Effect and mechanism of Celastrol in the treatment of renal carcinoma based on network pharmacology and experimental verification
YAN Tao1 GU Jia1¡¡ZHU Neng2¡¡SHI Yaning1 ZHANG Chanjuan1¡¡LI Hongfang1¡¡QIN Li1
1.Laboratory of Stem Cell Regulation with Chinese Medicine and Application, School of Pharmacy, Hunan University of Chinese Medicine, Hunan Province, Changsha 410208, China;
2.Department of Urology, the First Hospital of Hunan University of Chinese Medicine, Hunan Province, Changsha 410007, China
Abstract：Objective To investigate the effect and mechanism of Celastrol (CeT) in the treatment of renal carcinoma by network pharmacology, molecular docking techniques, and experimental verification methods. Methods The key targets and pathways of CeT in the treatment of renal carcinoma were analyzed by Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, PubChem, NCBI Gene, STRING databases, GO function, and KEGG pathway enrichment, and then Autodock Vina software was used for molecular docking verification. Human renal clear cell adenocarcinoma cell line 786-O cells were selected and divided into control group (normal culture), and 0.2, 0.4, 0.8 ¦Ìmol/L CeT group (given the corresponding concentration of CeT). After 24 h culture, apoptotic proteins and related pathway proteins in each group were detected by Western blot. Results A total of 53 CeT targets and 8 881 disease targets were screened, and 45 common targets were obtained by mutual mapping. Core targets such as Bax and Bcl-2 were obtained by analyzing common targets of protein-protein interaction network. GO enrichment analysis obtained 469 items, KEGG pathway enrichment analysis identified 67 related pathways, including apoptosis, phosp- ha tidylinositol 3 kinase (PI3K) /Akt kinase (Akt) pathway, cysteine aspartic acid specific protease-9 (caspase-9), nuclear factor ¦ÊB (NF-¦ÊB), P53, and other signaling pathways. Molecular docking results showed that CeT had good binding activity with core targets. Cell experiment results showed that the expressions of caspase-9 and P53 in 0.4 and 0.8 ¦Ìmol/L CeT groups were higher than those in the control group, while the expressions of Bcl-2 and NF-¦ÊB were lower than those in the control group, the expression of Bax in 0.4 ¦Ìmol/L CeT group was higher than that in control group, expression of PI3K in 0.8 ¦Ìmol/L CeT group was lower than that in control group, the expressions of P-Akt /Akt in 0.2, 0.4, and 0.8 ¦Ìmol/L CeT groups were lower than those in control group, and the differences were statistically significant (P£¼0.05). The expression of NF-¦ÊB in 0.8 ¦Ìmol/L CeT group was lower than that in 0.2 ¦Ìmol/L CeT group, and the differences were statistically significant (P£¼0.05). Conclusion CeT may affect the expression of target proteins such as Bax and Bcl-2 through PI3K/Akt pathway, NF-¦ÊB, and P53 signaling pathways, and play a role of multi-target and multi-pathway treatment for renal carcinoma.
颜涛1 谷佳1 朱能2 石雅宁1 张婵娟1 李洪芳1 覃丽1. 基于网络药理学和实验验证雷公藤红素治疗肾癌的作用及机制[J]. 中国医药导报, 2023, 20(14): 4-10.
YAN Tao1 GU Jia1??ZHU Neng2??SHI Yaning1 ZHANG Chanjuan1??LI Hongfang1??QIN Li1. Effect and mechanism of Celastrol in the treatment of renal carcinoma based on network pharmacology and experimental verification. 中国医药导报, 2023, 20(14): 4-10.
[1] Hu SL，Chang A，Perazella MA，et al. American Society of Nephrology Onco-Nephrology Forum. The Nephrologist’s Tumor： Basic Biology and Management of Renal Cell Carc- inoma [J]. J Am Soc Nephrol，2016，27（8）：2227-2237.
[2] Choueiri TK. Clinical treatment decisions for advanced renal cell cancer [J]. J Natl Compr Canc Netw，2013，11（S5）：694- 697.
[3] Corson TW，Crews CM. Molecular understanding and modern application of traditional medicines：triumphs and trials [J]. Cell，2007，130（5）：769-774.
[4] Kashyap D，Sharma A，Tuli HS，et al. Molecular targets of celastrol in cancer：recent trends and advancements [J]. Crit Rev Oncol Hematol，2018，128：70-81.
[5] Kannaiyan R，Manu KA，Chen L，et al. Celastrol inhibits tumor cell proliferation and promotes apoptosis through the activation of c-Jun N-terminal kinase and suppression of PI3 K/Akt signaling pathways [J]. Apoptosis，2011，16（10）：1028- 1041.
[6] Zhang CJ，Zhu N，Wang YX，et al. Celastrol Attenuates Lipid Accumulation and Stemness of Clear Cell Renal Cell Carcinoma via CAV-1/LOX-1 Pathway [J]. Front Pharmacol， 2021，12：658092.
[7] Li LH，Du B，Zhang HY，et al. A network pharmacology approach to explore the mechanisms of erxian decoction in polycystic ovary syndrome [J]. Chin Med：UK，2018，13（1）：1-12.
[8] 王凤雪，高宇，刘海波.中药网络药理学研究流程及代表性数据库工具[J].中国现代中药，2021，23（6）：1111-1118.
[9] 赵志恒，毕经会，叶诗洁，等.基于网络药理学和分子对接探究黄芪-女贞子治疗免疫缺陷病的作用机制[J].食品工业科技，2022，43（3）：374-383.
[10] Wu W， Jing D， Huang X， et al. Drp1-mediated mitochondrial fission is involved in oxidized low-density lipoprotein- induced AF cella poptosis [J]. J Orthop Res，2021，39（7）：1496-1504.
[11] Shinder BM，Rhee K，Farrell D，et al. Surgical management of advanced and metastatic renal cell carcinoma：A multi- disciplinary approach [J]. Front Oncol，2017，7：107.
[12] Buti S，Bersanelli M，Sikokis A，et al. Chemotherapy in met- astatic renal cell carcinoma today？A systematic review [J]. Anticancer Drugs，2013，24（6）：535-554.
[13] Du TA. Cell death：balance through a bivalent regulator [J]. Nat Rev Mol Cell Biol，2013，14（9）：546.
[14] Mohammad RM，Muqbil I，Lowe L，et al. Broad targeting of resistance to apoptosis in cancer [J]. Semin Cancer Biol，2015，35（S0）：78-103.
[15] Masood A，Azmi AS，Mohammad RM. Small molecule inhi- bitors of bcl-2 family proteins for pancreatic cancer ther- apy [J]. Cancers（Basel），2011，3（2）：1527-1549.
[16] Li B，Dou QP. Bax degradation by the ubiquitin/proteasome- dependent pathway：involvement in tumor survival and pro- gression [J]. Proc Natl Acad Sci U S A，2000，97（8）：3850- 3855.
[17] Czabotar PE，Lessene G，Strasser A，et al. Control of apo- ptosis by the BCL-2 protein family：implications for physiology and therapy [J]. Nat Rev Mol Cell Biol，2013，15（1）：49-63.
[18] Lord SJ， Rajotte RV， Korbutt GS， et al. Granzyme B：a natural born killer [J]. Immunol Rev，2003，193：31-38.
[19] Korsmeyer SJ，Shutter JR，Veis DJ，et al. Bcl-2/Bax：a rheo- stat that regulates an anti-oxidant pathway and cell death [J]. Semin Cancer Biol，1993，4（6）：327-332.
[20] Ma Z， Zhang W， Wu Y， et al. Cyclophilin A inhibits A549 cell oxidative stress and apoptosis by modulating the PI3K/ Akt/mTOR signaling pathway [J]. Biosci Rep，2021，29，41（1）：BSR20203219.
[21] Xu C，Huang X，Huang Y，et al. Naringin induces apoptosis of gastric carcinoma cells via blocking the PI3K/AKT pathway and activating pro-death autophagy [J]. Mol Med Rep，2021，24（5）：772.
[22] Yu X，Liu Y，Wang Y，et al. Baicalein induces cervical cancer apoptosis through the NF-κB signaling pathway [J]. Mol Med Rep，2018，17（4）：5088-5094.
[23] Anaya-Eugenio GD，Eggers NA，Ren Y，et al. Apoptosis Induced by（+）-Betulin Through NF-κB Inhibition in MDA- MB-231 Breast Cancer Cells [J]. Anticancer Res，2020，40 （12）：6637-6647.
[24] Wang X，Simpson ER，Brown KA. p53：Protection against Tumor Growth beyond Effects on Cell Cycle and Apoptosis [J]. Cancer Research，2015，75（23）：5001-5007.
[25] Lee SB，Lee S，Park JY，et al. Induction of p53-Dependent Apoptosis by Prostaglandin A2 [J]. Biomolecules，2020， 10（3）：492.
京公网安备 11010502046598号