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


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Abstract

Objective: 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.

About the authors

Ning Liu

Department of Hematology, Affiliated Hospital of Nanjing University of Chinese Medicine

Email: info@benthamscience.net

Xinzhuo Zhan

Department of Hematology, Affiliated Hospital of Nanjing University of Chinese Medicine

Email: info@benthamscience.net

Jie Bai

Department of Hematology, Affiliated Hospital of Nanjing University of Chinese Medicine

Email: info@benthamscience.net

Hui Yu

Department of Hematology, Affiliated Hospital of Nanjing University of Chinese Medicine

Email: info@benthamscience.net

Xiaoli Chen

Department of Hematology, Affiliated Hospital of Nanjing University of Chinese Medicine

Email: info@benthamscience.net

Xiangtu Kong

Department of Hematology, Affiliated Hospital of Nanjing University of Chinese Medicine

Author for correspondence.
Email: info@benthamscience.net

Haiwen Ni

Department of Hematology, The Affiliated Hospital of Nanjing University of Chinese Medicine

Author for correspondence.
Email: info@benthamscience.net

References

  1. Ames, A.; Lee, D. Updates in the diffuse large B-Cell lymphoma treatment landscape. J. Adv. Pract. Oncol., 2022, 13(3), 341-344. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 10.1016/j.cyto.2020.155048 PMID: 32135464

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