Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 393, Issue 2, pp 273–286 | Cite as

Chrysophanol suppresses growth and metastasis of T cell acute lymphoblastic leukemia via miR-9/PD-L1 axis

  • Junjie Yin
  • Qingsong YinEmail author
  • Bo Liang
  • Ruihua Mi
  • Hao Ai
  • Lin Chen
  • Xudong Wei
Original Article


T cell acute lymphoblastic leukemia (T-ALL) was a malignant lymphoma. Therefore, the development of novel therapeutic agents against T-ALL is imperative. Previous studies have shown that chrysophanol (CHL), an anthraquinone compound isolated from the Rheum palmatum L., exerts anti-proliferative and anti-metastatic effects in multiple malignant tumors. However, the effect of CHL on the progression of TALL is poorly understood. The aim of this study was to explore the role of CHL in the biological behavior of T-ALL cells and determine its underlying mechanism. Both T-ALL cell lines (Jurkat and TALL-104) were treated with CHL. The proliferation, apoptosis, migration, and invasion of T-ALL cells were determined by CCK-8, flow cytometry, wound healing, and Transwell assay, respectively. Western blot and RT-qPCR were applied to examine gene expression. The dual-luciferase reporter gene assay was employed to examine the regulation mechanism of miR-9 and PD-L1. A T-ALL xenograft model also was used to examine the effect of CHL on the tumor growth and metastasis in vivo. CHL treatment significantly inhibited the proliferation, migration, and invasion ability of both Jurkat and TALL-104 cells and induced cell apoptosis and the expression of miR-9. Moreover, miR-9 was proved to target PD-L1 by binding to its 3′-untranslated region (UTR). Mechanically, pretreated with PD-L1 inhibitor could augment the anti-proliferation and anti-metastatic effect of CHL, while miR-9-silenced alleviated this effect. Consistent with in vitro studies, CHL significantly suppressed the growth and metastasis of tumor in vivo. Our finding uncovers the antitumorigenic effect of CHL in T-ALL progression through upregulating the expression of miR-9 and suppressing PD-L1 expression, which may provide a new potential strategy for T-ALL clinical treatment.


T cell acute lymphoblastic leukemia Chrysophanol miR-9 PD-L1 Growth and metastasis 


Authors’ contribution

Qingsong Yin and Xudong Wei provided the fund and designed the project.

Junjie Yin performed the experiences and wrote the paper.

Bo Liang and Ruihua Mi performed the experiences.

Hao Ai and Lin Chen collected and analyzed the data.

Funding information

The study was funded by the Natural Science Foundation of China (No. 81170520).

Compliance with ethical standards

Conflict of interest

The authors declare no competing interests.


  1. Abdul Wahid SF, Ismail NA, Mohd-Idris MR, Jamaluddin FW, Tumian N, Sze-Wei EY, Muhammad N, Nai ML (2014) Comparison of reduced-intensity and myeloablative conditioning regimens for allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia and acute lymphoblastic leukemia: a meta-analysis. Stem Cells Dev 23:2535–2552PubMedPubMedCentralGoogle Scholar
  2. Anastasiadou E, Stroopinsky D, Alimperti S, Jiao AL, Pyzer AR, Cippitelli C, Pepe G, Severa M, Rosenblatt J, Etna MP, Rieger S, Kempkes B, Coccia EM, Sui SJH, Chen CS, Uccini S, Avigan D, Faggioni A, Trivedi P, Slack FJ (2019) Epstein-Barr virus-encoded EBNA2 alters immune checkpoint PD-L1 expression by downregulating miR-34a in B-cell lymphomas. Leukemia 33:132–147PubMedGoogle Scholar
  3. Ashizawa M, Okayama H, Ishigame T, Thar Min AK, Saito K, Ujiie D, Murakami Y, Kikuchi T, Nakayama Y, Noda M, Tada T, Endo H, Fujita S, Sakamoto W, Saito M, Saze Z, Momma T, Ohki S, Mimura K, Kono K (2019) miRNA-148a-3p regulates immunosuppression in DNA mismatch repair-deficient colorectal Cancer by targeting PD-L1. Mol Cancer Res 17:1403–1413PubMedGoogle Scholar
  4. Bai J, Wu J, Tang R, Sun C, Ji J, Yin Z, Ma G, Yang W (2019). Emodin, a natural anthraquinone, suppresses liver cancer in vitro and in vivo by regulating VEGFR2 and miR-34a. Investig New DrugsGoogle Scholar
  5. Chen YC, Shen SC, Lee WR, Hsu FL, Lin HY, Ko CH, Tseng SW (2002) Emodin induces apoptosis in human promyeloleukemic HL-60 cells accompanied by activation of caspase 3 cascade but independent of reactive oxygen species production. Biochem Pharmacol 64:1713–1724PubMedGoogle Scholar
  6. Choi JS (2016) Chrysophanic acid induces necrosis but not Necroptosis in human renal cell carcinoma Caki-2 cells. J Cancer Prev 21:81–87PubMedPubMedCentralGoogle Scholar
  7. Darzynkiewicz Z, Carter SP, Kapuscinski J, Watanabe KA (1989) Effect of derivatives of chrysophanol, a new type of potential antitumor agents of anthraquinone family, on growth and cell cycle of L1210 leukemic cells. Cancer Lett 46:181–187PubMedGoogle Scholar
  8. Deng M, Xue YJ, Xu LR, Wang QW, Wei J, Ke XQ, Wang JC, Chen XD (2019) Chrysophanol suppresses hypoxia-induced epithelial-Mesenchymal transition in colorectal Cancer cells. Anat Rec (Hoboken) 302:1561–1570Google Scholar
  9. Deng X, Tu Z, Xiong M, Tembo K, Zhou L, Liu P, Pan S, Xiong J, Yang X, Leng J, Zhang Q, Xiao R, Zhang Q (2017) Wnt5a and CCL25 promote adult T-cell acute lymphoblastic leukemia cell migration, invasion and metastasis. Oncotarget 8:39033–39047PubMedPubMedCentralGoogle Scholar
  10. Giebel S, Czyz A, Ottmann O, Baron F, Brissot E, Ciceri F, Cornelissen JJ, Esteve J, Gorin NC, Savani B, Schmid C, Mohty M, Nagler A (2016) Use of tyrosine kinase inhibitors to prevent relapse after allogeneic hematopoietic stem cell transplantation for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: a position statement of the acute leukemia working Party of the European Society for blood and marrow transplantation. Cancer 122:2941–2951PubMedGoogle Scholar
  11. Guo F, Hou X, Sun Q (2018) MicroRNA-9-5p functions as a tumor suppressor in papillary thyroid cancer via targeting BRAF. Oncol Lett 16:6815–6821PubMedPubMedCentralGoogle Scholar
  12. Han M, Gao H, Xie J, Yuan YP, Yuan Q, Gao MQ, Liu KL, Chen XH, Han YT, Han ZW (2019) Hispidulin induces ER stress-mediated apoptosis in human hepatocellular carcinoma cells in vitro and in vivo by activating AMPK signaling pathway. Acta Pharmacol Sin 40:666–676PubMedGoogle Scholar
  13. Han Y, Liu Y, Fu X, Zhang Q, Huang H, Zhang C, Li W, Zhang J (2018) miR-9 inhibits the metastatic ability of hepatocellular carcinoma via targeting beta galactoside alpha-2,6-sialyltransferase 1. J Physiol Biochem 74:491–501PubMedGoogle Scholar
  14. Kansagra A, Dahiya S, Litzow M (2018) Continuing challenges and current issues in acute lymphoblastic leukemia. Leuk Lymphoma 59:526–541PubMedGoogle Scholar
  15. Kloten V, Lampignano R, Krahn T, Schlange T (2019) Circulating tumor cell PD-L1 expression as biomarker for therapeutic efficacy of immune checkpoint inhibition in NSCLC. Cells 8Google Scholar
  16. Lee JS, Ruppin E (2019). Multiomics prediction of response rates to therapies to inhibit programmed cell death 1 and programmed cell death 1 ligand 1. JAMA OncolGoogle Scholar
  17. Li X, Chu S, Liu Y, Chen N (2019) Neuroprotective effects of anthraquinones from rhubarb in central nervous system diseases. Evid Based Complement Alternat Med 2019:3790728PubMedPubMedCentralGoogle Scholar
  18. Lim W, An Y, Yang C, Bazer FW, Song G (2018) Chrysophanol induces cell death and inhibits invasiveness via mitochondrial calcium overload in ovarian cancer cells. J Cell Biochem 119:10216–10227PubMedGoogle Scholar
  19. Lim W, Yang C, Bazer FW, Song G (2017) Chrysophanol induces apoptosis of Choriocarcinoma through regulation of ROS and the AKT and ERK1/2 pathways. J Cell Physiol 232:331–339PubMedGoogle Scholar
  20. Liu J, Fan L, Yu H, Zhang J, He Y, Feng D, Wang F, Li X, Liu Q, Li Y, Guo Z, Gao B, Wei W, Wang H, Sun G (2019a) Endoplasmic reticulum stress causes liver Cancer cells to release exosomal miR-23a-3p and up-regulate programmed death ligand 1 expression in macrophages. Hepatology 70:241–258PubMedGoogle Scholar
  21. Liu Y, Lei P, Qiao H, Sun K, Lu X, Bao F, Yu R, Lian C, Li Y, Chen W, Xue F (2019b) miR-9 enhances the chemosensitivity of AML cells to daunorubicin by targeting the EIF5A2/MCL-1 Axis. Int J Biol Sci 15:579–586PubMedPubMedCentralGoogle Scholar
  22. Lu J, Li J, Hu Y, Guo Z, Sun D, Wang P, Guo K, Duan DD, Gao S, Jiang J, Wang J, Liu P (2019) Chrysophanol protects against doxorubicin-induced cardiotoxicity by suppressing cellular PARylation. Acta Pharm Sin B 9:782–793PubMedGoogle Scholar
  23. Lu J, Xu X, Liu X, Peng Y, Zhang B, Wang L, Luo H, Peng X, Li G, Tian W, He M, Li X (2014) Predictive value of miR-9 as a potential biomarker for nasopharyngeal carcinoma metastasis. Br J Cancer 110:392–398PubMedGoogle Scholar
  24. Lu L, Li K, Mao YH, Qu H, Yao B, Zhong WW, Ma B, Wang ZY (2017) Gold-chrysophanol nanoparticles suppress human prostate cancer progression through inactivating AKT expression and inducing apoptosis and ROS generation in vitro and in vivo. Int J Oncol 51:1089–1103PubMedPubMedCentralGoogle Scholar
  25. McCubrey JA, Lertpiriyapong K, Steelman LS, Abrams SL, Yang LV, Murata RM, Rosalen PL, Scalisi A, Neri LM, Cocco L, Ratti S, Martelli AM, Laidler P, Dulinska-Litewka J, Rakus D, Gizak A, Lombardi P, Nicoletti F, Candido S, Libra M, Montalto G, Cervello M (2017) Effects of resveratrol, curcumin, berberine and other nutraceuticals on aging, cancer development, cancer stem cells and microRNAs. Aging (Albany NY) 9:1477–1536Google Scholar
  26. Mittal N, Li L, Sheng Y, Hu C, Li F, Zhu T, Qiao X, Qian Z (2019) A critical role of epigenetic inactivation of miR-9 in EVI1(high) pediatric AML. Mol Cancer 18:30PubMedPubMedCentralGoogle Scholar
  27. Mohammadi-Yeganeh S, Mansouri A, Paryan M (2015) Targeting of miR9/NOTCH1 interaction reduces metastatic behavior in triple-negative breast cancer. Chem Biol Drug Des 86:1185–1191PubMedGoogle Scholar
  28. Mulder TA, Wahlin BE, Osterborg A, Palma M (2019) Targeting the immune microenvironment in lymphomas of B-cell origin: from biology to clinical application. Cancers (Basel) 11Google Scholar
  29. Ni CH, Chen PY, Lu HF, Yang JS, Huang HY, Wu SH, Ip SW, Wu CT, Chiang SY, Lin JG, Wood WG, Chung JG (2012) Chrysophanol-induced necrotic-like cell death through an impaired mitochondrial ATP synthesis in Hep3B human liver cancer cells. Arch Pharm Res 35:887–895PubMedGoogle Scholar
  30. Nourmohammadi B, Tafsiri E, Rahimi A, Nourmohammadi Z, Daneshvar Kakhaki A, Cho W, Karimipoor M (2019) Expression of miR-9 and miR-200c, ZEB1, ZEB2 and E-cadherin in non-small cell lung cancers in Iran. Asian Pac J Cancer Prev 20:1633–1639PubMedGoogle Scholar
  31. Orso F, Quirico L, Dettori D, Coppo R, Virga F, Ferreira LC, Paoletti C, Baruffaldi D, Penna E, Taverna D (2019) Role of miRNAs in tumor and endothelial cell interactions during tumor progression. Semin Cancer BiolGoogle Scholar
  32. Otter SJ, Chatterjee J, Stewart AJ, Michael A (2019) The role of biomarkers for the prediction of response to checkpoint immunotherapy and the rationale for the use of checkpoint immunotherapy in cervical Cancer. Clin Oncol (R Coll Radiol)Google Scholar
  33. Park S, Lim W, Song G (2018) Chrysophanol selectively represses breast cancer cell growth by inducing reactive oxygen species production and endoplasmic reticulum stress via AKT and mitogen-activated protein kinase signal pathways. Toxicol Appl Pharmacol 360:201–211PubMedGoogle Scholar
  34. Park YR, Lee ST, Kim SL, Zhu SM, Lee MR, Kim SH, Kim IH, Lee SO, Seo SY, Kim SW (2019) Down-regulation of miR-9 promotes epithelial mesenchymal transition via regulating anoctamin-1 (ANO1) in CRC cells. Cancer Genet 231-232:22–31PubMedGoogle Scholar
  35. Paul S, Kantarjian H, Jabbour EJ (2016) Adult acute lymphoblastic leukemia. Mayo Clin Proc 91:1645–1666PubMedGoogle Scholar
  36. Refae S, Gal J, Ebran N, Otto J, Borchiellini D, Peyrade F, Chamorey E, Brest P, Milano G, Saada-Bouzid E (2019) Germinal immunogenetics predict treatment outcome for PD-1/PD-L1 checkpoint inhibitors. Investig New DrugsGoogle Scholar
  37. Richardsen E, Andersen S, Al-Saad S, Rakaee M, Nordby Y, Pedersen MI, Ness N, Ingebriktsen LM, Fassina A, Tasken KA, Mills IG, Donnem T, Bremnes RM, Busund LT (2019) Low expression of miR-424-3p is highly correlated with clinical failure in prostate Cancer. Sci Rep 9:10662PubMedPubMedCentralGoogle Scholar
  38. Roolf C, Saleweski JN, Stein A, Richter A, Maletzki C, Sekora A, Escobar HM, Wu XF, Beller M, Junghanss C (2019). Novel isoquinolinamine and isoindoloquinazolinone compounds exhibit antiproliferative activity in acute lymphoblastic leukemia cells. Biomol Ther (Seoul): 492–501Google Scholar
  39. Setti Boubaker N, Cicchillitti L, Said R, Gurtner A, Ayed H, Blel A, Karray O, Essid MA, Gharbi M, Bouzouita A, Rammeh Rommeni S, Chebil M, Piaggio G, Ouerhani S (2019) The clinical and prognostic value of miR-9 gene expression in Tunisian patients with bladder cancer. Mol Biol RepGoogle Scholar
  40. Song G, Zhang Y, Yu S, Lv W, Guan Z, Sun M, Wang J (2019) Chrysophanol attenuates airway inflammation and remodeling through nuclear factor-kappa B signaling pathway in asthma. Phytother Res 33:2702–2713PubMedGoogle Scholar
  41. Sun Y, Yu W, Guan W, Cai L, Qiao M, Zheng L, Jiang R, Wang R, Wang L (2019) Integrated assessment of PD-L1 expression and molecular classification facilitates therapy selection and prognosis prediction in gastric cancer. Cancer Manag Res 11:6397–6410PubMedPubMedCentralGoogle Scholar
  42. Tao F, Zhang Y, Zhang Z (2019) The role of herbal bioactive components in mitochondria function and Cancer therapy. Evid Based Complement Alternat Med 2019:3868354PubMedPubMedCentralGoogle Scholar
  43. Tegelberg A, Kopp S (1988) Skin surface temperature over the masseter muscle in individuals with rheumatoid arthritis. Acta Odontol Scand 46:151–158PubMedGoogle Scholar
  44. Tetik Vardarli A, Duzgun Z, Erdem C, Kaymaz BT, Eroglu Z, Cetintas VB (2018) Matrine induced G0/G1 arrest and apoptosis in human acute T-cell lymphoblastic leukemia (T-ALL) cells. Bosn J Basic Med Sci 18:141–149PubMedGoogle Scholar
  45. Touat M, Maisonobe T, Knauss S, Ben Hadj Salem O, Hervier B, Aure K, Szwebel TA, Kramkimel N, Lethrosne C, Bruch JF, Laly P, Cadranel J, Weiss N, Behin A, Allenbach Y, Benveniste O, Lenglet T, Psimaras D, Stenzel W, Leonard-Louis S (2018) Immune checkpoint inhibitor-related myositis and myocarditis in patients with cancer. Neurology 91:e985–e994PubMedGoogle Scholar
  46. Trinh TA, Lee D, Park S, Kim SH, Park JG, Kim JH, Kang KS (2019) Stilbenes contribute to the anticancer effects of Rheum undulatum L. through activation of apoptosis. Oncol Lett 17:2953–2959PubMedPubMedCentralGoogle Scholar
  47. Ultimo S, Martelli AM, Zauli G, Vitale M, Calin GA, Neri LM (2018) Roles and clinical implications of microRNAs in acute lymphoblastic leukemia. J Cell Physiol 233:5642–5654PubMedGoogle Scholar
  48. Vadillo E, Dorantes-Acosta E, Pelayo R, Schnoor M (2018) T cell acute lymphoblastic leukemia (T-ALL): new insights into the cellular origins and infiltration mechanisms common and unique among hematologic malignancies. Blood Rev 32:36–51PubMedGoogle Scholar
  49. Versteven M, Van den Bergh JMJ, Marcq E, Smits ELJ, Van Tendeloo VFI, Hobo W, Lion E (2018) Dendritic cells and programmed death-1 blockade: a joint venture to combat cancer. Front Immunol 9:394PubMedPubMedCentralGoogle Scholar
  50. Wei W, Dong Z, Gao H, Zhang YY, Shao LH, Jin LL, Lv YH, Zhao G, Shen YN, Jin SZ (2019) MicroRNA-9 enhanced radiosensitivity and its mechanism of DNA methylation in non-small cell lung cancer. Gene 710:178–185PubMedGoogle Scholar
  51. Xie L, Tang H, Song J, Long J, Zhang L, Li X (2019a) Chrysophanol: a review of its pharmacology, toxicity and pharmacokinetics. J Pharm Pharmacol 71:1475–1487PubMedGoogle Scholar
  52. Xie Q, Lin S, Zheng M, Cai Q, Tu Y (2019b) Long noncoding RNA NEAT1 promotes the growth of cervical cancer cells via sponging miR-9-5p. Biochem Cell Biol 97:100–108PubMedGoogle Scholar
  53. Yang XY, Sheng Y (2019) MiR-101 represses T-cell acute lymphoblastic leukemia by targeting CXCR7/STAT3 axis. Oncol ResGoogle Scholar
  54. Zang Y, Yu R, Bai Y, Chen X (2018) MicroRNA-9 suppresses cancer proliferation and cell cycle progression in acute lymphoblastic leukemia with inverse association of neuropilin-1. J Cell Biochem 119:6604–6613PubMedGoogle Scholar
  55. Zhai B, Zhang N, Han X, Li Q, Zhang M, Chen X, Li G, Zhang R, Chen P, Wang W, Li C, Xiang Y, Liu S, Duan T, Lou J, Xie T, Sui X (2019) Molecular targets of beta-elemene, a herbal extract used in traditional Chinese medicine, and its potential role in cancer therapy: a review. Biomed Pharmacother 114:108812PubMedGoogle Scholar
  56. Zhang D, Han Y, Xu L (2016) Upregulation of miR-124 by physcion 8-O-beta-glucopyranoside inhibits proliferation and invasion of malignant melanoma cells via repressing RLIP76. Biomed Pharmacother 84:166–176PubMedGoogle Scholar
  57. Zhao Y, Huang Y, Fang Y, Zhao H, Shi W, Li J, Duan Y, Sun Y, Gao L, Luo Y (2018) Chrysophanol attenuates nitrosative/oxidative stress injury in a mouse model of focal cerebral ischemia/reperfusion. J Pharmacol Sci 138:16–22PubMedGoogle Scholar
  58. Zhou WY, Zhang MM, Liu C, Kang Y, Wang JO, Yang XH (2019) Long noncoding RNA LINC00473 drives the progression of pancreatic cancer via upregulating programmed death-ligand 1 by sponging microRNA-195-5p. J Cell Physiol 234:23176–23189PubMedGoogle Scholar
  59. Zhu B, Xi X, Liu Q, Cheng Y, Yang H (2019) MiR-9 functions as a tumor suppressor in acute myeloid leukemia by targeting CX chemokine receptor 4. Am J Transl Res 11:3384–3397PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of HematologyThe Affiliated Cancer Hospital of Zhengzhou UniversityZhengzhou CityChina
  2. 2.Department of HematologyThe Central Hospital of XinxiangXinxiang CityChina

Personalised recommendations