Login Register Cart 0
Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Combined Effects of Programmed Cell Death-1 Blockade and Endostar on Brain Metastases of Lung Cancer

Author(s): Xuejiao Qi, Yinlong Zhao, Song Yang, YuMeng Sun, Honglei Liu, Pengyu Liu, Shiyao Feng, Hongbo Tui, Zheng Yuan, Jiankai Yang* and Hui Bu*

Volume 23, Issue 6, 2023

Published on: 22 September, 2022

Page: [709 - 716] Pages: 8

DOI: 10.2174/1871520622666220827125929

Price: $65

Abstract

Background: The blockade of programmed cell death-1 (PD-1) and recombinant human endostatin can be used for the treatment of non-small cell lung cancer (NSCLC) and its metastasis. This study aims to explore the therapeutically potential of PD-1 blockade plus Endostar in brain metastasis of NSCLC.

Methods: The mouse brain metastases model was established using Lewis lung carcinoma luciferase (LLC-Luc) and PC-9-Luc cells. Tumor metastasis in the brain and tumor burden were analyzed by using bioluminescence imaging (BLI), qRT-PCR and ELISA which were used to determine the mRNA and protein levels of biomarkers in tumor tissues. Immunohistochemical staining was used to determine the expression and location of CD31 in tumor tissues in the brain.

Results: Treatment with anti-PD-1 and Endostar suppressed tumor metastasis in the brain and prolonged overall survival rate in LLC-Luc and PC-9-Luc brain metastases mouse model. In addition, treatment with anti-PD-1 and Endostar inhibited the expressions of CD31 and VEGF in tumor tissues in the brain. Furthermore, treatment with anti-PD- 1 and Endostar significantly suppressed the levels of IL1β, IFNγ, and TGFβ in the tumor tissues.

Conclusion: The combination of PD-1 blockade and endostar suppressed brain metastases of NSCLC.

Keywords: Lung cancer, brain metastasis, immune checkpoint, PD-1, endostar, tumor metastasis.

« Previous Next »
Graphical Abstract

[1]
Minna, J.D.; Roth, J.A.; Gazdar, A.F. Focus on lung cancer. Cancer Cell, 2002, 1(1), 49-52.
[http://dx.doi.org/10.1016/S1535-6108(02)00027-2] [PMID: 12086887]
[2]
Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2021, 71(3), 209-249.
[http://dx.doi.org/10.3322/caac.21660] [PMID: 33538338]
[3]
Herbst, R.S.; Morgensztern, D.; Boshoff, C. The biology and management of non-small cell lung cancer. Nature, 2018, 553(7689), 446-454.
[http://dx.doi.org/10.1038/nature25183] [PMID: 29364287]
[4]
Arbour, K.C.; Riely, G.J. Systemic therapy for locally advanced and metastatic non–small cell lung cancer: A review. JAMA, 2019, 322(8), 764-774.
[http://dx.doi.org/10.1001/jama.2019.11058] [PMID: 31454018]
[5]
Jamal-Hanjani, M.; Wilson, G.A.; McGranahan, N.; Birkbak, N.J.; Watkins, T.B.K.; Veeriah, S.; Shafi, S.; Johnson, D.H.; Mitter, R.; Rosenthal, R.; Salm, M.; Horswell, S.; Escudero, M.; Matthews, N.; Rowan, A.; Chambers, T.; Moore, D.A.; Turajlic, S.; Xu, H.; Lee, S.M.; Forster, M.D.; Ahmad, T.; Hiley, C.T.; Abbosh, C.; Falzon, M.; Borg, E.; Marafioti, T.; Lawrence, D.; Hayward, M.; Kolvekar, S.; Panagiotopoulos, N.; Janes, S.M.; Thakrar, R.; Ahmed, A.; Blackhall, F.; Summers, Y.; Shah, R.; Joseph, L.; Quinn, A.M.; Crosbie, P.A.; Naidu, B.; Middleton, G.; Langman, G.; Trotter, S.; Nicolson, M.; Remmen, H.; Kerr, K.; Chetty, M.; Gomersall, L.; Fennell, D.A.; Nakas, A.; Rathinam, S.; Anand, G.; Khan, S.; Russell, P.; Ezhil, V.; Ismail, B.; Irvin-Sellers, M.; Prakash, V.; Lester, J.F.; Kornaszewska, M.; Attanoos, R.; Adams, H.; Davies, H.; Dentro, S.; Taniere, P.; O’Sullivan, B.; Lowe, H.L.; Hartley, J.A.; Iles, N.; Bell, H.; Ngai, Y.; Shaw, J.A.; Herrero, J.; Szallasi, Z.; Schwarz, R.F.; Stewart, A.; Quezada, S.A.; Le Quesne, J.; Van Loo, P.; Dive, C.; Hackshaw, A.; Swanton, C. Tracking the evolution of non–small-cell lung cancer. N. Engl. J. Med., 2017, 376(22), 2109-2121.
[http://dx.doi.org/10.1056/NEJMoa1616288] [PMID: 28445112]
[6]
Waqar, S.N.; Samson, P.P.; Robinson, C.G.; Bradley, J.; Devarakonda, S.; Du, L.; Govindan, R.; Gao, F.; Puri, V.; Morgensztern, D. Non–small-cell lung cancer with brain metastasis at presentation. Clin. Lung Cancer, 2018, 19(4), e373-e379.
[http://dx.doi.org/10.1016/j.cllc.2018.01.007] [PMID: 29526531]
[7]
Donini, C.; D’Ambrosio, L.; Grignani, G.; Aglietta, M.; Sangiolo, D. Next generation immune-checkpoints for cancer therapy. J. Thorac. Dis., 2018, 10(S13)(Suppl. 13), S1581-S1601.
[http://dx.doi.org/10.21037/jtd.2018.02.79] [PMID: 29951308]
[8]
Ni, L.; Dong, C. New checkpoints in cancer immunotherapy. Immunol. Rev., 2017, 276(1), 52-65.
[http://dx.doi.org/10.1111/imr.12524] [PMID: 28258699]
[9]
Yan, Y.; Zhang, L.; Zuo, Y.; Qian, H.; Liu, C. Immune checkpoint blockade in cancer immunotherapy: Mechanisms, clinical outcomes, and safety profiles of PD-1/PD-L1 inhibitors. Arch. Immunol. Ther. Exp. (Warsz.), 2020, 68(6), 36.
[http://dx.doi.org/10.1007/s00005-020-00601-6] [PMID: 33185750]
[10]
Liu, C.; Seeram, N.P.; Ma, H. Small molecule inhibitors against PD-1/PD-L1 immune checkpoints and current methodologies for their development: A review. Cancer Cell Int., 2021, 21(1), 239.
[http://dx.doi.org/10.1186/s12935-021-01946-4] [PMID: 33906641]
[11]
Okazaki, T.; Honjo, T. The PD-1-PD-L pathway in immunological tolerance. Trends Immunol., 2006, 27(4), 195-201.
[http://dx.doi.org/10.1016/j.it.2006.02.001] [PMID: 16500147]
[12]
Xia, L.; Liu, Y.; Wang, Y. PD-1/PD-L1 blockade therapy in advanced non-small-cell lung cancer: Current status and future directions. Oncologist, 2019, 24(S1)(Suppl. 1), S31-S41.
[http://dx.doi.org/10.1634/theoncologist.2019-IO-S1-s05] [PMID: 30819829]
[13]
Zhou, S.; Xie, J.; Huang, Z.; Deng, L.; Wu, L.; Yu, J.; Meng, X. Anti-PD-(L)1 immunotherapy for brain metastases in non-small cell lung cancer: Mechanisms, advances, and challenges. Cancer Lett., 2021, 502, 166-179.
[http://dx.doi.org/10.1016/j.canlet.2020.12.043] [PMID: 33450361]
[14]
Reck, M.; Mok, T.S.K.; Nishio, M.; Jotte, R.M.; Cappuzzo, F.; Orlandi, F.; Stroyakovskiy, D.; Nogami, N.; Rodríguez-Abreu, D.; Moro-Sibilot, D.; Thomas, C.A.; Barlesi, F.; Finley, G.; Lee, A.; Coleman, S.; Deng, Y.; Kowanetz, M.; Shankar, G.; Lin, W.; Socinski, M.A.; Reck, M.; Mok, T.S.K.; Nishio, M.; Jotte, R.M.; Cappuzzo, F.; Orlandi, F.; Stroyakovskiy, D.; Nogami, N.; Rodríguez-Abreu, D.; Moro-Sibilot, D.; Thomas, C.A.; Barlesi, F.; Finley, G.; Lee, A.; Coleman, S.; Deng, Y.; Kowanetz, M.; Shankar, G.; Lin, W.; Socinski, M.A. Atezolizumab plus bevacizumab and chemotherapy in non-small-cell lung cancer (IMpower150): Key subgroup analyses of patients with EGFR mutations or baseline liver metastases in a randomised, open-label phase 3 trial. Lancet Respir. Med., 2019, 7(5), 387-401.
[http://dx.doi.org/10.1016/S2213-2600(19)30084-0] [PMID: 30922878]
[15]
Plate, K.H.; Breier, G.; Risau, W. Molecular mechanisms of developmental and tumor angiogenesis. Brain Pathol., 1994, 4(3), 207-218.
[http://dx.doi.org/10.1111/j.1750-3639.1994.tb00835.x] [PMID: 7524960]
[16]
Yang, H.; Wang, J.; Fan, J.H.; Zhang, Y.Q.; Zhao, J.X.; Dai, X.J.; Liu, Q.; Shen, Y.J.; Liu, C.; Sun, W.D.; Sun, Y. Ilexgenin A exerts anti-inflammation and anti-angiogenesis effects through inhibition of STAT3 and PI3K pathways and exhibits synergistic effects with Sorafenib on hepatoma growth. Toxicol. Appl. Pharmacol., 2017, 315, 90-101.
[http://dx.doi.org/10.1016/j.taap.2016.12.008] [PMID: 27986624]
[17]
Hall, R.D.; Le, T.M.; Haggstrom, D.E.; Gentzler, R.D. Angiogenesis inhibition as a therapeutic strategy in non-small cell lung cancer (NSCLC). Transl. Lung Cancer Res., 2015, 4(5), 515-523.
[PMID: 26629420]
[18]
Ling, Y.; Yang, Y.; Lu, N.; You, Q.D.; Wang, S.; Gao, Y.; Chen, Y.; Guo, Q.L. Endostar, a novel recombinant human endostatin, exerts antiangiogenic effect via blocking VEGF-induced tyrosine phosphorylation of KDR/Flk-1 of endothelial cells. Biochem. Biophys. Res. Commun., 2007, 361(1), 79-84.
[http://dx.doi.org/10.1016/j.bbrc.2007.06.155] [PMID: 17644065]
[19]
Li, Y.; Huang, P.; Peng, H.; Yue, H.; Wu, M.; Liu, S.; Qin, R.; Fan, J.; Han, Y. Antitumor effects of Endostar(rh-endostatin) combined with gemcitabine in different administration sequences to treat Lewis lung carcinoma. Cancer Manag. Res., 2019, 11, 3469-3479.
[http://dx.doi.org/10.2147/CMAR.S192868] [PMID: 31114380]
[20]
Zhou, J.F.; Bai, C.M.; Wang, Y.Z.; Li, X.Y.; Cheng, Y.J.; Chen, S.C. Endostar combined with chemotherapy for treatment of metastatic colorectal and gastric cancer: A pilot study. Chin. Med. J. (Engl.), 2011, 124(24), 4299-4303.
[PMID: 22340403]
[21]
Yang, Z.; Guo, Q.; Wang, Y.; Chen, K.; Zhang, L.; Cheng, Z.; Xu, Y.; Yin, X.; Bai, Y.; Rabbie, S. AZD3759, a BBB-penetrating EGFR inhibitor for the treatment of EGFR mutant NSCLC with CNS metastases. Sci. Transl. Med. 2016, 8(368), 368ra172.
[http://dx.doi.org/10.1126/scitranslmed.aag0976] [PMID: 27928026]
[22]
Wood, S.L.; Pernemalm, M.; Crosbie, P.A.; Whetton, A.D. The role of the tumor-microenvironment in lung cancer-metastasis and its relationship to potential therapeutic targets. Cancer Treat. Rev., 2014, 40(4), 558-566.
[http://dx.doi.org/10.1016/j.ctrv.2013.10.001] [PMID: 24176790]
[23]
Tamura, T.; Kurishima, K.; Nakazawa, K.; Kagohashi, K.; Ishikawa, H.; Satoh, H.; Hizawa, N. Specific organ metastases and survival in metastatic non-small-cell lung cancer. Mol. Clin. Oncol., 2015, 3(1), 217-221.
[http://dx.doi.org/10.3892/mco.2014.410] [PMID: 25469298]
[24]
Fang, L.; Zhao, W.; Ye, B.; Chen, D. Combination of immune checkpoint inhibitors and anti-angiogenic agents in brain metastases from non-small cell lung cancer. Front. Oncol., 2021, 11, 670313.
[http://dx.doi.org/10.3389/fonc.2021.670313] [PMID: 34017689]
[25]
Berghoff, A.S.; Preusser, M. Anti-angiogenic therapies in brain metastases. Mag. Eur. Med. Oncol., 2018, 11(1), 14-17.
[http://dx.doi.org/10.1007/s12254-018-0384-2] [PMID: 29606977]
[26]
Shukla, N.A.; Yan, M.N.; Hanna, N. The story of angiogenesis inhibitors in non–small-cell lung cancer: The past, present, and future. Clin. Lung Cancer, 2020, 21(4), 308-313.
[http://dx.doi.org/10.1016/j.cllc.2020.02.024] [PMID: 32291211]
[27]
Zhao, X.L.; Su, Y.J.; You, J.; Gong, L.Q.; Zhang, Z.F.; Wang, M.; Zhao, Z.Q.; Zhang, Z.; Li, X.L.; Wang, C.L. Combining antiangiogenic therapy with neoadjuvant chemotherapy increases treatment efficacy in stage IIIA (N2) non-small cell lung cancer without increasing adverse effects.Oncotarget. 2016, 7(38), 62619-62626.
[http://dx.doi.org/10.18632/oncotarget.11547] [PMID: 27566586]
[28]
Wu, Y.L.; Zhang, L.; Fan, Y.; Zhou, J.; Zhang, L.; Zhou, Q.; Li, W.; Hu, C.; Chen, G.; Zhang, X.; Zhou, C.; Dang, T.; Sadowski, S.; Kush, D.A.; Zhou, Y.; Li, B.; Mok, T. Randomized clinical trial of pembrolizumab vs. chemotherapy for previously untreated Chinese patients with PD-L1-positive locally advanced or metastatic non-small-cell lung cancer: KEYNOTE-042 China Study. Int. J. Cancer, 2021, 148(9), 2313-2320.
[http://dx.doi.org/10.1002/ijc.33399] [PMID: 33231285]
[29]
Nishida, N.; Yano, H.; Nishida, T.; Kamura, T.; Kojiro, M. Angiogenesis in cancer. Vasc. Health Risk Manag., 2006, 2(3), 213-219.
[http://dx.doi.org/10.2147/vhrm.2006.2.3.213] [PMID: 17326328]
[30]
Wang, X.S.; Shi, Q.; Williams, L.A.; Mao, L.; Cleeland, C.S.; Komaki, R.R.; Mobley, G.M.; Liao, Z. Inflammatory cytokines are associated with the development of symptom burden in patients with NSCLC undergoing concurrent chemoradiation therapy. Brain Behav. Immun., 2010, 24(6), 968-974.
[http://dx.doi.org/10.1016/j.bbi.2010.03.009] [PMID: 20353817]
[31]
Ramachandran, S.; Verma, A. K.; Dev, K.; Goyal, Y.; Bhatt, D.; Alsahli, M. A.; Rahmani, A. H.; Almatroudi, A.; Almatroodi, S. A.; Alrumaihi, F. Role of cytokines and chemokines in NSCLC immune navigation and proliferation. Oxid. Med. Cell. Longev., 2021, 2021
[http://dx.doi.org/10.1155/2021/5563746] [PMID: 34336101]
[32]
Esandi, M.C.; van Someren, G.D.; Bout, A.; Mulder, A.H.; van Bekkum, D.W.; Valerio, D.; Noteboom, J.L. IL-1/IL-3 gene therapy of non-small cell lung cancer (NSCLC) in rats using ‘cracked’ adenoproducer cells. Gene Ther., 1998, 5(6), 778-788.
[http://dx.doi.org/10.1038/sj.gt.3300662] [PMID: 9747458]
[33]
Maitah, M.Y.; Ali, S.; Ahmad, A.; Gadgeel, S.; Sarkar, F.H. Up-regulation of sonic hedgehog contributes to TGF-β1-induced epithelial to mesenchymal transition in NSCLC cells. PLoS One, 2011, 6(1), e16068.
[http://dx.doi.org/10.1371/journal.pone.0016068] [PMID: 21249152]

Rights & Permissions Print Cite
Article Metrics
41
5
© 2024 Bentham Science Publishers | Privacy Policy