao, Y.; Gong, L.; Zhang, W.; Guo, S.; Yan, Q.; Li, M.; Fan, L.; Wang, Z. Genomic mutation profile of primary gastrointestinal diffuse large B-cell lymphoma. Front. Oncol., 2021, 11, 622648.
[http://dx.doi.org/10.3389/fonc.2021.622648] [PMID: 33747936]
[9]
Phillips, F.; Verstockt, B.; Ribaldone, D.G.; Guerra, I.; Teich, N.; Katsanos, K.; Filip, R.; Molnar, T.; Karmiris, K.; Kopylov, U.; Ellul, P.; Sanchez, M.C.; Goren, I.; Gecse, K.; Beaugerie, L.; Bossuyt, P.; Sebastian, S. Diagnosis and outcome of extranodal primary intestinal lymphoma in inflammatory bowel disease: An ECCO CONFER case series. J. Crohn’s Colitis, 2022, 16(3), 500-505.
[http://dx.doi.org/10.1093/ecco-jcc/jjab164]
[10]
Guan, Z.; Chen, L.; Zhou, Y.; Luo, Y.; Cui, Y.; Liu, R.; Shou, B. The synergistic antitumour effect of multi-components from Pulsatilla chinensis saponins in NCI-H460 lung cancer cell line through induction of apoptosis. Pharm. Biol., 2020, 58(1), 427-437.
[http://dx.doi.org/10.1080/13880209.2020.1761404] [PMID: 32476531]
[11]
Ye, W.; Zhang, Q.; Hsiao, W.W.; Zhao, S.; Che, C.T. New lupane glycosides from Pulsatilla chinensis. Planta Med., 2002, 68(2), 183-186.
[http://dx.doi.org/10.1055/s-2002-20254] [PMID: 11859478]
[12]
Hong, S.W.; Jung, K.H.; Lee, H.S.; Choi, M.J.; Son, M.K.; Zheng, H.M.; Hong, S.S. SB365 inhibits angiogenesis and induces apoptosis of hepatocellular carcinoma through modulation of PI3K/Akt/mTOR signaling pathway. Cancer Sci., 2012, 103(11), 1929-1937.
[http://dx.doi.org/10.1111/j.1349-7006.2012.02409.x] [PMID: 22909393]
[13]
Son, M.K.; Jung, K.H.; Hong, S.W.; Lee, H.S.; Zheng, H.M.; Choi, M.J.; Seo, J.H.; Suh, J.K.; Hong, S.S. SB365, Pulsatilla saponin D suppresses the proliferation of human colon cancer cells and induces apoptosis by modulating the AKT/mTOR signalling pathway. Food Chem., 2013, 136(1), 26-33.
[http://dx.doi.org/10.1016/j.foodchem.2012.07.096] [PMID: 23017388]
[14]
Ye, B.; Zhou, Y.; Liu, Y.; Li, X.; Li, T.; Qi, X. Pulsatilla saponin A induces apoptosis and differentiation of myeloma cells. Anticancer. Agents Med. Chem., 2021, 21(7), 919-926.
[http://dx.doi.org/10.2174/1871520620666200721125036] [PMID: 32698748]
[15]
Liu, J.; Zhang, L.; Wang, Z.; Chen, S.; Feng, S.; He, Y.; Zhang, S. Network pharmacology-based strategy to identify the pharmacological mechanisms of Pulsatilla decoction against crohn’s disease. Front. Pharmacol., 2022, 13, 844685.
[http://dx.doi.org/10.3389/fphar.2022.844685] [PMID: 35450039]
[16]
Wang, S.; Tang, S.; Chen, X.; Li, X.; Jiang, S.; Li, H.; Jia, P.; Song, M.; Di, P.; Li, W. Pulchinenoside B4 exerts the protective effects against cisplatin-induced nephrotoxicity through NF-κB and MAPK mediated apoptosis signaling pathways in mice. Chem. Biol. Interact., 2020, 331, 109233.
[http://dx.doi.org/10.1016/j.cbi.2020.109233] [PMID: 32991863]
[17]
Li, Y.; Zou, M.; Han, Q.; Deng, L.; Weinshilboum, R.M. Therapeutic potential of triterpenoid saponin anemoside B4 from Pulsatilla chinensis. Pharmacol. Res., 2020, 160, 105079.
[http://dx.doi.org/10.1016/j.phrs.2020.105079] [PMID: 32679180]
[18]
Künstner, A.; Witte, H.M.; Riedl, J.; Bernard, V.; Stölting, S.; Merz, H.; Olschewski, V.; Peter, W.; Ketzer, J.; Busch, Y.; Trojok, P.; Bubnoff, N.; Busch, H.; Feller, A.C.; Gebauer, N. Mutational landscape of high-grade B-cell lymphoma with MYC-, BCL2 and/or BCL6 rearrangements characterized by whole-exome sequencing. Haematologica, 2021, 107(8), 1850-1863.
[http://dx.doi.org/10.3324/haematol.2021.279631] [PMID: 34788985]
[19]
Fei, Y.; Yu, J.; Li, Y.; Li, L.; Zhou, S.; Zhang, T.; Li, L.; Qiu, L.; Meng, B.; Pan, Y.; Ren, X.; Qian, Z.; Wang, X.; Zhang, H. Plasma soluble PD-L1 and STAT3 predict the prognosis in diffuse large B cell lymphoma patients. J. Cancer, 2020, 11(23), 7001-7008.
[http://dx.doi.org/10.7150/jca.47816] [PMID: 33123290]
[20]
Barbarino, V.; Henschke, S.; Blakemore, S.; Izquierdo, E.; Michalik, M.; Nickel, N.; Möllenkotte, I.; Vorholt, D.; Müller, L.; Brinker, R.; Fedorchenko, O.; Mikhael, N.; Seeger-Nukpezah, T.; Hallek, M.; Pallasch, C. Macrophage-mediated antibody dependent effector function in aggressive B-cell lymphoma treatment is enhanced by ibrutinib via inhibition of JAK2. Cancers, 2020, 12(8), 2303.
[http://dx.doi.org/10.3390/cancers12082303] [PMID: 32824276]
[21]
Szydłowski, M.; Garbicz, F.; Jabłońska, E.; Górniak, P.; Komar, D.; Pyrzyńska, B.; Bojarczuk, K.; Prochorec-Sobieszek, M.; Szumera-Ciećkiewicz, A.; Rymkiewicz, G.; Cybulska, M.; Statkiewicz, M.; Gajewska, M.; Mikula, M.; Gołas, A.; Domagała, J.; Winiarska, M.; Graczyk-Jarzynka, A.; Białopiotrowicz, E.; Polak, A.; Barankiewicz, J.; Puła, B.; Pawlak, M.; Nowis, D.; Golab, J.; Tomirotti, A.M.; Brzózka, K.; Pacheco-Blanco, M.; Kupcova, K.; Green, M.R.; Havranek, O.; Chapuy, B.; Juszczyński, P. Inhibition of PIM kinases in DLBCL targets myc transcriptional program and augments the efficacy of anti-CD20 antibodies. Cancer Res., 2021, 81(23), 6029-6043.
[http://dx.doi.org/10.1158/0008-5472.CAN-21-1023] [PMID: 34625423]
[22]
Xu, J.; Liu, J.L.; Medeiros, L.J.; Huang, W.; Khoury, J.D.; McDonnell, T.J.; Tang, G.; Schlette, E.; Yin, C.C.; Bueso-Ramos, C.E.; Lin, P.; Li, S. MYC rearrangement and MYC/BCL2 double expression but not cell-of-origin predict prognosis in R-CHOP treated diffuse large B-cell lymphoma. Eur. J. Haematol., 2020, 104(4), 336-343.
[http://dx.doi.org/10.1111/ejh.13384] [PMID: 31944390]
[23]
Hashiguchi, T.; Bruss, N.; Best, S.; Lam, V.; Danilova, O.; Paiva, C.J.; Wolf, J.; Gilbert, E.W.; Okada, C.Y.; Kaur, P.; Drew, L.; Cidado, J.; Hurlin, P.; Danilov, A.V. Cyclin-dependent kinase-9 is a therapeutic target in MYC-expressing diffuse large B-cell lymphoma. Mol. Cancer Ther., 2019, 18(9), 1520-1532.
[http://dx.doi.org/10.1158/1535-7163.MCT-18-1023] [PMID: 31243099]
[24]
Neves Filho, E.H.; Hirth, C.G.; Frederico, I.A.; Burbano, R.M.; Carneiro, T.; Rabenhorst, S.H. EZH2 expression is dependent on MYC and TP53 regulation in diffuse large B-cell lymphoma. Acta Pathol. Microbiol. Scand. Suppl., 2020, 128(4), 308-315.
[http://dx.doi.org/10.1111/apm.13029] [PMID: 31991488]
[25]
Yi, J.H.; Yoon, S.E.; Ryu, K.J.; Ko, Y.H.; Kim, W.S.; Kim, S.J. Pre-treatment serum IL-10 predicts the risk of secondary central nervous system involvement in patients with diffuse large B-cell lymphoma. Cytokine, 2020, 129, 155048.
[http://dx.doi.org/10.1016/j.cyto.2020.155048] [PMID: 32135464]