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2000
Volume 25, Issue 4
  • ISSN: 1566-5240
  • E-ISSN: 1875-5666

Abstract

Background

This study investigates the inhibitory mechanism of anlotinib on human Mantle Cell Lymphoma (MCL) cells through and experiments.

Methods

cellular experiments validate the effects of anlotinib on MCL cell proliferation and apoptosis. Moreover, a subcutaneous xenograft nude mice model of Mino MCL cells was established to assess the anti-tumour effect and tumour microenvironment regulation of anlotinib .

Results

The results indicate that MCL cell proliferation was significantly inhibited upon anlotinib exposure. The alterations in the expression of apoptosis-related proteins further confirm that anlotinib can induce apoptosis in MCL cells. Additionally, anlotinib significantly reduced the PI3K/Akt/mTOR phosphorylation level in MCL cells. The administration of a PI3K phosphorylation agonist, 740YP, could reverse the inhibitory effect of anlotinib on MCL. In the xenograft mouse model using Mino MCL cells, anlotinib treatment led to a gradual reduction in body weight and a significant increase in survival time compared to the control group. Additionally, anlotinib attenuated PD-1 expression and elevated inflammatory factors, CD4, and CD8 levels in tumour tissues.

Conclusion

Anlotinib effectively inhibits proliferation and induces apoptosis in MCL both and . This inhibition is likely linked to suppressing phosphorylation in the PI3K/Akt/mTOR pathway.

© 2025 Bentham Science Publishers
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2025-10-01

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References

  1. OwenC. BerinsteinN.L. ChristofidesA. SehnL.H. Review of Bruton tyrosine kinase inhibitors for the treatment of relapsed or refractory mantle cell lymphoma.Curr. Oncol.201926223324010.3747/co.26.4345 31043832
     [Google Scholar]
  2. Aschebrook-KilfoyB. CacesD.B.D. OllberdingN.J. SmithS.M. ChiuB.C.H. An upward trend in the age-specific incidence patterns for mantle cell lymphoma in the USA.Leuk. Lymphoma20135481677168310.3109/10428194.2012.760041 23350889
     [Google Scholar]
  3. JainP. WangM. Mantle cell lymphoma: 2019 update on the diagnosis, pathogenesis, prognostication, and management.Am. J. Hematol.201994671072510.1002/ajh.25487 30963600
     [Google Scholar]
  4. DreylingM. CampoE. HermineO. Newly diagnosed and relapsed mantle cell lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann. Oncol.201728iv62iv7110.1093/annonc/mdx223 28881919
     [Google Scholar]
  5. McKayP. LeachM. JacksonB. RobinsonS. RuleS. Guideline for the management of mantle cell lymphoma.Br. J. Haematol.20181821466210.1111/bjh.15283 29767454
     [Google Scholar]
  6. Reis-SobreiroM. RouéG. MorosA. Lipid raft-mediated Akt signaling as a therapeutic target in mantle cell lymphoma.Blood Cancer J.201335e11810.1038/bcj.2013.15 23727661
     [Google Scholar]
  7. KararJ. MaityA. PI3K/AKT/mTOR pathway in angiogenesis.Front. Mol. Neurosci.201145110.3389/fnmol.2011.00051 22144946
     [Google Scholar]
  8. KumarC. DiaoR. YinZ. Expression, purification, characterization and homology modeling of active Akt/PKB, a key enzyme involved in cell survival signaling.Biochim. Biophys. Acta, Gen. Subj.20011526325726810.1016/S0304‑4165(01)00143‑X 11410335
     [Google Scholar]
  9. KooJ. YueP. DengX. KhuriF.R. SunS.Y. mTOR complex 2 stabilizes Mcl-1 protein by suppressing its glycogen synthase kinase 3-dependent and SCF-FBXW7-mediated degradation.Mol. Cell. Biol.201535132344235510.1128/MCB.01525‑14 25918246
     [Google Scholar]
  10. PópuloH. LopesJ.M. SoaresP. The mTOR signalling pathway in human cancer.Int. J. Mol. Sci.20121321886191810.3390/ijms13021886 22408430
     [Google Scholar]
  11. HuaH. ZhangH. ChenJ. WangJ. LiuJ. JiangY. Targeting Akt in cancer for precision therapy.J. Hematol. Oncol.202114112810.1186/s13045‑021‑01137‑8 34419139
     [Google Scholar]
  12. WangG. SunM. JiangY. Anlotinib, a novel small molecular tyrosine kinase inhibitor, suppresses growth and metastasis via dual blockade of VEGFR2 and MET in osteosarcoma.Int. J. Cancer2019145497999310.1002/ijc.32180 30719715
     [Google Scholar]
  13. LinB. SongX. YangD. BaiD. YaoY. LuN. Anlotinib inhibits angiogenesis via suppressing the activation of VEGFR2, PDGFRβ and FGFR1.Gene2018654778610.1016/j.gene.2018.02.026 29454091
     [Google Scholar]
  14. LuJ. ZhongH. WuJ. Circulating DNA‐based sequencing guided anlotinib therapy in non‐small cell lung cancer.Adv. Sci.2019619190072110.1002/advs.201900721 31592412
     [Google Scholar]
  15. TangY. OuZ. YaoZ. QiaoG. A case report of immune checkpoint inhibitor nivolumab combined with anti-angiogenesis agent anlotinib for advanced esophageal squamous cell carcinoma.Medicine20199840e1716410.1097/MD.0000000000017164 31577707
     [Google Scholar]
  16. YuanS. PengL. LiuY. Low-dose anlotinib confers improved survival in combination with immune checkpoint inhibitor in advanced non-small cell lung cancer patients.Cancer Immunol. Immunother.202372243744810.1007/s00262‑022‑03259‑5 35931835
     [Google Scholar]
  17. DongB-J. DuX-X. DongY-H. PD-1 inhibitor plus anlotinib for metastatic castration-resistant prostate cancer: A real-world study.Asian J. Androl.202325217918310.4103/aja2022102 36537376
     [Google Scholar]
  18. PiaoM.N. MaX.T. TankereP. LiamC.K. LiJ.L. WangJ.P. Anlotinib combined with chemotherapy and immunotherapy for advanced pulmonary sarcomatoid cancer: A case report and literature review.Ann. Transl. Med.20221018103010.21037/atm‑22‑4312 36267791
     [Google Scholar]
  19. ChenQ. LiY. ZhangW. WangC. YangS. GuoQ. Safety and efficacy of ICI plus anlotinib vs. anlotinib alone as third-line treatment in extensive-stage small cell lung cancer: A retrospective study.J. Cancer Res. Clin. Oncol.2022148240140810.1007/s00432‑021‑03858‑2 34797416
     [Google Scholar]
  20. LanC.Y. ZhaoJ. YangF. Anlotinib combined with TQB2450 in patients with platinum-resistant or -refractory ovarian cancer: A multi-center, single-arm, phase 1b trial.Cell Rep. Med.20223710068910.1016/j.xcrm.2022.100689 35858589
     [Google Scholar]
  21. LiT. HuW. JinL. YinX. KangD. PiaoL. Case Report: PD-L1-negative advanced bladder cancer effectively treated with anlotinib and tislelizumab: A report of two cases.Front. Oncol.202313116436810.3389/fonc.2023.1164368 37124509
     [Google Scholar]
  22. ZhouL. XuG. ChenT. Anlotinib plus camrelizumab achieved long‐term survival in a patient with metastatic esophageal neuroendocrine carcinoma.Cancer Rep.202369e185510.1002/cnr2.1855 37381647
     [Google Scholar]
  23. WangY. ZhangQ. MiaoL. ZhouY. Nivolumab in combination with anlotinib achieved remarkable efficacy in a patient with driver-negative lung squamous cell carcinoma and PS of 4.Ann. Palliat. Med.2020964384438810.21037/apm‑20‑2096 33302689
     [Google Scholar]
  24. ZanN. ZhangX. DuL. Case report: Toripalimab combined with anlotinib in a patient with metastatic upper tract urothelial carcinoma after pembrolizumab failure.Front. Oncol.20221279640710.3389/fonc.2022.796407 35296012
     [Google Scholar]
  25. ZhuS. YuC. WangC. DingG. ChengS. Case report: Significant benefits of tislelizumab combined with anlotinib in first-line treatment of metastatic renal pelvic urothelial carcinoma with sarcomatoid carcinoma differentiation.Front. Oncol.20221296910610.3389/fonc.2022.969106 36330483
     [Google Scholar]
  26. DasV. KaishapP.P. DuarahG. ChikkaputtaiahC. Deka BoruahH.P. PalM. Cytotoxic and apoptosis-inducing effects of novel 8-amido isocoumarin derivatives against breast cancer cells.Naunyn Schmiedebergs Arch. Pharmacol.202139471437144910.1007/s00210‑021‑02063‑9 33649978
     [Google Scholar]
  27. YangQ. NiL. ImaniS. Anlotinib suppresses colorectal cancer proliferation and angiogenesis via inhibition of AKT/ERK signaling cascade.Cancer Manag. Res.2020124937494810.2147/CMAR.S252181 32606981
     [Google Scholar]
  28. ChiY. FangZ. HongX. Safety and efficacy of anlotinib, a multikinase angiogenesis inhibitor, in patients with refractory metastatic soft-tissue sarcoma.Clin. Cancer Res.201824215233523810.1158/1078‑0432.CCR‑17‑3766 29895706
     [Google Scholar]
  29. HuH. LiuY. TanS. Anlotinib exerts anti-cancer effects on KRAS-mutated lung cancer cell through suppressing the MEK/ERK pathway.Cancer Manag. Res.2020123579358710.2147/CMAR.S243660 32547195
     [Google Scholar]
  30. ZhangA. LiuB. XuD. SunY. Advanced intrahepatic cholangiocarcinoma treated using anlotinib and microwave ablation.Medicine20199852e1843510.1097/MD.0000000000018435 31876723
     [Google Scholar]
  31. NavarroA. BeàS. JaresP. CampoE. Molecular pathogenesis of mantle cell lymphoma.Hematol. Oncol. Clin. North Am.202034579580710.1016/j.hoc.2020.05.002 32861278
     [Google Scholar]
  32. NoelM.S. FriedbergJ.W. BarrP.M. Novel agents in mantle cell lymphoma.Best Pract. Res. Clin. Haematol.201225219120010.1016/j.beha.2012.04.001 22687455
     [Google Scholar]
  33. XiaoZ. NiY. YinG. WuH. LiJ. MiaoK. Mantle cell lymphoma concurrent with T-large granular lymphocytic leukemia: report of a case and review of literature.Int. J. Clin. Exp. Pathol.20158333653369 26045870
     [Google Scholar]
  34. GuoH. ZengD. ZhangH. Dual inhibition of PI3K signaling and histone deacetylation halts proliferation and induces lethality in mantle cell lymphoma.Oncogene201938111802181410.1038/s41388‑018‑0550‑3 30361685
     [Google Scholar]
  35. MüllerA. ZangC. ChumduriC. DörkenB. DanielP.T. ScholzC.W. Concurrent inhibition of PI3K and mTORC1/mTORC2 overcomes resistance to rapamycin induced apoptosis by down-regulation of Mcl-1 in mantle cell lymphoma.Int. J. Cancer201313381813182410.1002/ijc.28206 23580240
     [Google Scholar]
  36. SongG. OuyangG. BaoS. The activation of Akt/PKB signaling pathway and cell survival.J. Cell. Mol. Med.200591597110.1111/j.1582‑4934.2005.tb00337.x 15784165
     [Google Scholar]
  37. BhattA.P. BhendeP.M. SinS.H. RoyD. DittmerD.P. DamaniaB. Dual inhibition of PI3K and mTOR inhibits autocrine and paracrine proliferative loops in PI3K/Akt/mTOR-addicted lymphomas.Blood2010115224455446310.1182/blood‑2009‑10‑251082 20299510
     [Google Scholar]
  38. KimA. ParkS. LeeJ.E. The dual PI3K and mTOR inhibitor NVP-BEZ235 exhibits anti-proliferative activity and overcomes bortezomib resistance in mantle cell lymphoma cells.Leuk. Res.201236791292010.1016/j.leukres.2012.02.010 22560334
     [Google Scholar]
  39. Hershkovitz-RokahO. PulverD. LenzG. ShpilbergO. Ibrutinib resistance in mantle cell lymphoma: Clinical, molecular and treatment aspects.Br. J. Haematol.2018181330631910.1111/bjh.15108 29359797
     [Google Scholar]
  40. DivakarS.K.A. Ramana ReddyM.V. CosenzaS.C. Dual inhibition of CDK4/Rb and PI3K/AKT/mTOR pathways by ON123300 induces synthetic lethality in mantle cell lymphomas.Leukemia2016301869310.1038/leu.2015.185 26174628
     [Google Scholar]
  41. PapinA. Le GouillS. ChironD. Rationale for targeting tumor cells in their microenvironment for mantle cell lymphoma treatment.Leuk. Lymphoma20185951064107210.1080/10428194.2017.1357177 28758825
     [Google Scholar]
  42. YaoY. CheY. LiuY. MCL cells in tumor microenvironment impair T-cell metabolic fitness and effector function.Blood202013616610.1182/blood‑2020‑139611
     [Google Scholar]
  43. YuanM. ZhuZ. MaoW. Anlotinib combined with anti-PD-1 Antibodies therapy in patients with advanced refractory solid tumors: A single-center, observational, prospective study.Front. Oncol.20211168350210.3389/fonc.2021.683502 34692475
     [Google Scholar]
  44. BalsasP. VelozaL. ClotG. SOX11, CD70, and Treg cells configure the tumor immune microenvironment of aggressive mantle cell lymphoma.Blood2021138222202221510.1182/blood.2020010527 34189576
     [Google Scholar]
  45. YangZ.Z. NovakA.J. ZiesmerS.C. WitzigT.E. AnsellS.M. CD70+ non-Hodgkin lymphoma B cells induce Foxp3 expression and regulatory function in intratumoral CD4+CD25− T cells.Blood200711072537254410.1182/blood‑2007‑03‑082578 17615291
     [Google Scholar]
  46. LeK. SunJ. KhawajaH. Mantle cell lymphoma polarizes tumor-associated macrophages into M2-like macrophages, which in turn promote tumorigenesis.Blood Adv.20215142863287810.1182/bloodadvances.2020003871 34297045
     [Google Scholar]
  47. Rivera VargasT. ApetohL. Danger signals: Chemotherapy enhancers?Immunol. Rev.2017280117519310.1111/imr.12581 29027217
     [Google Scholar]
  48. GaoQ. WangS. ChenX. Cancer-cell-secreted CXCL11 promoted CD8+ T cells infiltration through docetaxel-induced-release of HMGB1 in NSCLC.J. Immunother. Cancer2019714210.1186/s40425‑019‑0511‑6 30744691
     [Google Scholar]
  49. ZhangS. JiangV.C. HanG. Longitudinal single-cell profiling reveals molecular heterogeneity and tumor-immune evolution in refractory mantle cell lymphoma.Nat. Commun.2021121287710.1038/s41467‑021‑22872‑z 34001881
     [Google Scholar]
  50. SuY. LuoB. LuY. Anlotinib induces a T cell–inflamed tumor microenvironment by facilitating vessel normalization and enhances the efficacy of pd-1 checkpoint blockade in neuroblastoma.Clin. Cancer Res.202228479380910.1158/1078‑0432.CCR‑21‑2241 34844980
     [Google Scholar]
  51. YangY. LiL. JiangZ. WangB. PanZ. Anlotinib optimizes anti-tumor innate immunity to potentiate the therapeutic effect of PD-1 blockade in lung cancer.Cancer Immunol. Immunother.202069122523253210.1007/s00262‑020‑02641‑5 32577817
     [Google Scholar]
  52. WangL. QianJ. LuY. Immune evasion of mantle cell lymphoma: Expression of B7-H1 leads to inhibited T-cell response to and killing of tumor cells.Haematologica20139891458146610.3324/haematol.2012.071340 23508008
     [Google Scholar]
  53. HarringtonB.K. WheelerE. HornbuckleK. Modulation of immune checkpoint molecule expression in mantle cell lymphoma.Leuk. Lymphoma201960102498250710.1080/10428194.2019.1569231 30821551
     [Google Scholar]
  54. XerriL. ChetailleB. SeriariN. Programmed death 1 is a marker of angioimmunoblastic T-cell lymphoma and B-cell small lymphocytic lymphoma/chronic lymphocytic leukemia.Hum. Pathol.20083971050105810.1016/j.humpath.2007.11.012 18479731
     [Google Scholar]
  55. SalehK. CheminantM. ChironD. BurroniB. RibragV. SarkozyC. Tumor microenvironment and immunotherapy-based approaches in mantle cell lymphoma.Cancers20221413322910.3390/cancers14133229 35804999
     [Google Scholar]
  56. JainP. NomieK. KotlovN. Immune-depleted tumor microenvironment is associated with poor outcomes and BTK inhibitor resistance in mantle cell lymphoma.Blood Cancer J.202313115610.1038/s41408‑023‑00927‑2 37821434
     [Google Scholar]
  57. QuallsD. KumarA. Epstein-PetersonZ.D. Targeting the immune microenvironment in mantle cell lymphoma: implications for current and emerging therapies.Leuk. Lymphoma202263112515252710.1080/10428194.2022.2086244 35704674
     [Google Scholar]
  58. FukumuraD. KloepperJ. AmoozgarZ. DudaD.G. JainR.K. Enhancing cancer immunotherapy using antiangiogenics: Opportunities and challenges.Nat. Rev. Clin. Oncol.201815532534010.1038/nrclinonc.2018.29 29508855
     [Google Scholar]
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Anlotinib Inhibiting Mantle Cell Lymphoma Proliferation and Inducing Apoptosis through PI3K/AKT/mTOR Pathway
Current Molecular Medicine 25, 472 (2025); https://doi.org/10.2174/0115665240284638240408081133
/content/journals/cmm/10.2174/0115665240284638240408081133
/content/journals/cmm/10.2174/0115665240284638240408081133
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  • Article Type:     Research Article
Keyword(s): AKT; Anlotinib; apoptosis; mammalian target of rapamycin; mantle cell lymphoma; phosphoinositide 3-kinase; tumour microenvironment

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