Anticancer Effects of ACT001 Via NF-κB Suppression in Murine Triple-Negative Breast Cancer Cell Line 4T1

Overview

Journal Cancer Manag Res

Publisher Dove Medical Press

Specialty Oncology

Date 2020 Jul 4

PMID 32617021

Citations 11

Authors

Yanyang Liu

Li Wang

Jiewei Liu

Xiaoxiao Xie

Haoyue Hu

Feng Luo

Affiliations

Soon will be listed here.

Abstract

Purpose: ACT001 is a novel sesquiterpene lactone derivative with anticancer effects, including the reversal of tamoxifen resistance in estrogen receptor-positive breast cancer cells. However, few studies have investigated the anticancer effects of ACT001 in triple-negative breast cancer (TNBC), a highly aggressive cancer with a poor prognosis. This study aimed to investigate the effects of ACT001 on TNBC and the potential mechanism underlying these effects.

Materials And Methods: The anticancer effects of ACT001 on the murine TNBC cell line 4T1 were evaluated by Cell Counting Kit-8 assay, animal experiments, TUNEL staining, flow cytometry, immunofluorescence, enzyme-linked immunosorbent assay, and Western blotting analysis.

Results: ACT001 induced apoptosis in 4T1 cells by upregulating B cell lymphoma 2-associated X protein expression. Moreover, ACT001 markedly decreased levels of secretory granulocyte-macrophage colony stimulating factor (GM-CSF) in 4T1 tumors, decreased the number of myeloid-derived suppressor cells (MDSCs), and reduced angiogenesis. Furthermore, GM-CSF promoted angiogenesis and the proliferation of MDSCs in a dose-dependent manner. Finally, ACT001 suppressed phospho-NF-κB and IκB-α levels in 4T1 cells, thereby further decreasing GM-CSF levels.

Conclusion: Our results suggest that ACT001 exerts its anticancer effects by inducing apoptosis in murine TNBC cell line 4T1 and regulates the tumor microenvironment by attenuating angiogenesis and accumulation of MDSCs in 4T1 tumors. The underlying mechanism may involve the suppression of NF-κB activity.

Citing Articles

Selenium Nanoparticles Synergize with a KRAS Nanovaccine against Breast Cancer.

Ferro C, Matos A, Serpico L, Fontana F, Chiaro J, DAmico C Adv Healthc Mater. 2024; 14(5):e2401523.

PMID: 39205539 PMC: 11834378. DOI: 10.1002/adhm.202401523.

A Diet Lacking Selenium, but Not Zinc, Copper or Manganese, Induces Anticancer Activity in Mice with Metastatic Cancers.

Diaz-Ortega P, Calderon-Montano J, Jimenez-Alonso J, Guillen-Mancina E, Jimenez-Gonzalez V, Burgos-Moron E Nutrients. 2024; 16(14).

PMID: 39064692 PMC: 11280272. DOI: 10.3390/nu16142249.

Study on the mechanism of MDSC-platelets and their role in the breast cancer microenvironment.

Han X, Song X, Xiao Z, Zhu G, Gao R, Ni B Front Cell Dev Biol. 2024; 12:1310442.

PMID: 38404689 PMC: 10884319. DOI: 10.3389/fcell.2024.1310442.

ACT001 improved cardiovascular function in septic mice by inhibiting the production of proinflammatory cytokines and the expression of JAK-STAT signaling pathway.

Peng Z, Lv X, Wang X, Shang T, Chang J, Salahdiin K Front Pharmacol. 2023; 14:1265177.

PMID: 38094883 PMC: 10716238. DOI: 10.3389/fphar.2023.1265177.

ACT001 alleviates inflammation and pyroptosis through the PPAR-γ/NF-κB signaling pathway in LPS-induced alveolar macrophages.

Fu Q, Shen N, Fang T, Zhang H, Di Y, Liu X Genes Genomics. 2023; 46(3):323-332.

PMID: 37831404 DOI: 10.1007/s13258-023-01455-w.

References

Xi X, Liu N, Wang Q, Chu Y, Yin Z, Ding Y . ACT001, a novel PAI-1 inhibitor, exerts synergistic effects in combination with cisplatin by inhibiting PI3K/AKT pathway in glioma. Cell Death Dis. 2019; 10(10):757. PMC: 6779874. DOI: 10.1038/s41419-019-1986-2. View

Diana A, Carlino F, Franzese E, Oikonomidou O, Criscitiello C, De Vita F . Early Triple Negative Breast Cancer: Conventional Treatment and Emerging Therapeutic Landscapes. Cancers (Basel). 2020; 12(4). PMC: 7225917. DOI: 10.3390/cancers12040819. View

Su S, Liu Q, Chen J, Chen J, Chen F, He C . A positive feedback loop between mesenchymal-like cancer cells and macrophages is essential to breast cancer metastasis. Cancer Cell. 2014; 25(5):605-20. DOI: 10.1016/j.ccr.2014.03.021. View

Amorim M, Gil da Costa R, Lopes C, Bastos M . Sesquiterpene lactones: adverse health effects and toxicity mechanisms. Crit Rev Toxicol. 2013; 43(7):559-79. DOI: 10.3109/10408444.2013.813905. View

Aliper A, Frieden-Korovkina V, Buzdin A, Roumiantsev S, Zhavoronkov A . A role for G-CSF and GM-CSF in nonmyeloid cancers. Cancer Med. 2014; 3(4):737-46. PMC: 4303143. DOI: 10.1002/cam4.239. View

Finke J, Ko J, Rini B, Rayman P, Ireland J, Cohen P . MDSC as a mechanism of tumor escape from sunitinib mediated anti-angiogenic therapy. Int Immunopharmacol. 2011; 11(7):856-61. PMC: 3109226. DOI: 10.1016/j.intimp.2011.01.030. View

Nakshatri H, Bhat-Nakshatri P, Martin D, Goulet Jr R, Sledge Jr G . Constitutive activation of NF-kappaB during progression of breast cancer to hormone-independent growth. Mol Cell Biol. 1997; 17(7):3629-39. PMC: 232215. DOI: 10.1128/MCB.17.7.3629. View

De Sanctis F, Solito S, Ugel S, Molon B, Bronte V, Marigo I . MDSCs in cancer: Conceiving new prognostic and therapeutic targets. Biochim Biophys Acta. 2015; 1865(1):35-48. DOI: 10.1016/j.bbcan.2015.08.001. View

Taniguchi K, Karin M . NF-κB, inflammation, immunity and cancer: coming of age. Nat Rev Immunol. 2018; 18(5):309-324. DOI: 10.1038/nri.2017.142. View

10.

Zibara K, Awada Z, Dib L, El-Saghir J, Al-Ghadban S, Ibrik A . Anti-angiogenesis therapy and gap junction inhibition reduce MDA-MB-231 breast cancer cell invasion and metastasis in vitro and in vivo. Sci Rep. 2015; 5:12598. PMC: 4517444. DOI: 10.1038/srep12598. View

11.

Vagia E, Mahalingam D, Cristofanilli M . The Landscape of Targeted Therapies in TNBC. Cancers (Basel). 2020; 12(4). PMC: 7226210. DOI: 10.3390/cancers12040916. View

12.

Jin X, Jia Y, Shi Y, Li Q, Bao S, Lu W . ACT001 can prevent and reverse tamoxifen resistance in human breast cancer cell lines by inhibiting NF-κB activation. J Cell Biochem. 2018; 120(2):1386-1397. DOI: 10.1002/jcb.27146. View

13.

Suarez I, Salmeron-Garcia A, Cabeza J, Capitan-Vallvey L, Navas N . Development and use of specific ELISA methods for quantifying the biological activity of bevacizumab, cetuximab and trastuzumab in stability studies. J Chromatogr B Analyt Technol Biomed Life Sci. 2016; 1032:155-164. DOI: 10.1016/j.jchromb.2016.05.045. View

14.

Valdembri D, Serini G, Vacca A, Ribatti D, Bussolino F . In vivo activation of JAK2/STAT-3 pathway during angiogenesis induced by GM-CSF. FASEB J. 2001; 16(2):225-7. DOI: 10.1096/fj.01-0633fje. View

15.

Shou D, Wen L, Song Z, Yin J, Sun Q, Gong W . Suppressive role of myeloid-derived suppressor cells (MDSCs) in the microenvironment of breast cancer and targeted immunotherapies. Oncotarget. 2016; 7(39):64505-64511. PMC: 5325458. DOI: 10.18632/oncotarget.11352. View

16.

Morales J, Kmieciak M, Knutson K, Bear H, Manjili M . GM-CSF is one of the main breast tumor-derived soluble factors involved in the differentiation of CD11b-Gr1- bone marrow progenitor cells into myeloid-derived suppressor cells. Breast Cancer Res Treat. 2009; 123(1):39-49. PMC: 3095485. DOI: 10.1007/s10549-009-0622-8. View

17.

Lee J, Kang M, Byun W, Kim S, Seo I, Han J . Metformin overcomes resistance to cisplatin in triple-negative breast cancer (TNBC) cells by targeting RAD51. Breast Cancer Res. 2019; 21(1):115. PMC: 6805313. DOI: 10.1186/s13058-019-1204-2. View

18.

Elsawaf Z, Sinn H . Triple-Negative Breast Cancer: Clinical and Histological Correlations. Breast Care (Basel). 2011; 6(4):273-278. PMC: 3225211. DOI: 10.1159/000331643. View

19.

Sanmamed M, Chen L . A Paradigm Shift in Cancer Immunotherapy: From Enhancement to Normalization. Cell. 2018; 175(2):313-326. PMC: 6538253. DOI: 10.1016/j.cell.2018.09.035. View

20.

Diaz-Montero C, Salem M, Nishimura M, Garrett-Mayer E, Cole D, Montero A . Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy. Cancer Immunol Immunother. 2008; 58(1):49-59. PMC: 3401888. DOI: 10.1007/s00262-008-0523-4. View