Effect of Cryptotanshinone on Tumor Microenvironment of Diffuse Large B Cell Lymphoma Xenograft Model Mice by Inhibiting STAT3 Phosphorylation
WANG Li-pei1,2, JIN Chao-ying3, WANG Yi-qi3, LI Tian-yi3, ZHANG Shui-juan3, XIONG Yang3*
1. School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou 311121, China; 2. Key Laboratory of Ageing and Cancer Biology of Zhejiang Province, Institute of Ageing Research, School of Medicine, Hangzhou Normal University, Hangzhou 311121, China; 3. School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China
Abstract：OBJECTIVE To investigate the effect of cryptotanshinone on tumor microenvironment(TME) and its possible molecular mechanism in mice with diffuse large B cell lymphoma(DLBCL) based on STAT3 phosphorylation. METHODS The model of xenograft tumor was established by SUDHL-4 cell line(DLBCL) in NOD-SCID mice. The model mice were divided into model group, cryptotanshinone low-dose group and high-dose group. The tumor volumes were measured twice a week, and the mice were killed after 17 days, the weights of the mice and the tumor were measured, the expression of inflammatory factors and CCL2 in peripheral blood were detected by Elisa, the levels of STAT3 protein and its phosphorylation in the xenograft tumor were detected by Western blot, the expression of VEGF was observed by immunohistochemistry, and the mRNA levels of E-cadherin, MMP9 and Vimentin were detected by real-time PCR. RESULTS The results showed that the volume and weight of the xenograft tumors in the low and high-dose groups were significantly lower than model group, while the effect was more pronounced in the high-dose group(P<0.001,P<0.01 or P<0.05), and the expressions of IL-6, IL-10, TGF-β and CCL2 in the low and high-dose groups were significantly lower than model group, while IL-12 showed the opposite trend, also the high-dose group was more pronounced(P<0.001, P<0.01 or P<0.05). The expressions of p-STAT3, VEGF and the most of EMT markers in the low and high-dose group were significantly lower than model group, and the high-dose group still has the best effect(P<0.001, P<0.01 or P<0.05). CONCLUSION Cryptotanshinone can inhibit the growth of xenograft tumor in DLBCL mice, which may be related to the changes of TME, including suppression of STAT3 phosphorylation and subsequent down-regulation of tumor-associated inflammatory cytokines, chemokine CCL2, VEGF expression, and EMT markers.
汪丽佩, 金超英, 王一奇,李天一, 张水娟, 熊阳. 隐丹参酮抑制STAT3磷酸化改变弥漫大B细胞淋巴瘤移植瘤肿瘤微环境作用的研究[J]. 中国药学杂志, 2023, 58(8): 683-688.
WANG Li-pei, JIN Chao-ying, WANG Yi-qi, LI Tian-yi, ZHANG Shui-juan, XIONG Yang. Effect of Cryptotanshinone on Tumor Microenvironment of Diffuse Large B Cell Lymphoma Xenograft Model Mice by Inhibiting STAT3 Phosphorylation. Chinese Pharmaceutical Journal, 2023, 58(8): 683-688.
QIN W, FU D, SHI Q, et al. Molecular heterogeneity in localized diffuse large B-cell lymphoma. Front Oncol, 2021, 11: 638757. Doi: 10.3389/fonc.2021.638757.
[2]
ZHU F, WANG K B, RUI L. STAT3 activation and oncogenesis in lymphoma. Cancers(Basel), 2019, 12(1): 19. Doi: 10.3390/cancers12010019.
[3]
POLAK K L, CHERNOSKY N M, SMIGIEL J M, et al. Balancing STAT activity as a therapeutic strategy. Cancers(Basel), 2019, 11(11): 1716.Doi: 10.3390/cancers11111716.
[4]
WANG Y Q, HUO H J, LU L L, et al. SUDHL-4 cell culture in vitro and establishment of mouse tumor model. Chin J Exp Hematol(中国实验血液学杂志),2012,20(2):329-334.
[5]
DAVIS R E, NGO V N, LENZ G, et al. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature, 2010, 463(7277): 88-92.
[6]
CHAO C, CHIU V, XU L, et al. Survival differences by race/ethnicity and neighborhood socioeconomic status in adolescents and young adults diagnosed with non-Hodgkin lymphoma. J Adolesc Young Adult Oncol, 2015, 4(2): 76-83.
[7]
MIZOWAKI T, SASAYAMA T, TANAKA K, et al. STAT3 activation is associated with cerebrospinal fluid interleukin-10(IL-10) in primary central nervous system diffuse large B cell lymphoma. J Neurooncol, 2015, 124(2): 165-174.
[8]
TEO A E, CHEN Z, MIRANDA R N, et al. Differential PAX5 levels promote malignant B-cell infiltration, progression and drug resistance, and predict a poor prognosis in MCL patients independent of CCND1. Leukemia, 2016, 30(3): 580-593.
[9]
SONG L, LI Y J, XING X M, et al. Expression and significance of leptin receptor, p-STAT3 and p-AKT in diffuse large B-cell lymphoma. Acta Higtochem, 2014, 116(1): 126-130.
[10]
VAJPAYEE N, HUSSAIN J, TOLOCOCA I, et al. Expression of signal transducer and activator of transcription 3(STAT3) in primary central nervous system diffuse large B-cell lymphoma: a retrospective analysis of 17 cases. J Neuron oncol, 2010, 100(2): 249-253.
[11]
HAN L, CHEN G D, ZENG S S, et al. TNF-α-inducing protein of Helicobacter pylori induces epithelialmesenchymal transition(EMT) in gastric cancer cells through activating IL-6/STAT3 signaling pathway. J Immunol(免疫学杂志),2019,35(2):105-111.
[12]
SHI X M, LIU Y P, QU D, et al. Research progress of anti-tumor components of traditional Chinese medicine inhibiting the expression of HIF-1α. Acta Pharmacol Sin B(药学学报),2021,56(10):2689-2719.
[13]
XIONG A, YANG Z, SHEN Y, et al. Transcription factor STAT3 as a novel molecular target for cancer prevention. Cancers(Basel), 2014, 6(2): 926-957.
[14]
HPKEN UE, REHM A. Targeting the Tumor Microenvironment of Leukemia and Lymphoma. Trends Cancer, 2019, 5(6): 351-364.
[15]
WANG Y, LI Y Q, CHAI Y. Can CCL2 be a potential therapeutic target for multiple myeloma? . Chin J Immunol(中国免疫学杂志), 2021:1-16.. http://kns.cnki.net/kcms/detail/22.1126.R.20211207.0146.002.html.
[16]
ATRI C, GUERFALI F Z, LAOUINI D. Role of human macrophage polarization in inflammation during infectious diseases. Int J Mol Sci, 2018, 19(6): 1801.Doi: 10.3390/ijms 19061801.
[17]
VERDEIL G, LAWRENCE T, SCHMITT-VERHULST A M, et al. Targeting STAT3 and STAT5 in tumor-associated immune cells to improve immunotherapy. Cancers(Basel), 2019, 11(12): 1832. Doi: 10.3390/cancers11121832.
[18]
FENG K R, LI W X, WANG X Y, et al. Chemical components and pharmacological action for Salviae Miltiorrhizae Radix et Rhizoma and predictive analysis on quality markers. Chin Tradit Herb Drugs(中草药),2022,53(2):609-618.
[19]
DU W, WEI Y H, ZHAO G, et al. Simultaneous determination of four tanshinones in rat plasma by high performance liquid chromatography and its application to pharmacokinetic studies . Chin Pharm J(中国药学杂志),2008,43(10):786-789.
[20]
LIU H, XIA L J, LI J Y, et al. Inhibitory effects and mechanisms of cryptotanshinone on the growth of tamoxifen resistant breast cancer cells. Acta Pharmacol Sin B(药学学报 英文版), 2022,57(9):2751-2758.
2023, Vol. 58 
