Sorafenib improves alkylating therapy by blocking induced inflammation, invasion and angiogenesis in breast cancer cells.
| Title: | Sorafenib improves alkylating therapy by blocking induced inflammation, invasion and angiogenesis in breast cancer cells. |
|---|---|
| Authors: | Zanotto-Filho A; Greehey Children's Cancer Research Institute, University of Texas Health at San Antonio, San Antonio, TX, USA; Departamento de Farmacologia, Universidade Federal de Santa Catarina (UFSC), Florianópolis, SC, Brazil.; Rajamanickam S; Greehey Children's Cancer Research Institute, University of Texas Health at San Antonio, San Antonio, TX, USA.; Loranc E; Greehey Children's Cancer Research Institute, University of Texas Health at San Antonio, San Antonio, TX, USA.; Masamsetti VP; Greehey Children's Cancer Research Institute, University of Texas Health at San Antonio, San Antonio, TX, USA.; Gorthi A; Greehey Children's Cancer Research Institute, University of Texas Health at San Antonio, San Antonio, TX, USA; Department of Cell Systems and Anatomy, University of Texas Health at San Antonio, San Antonio, TX, USA.; Romero JC; Greehey Children's Cancer Research Institute, University of Texas Health at San Antonio, San Antonio, TX, USA; Department of Cell Systems and Anatomy, University of Texas Health at San Antonio, San Antonio, TX, USA.; Tonapi S; Greehey Children's Cancer Research Institute, University of Texas Health at San Antonio, San Antonio, TX, USA; Department of Cell Systems and Anatomy, University of Texas Health at San Antonio, San Antonio, TX, USA.; Gonçalves RM; Departamento de Farmacologia, Universidade Federal de Santa Catarina (UFSC), Florianópolis, SC, Brazil.; Reddick RL; Department of Pathology, University of Texas Health at San Antonio, San Antonio, TX, USA.; Benavides R; Department of Pathology, University of Texas College of Pharmacy, Austin, TX, USA.; Kuhn J; Department of Pathology, University of Texas Health at San Antonio, San Antonio, TX, USA; Department of Pathology, University of Texas College of Pharmacy, Austin, TX, USA.; Chen Y; Department of Epidemiology and Biostatistics, University of Texas Health at San Antonio, San Antonio, TX, USA.; Bishop AJR; Greehey Children's Cancer Research Institute, University of Texas Health at San Antonio, San Antonio, TX, USA; Department of Cell Systems and Anatomy, University of Texas Health at San Antonio, San Antonio, TX, USA. Electronic address: bishopa@uthscsa.edu. |
| Source: | Cancer letters [Cancer Lett] 2018 Jul 01; Vol. 425, pp. 101-115. Date of Electronic Publication: 2018 Mar 30. |
| Publication Type: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. |
| Language: | English |
| Journal Info: | Publisher: Elsevier Science Ireland Country of Publication: Ireland NLM ID: 7600053 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1872-7980 (Electronic) Linking ISSN: 03043835 NLM ISO Abbreviation: Cancer Lett Subsets: MEDLINE |
| Imprint Name(s): | Publication: Limerick : Elsevier Science Ireland; Original Publication: Amsterdam, Elsevier/North-Holland. |
| MeSH Terms: | Antineoplastic Agents, Alkylating/*administration & dosage ; Breast Neoplasms/*drug therapy ; Cyclophosphamide/*administration & dosage ; Neovascularization, Pathologic/*drug therapy ; Sorafenib/*administration & dosage; Antineoplastic Agents, Alkylating/pharmacology ; Breast Neoplasms/metabolism ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Cyclophosphamide/pharmacology ; Gene Expression Regulation, Neoplastic/drug effects ; Signal Transduction/drug effects ; Sorafenib/pharmacology ; Animals ; Cell Line, Tumor ; Drug Synergism ; Female ; Humans ; MCF-7 Cells ; Mice ; Xenograft Model Antitumor Assays |
| Abstract: | Molecular targeted compounds are emerging as a strategy to improve classical chemotherapy. Herein, we describe that using low dose of the multikinase inhibitor sorafenib improves cyclophosphamide antitumor activity by inhibiting angiogenesis, metastasis and promoting tumor healing in MDA-MB231 xenografts and the 4T1-12B syngeneic breast cancer metastasis model. Mechanistic studies in MDA-MB231 cells revealed that alkylation upregulates inflammatory genes/proteins such as COX-2, IL8, CXCL2 and MMP1 in a MEK1/2-ERK1/2-dependent manner. These proteins enrich the secretome of cancer cells, stimulating cell invasion and angiogenesis via autocrine and paracrine mechanisms. Sorafenib inhibits MEK1/2-ERK1/2 pathway thereby decreasing inflammatory genes and mitigating cell invasion and angiogenesis at basal and alkylation-induced conditions whereas NRF2 and ER stress pathways involved in alkylation survival are not affected. In non-invasive/non-angiogenic breast cancer cells (SKBR3 and MCF7), alkylation did not elicit inflammatory responses with the only sorafenib effect being ERK1/2-independent ROS-dependent cytotoxicity when using higher drug concentrations. In summary, our data show that alkylating agents may elicit inflammatory responses that seems to contribute to malignant progression in specific breast cancer cells. Identifying and targeting drivers of this phenotype may offer opportunities to optimize combined drug regimens between classical chemotherapeutics and targeted agents.; (Copyright © 2018 Elsevier B.V. All rights reserved.) |
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| Grant Information: | R15 ES019128 United States ES NIEHS NIH HHS; S10 OD021805 United States OD NIH HHS; T32 CA148724 United States CA NCI NIH HHS; P30 CA054174 United States CA NCI NIH HHS; K22 ES012264 United States ES NIEHS NIH HHS; R01 CA152063 United States CA NCI NIH HHS |
| Contributed Indexing: | Keywords: Alkylation; Inflammation; MEK1/2-ERK1/2; Secretome; Sorafenib |
| Substance Nomenclature: | 0 (Antineoplastic Agents, Alkylating); 8N3DW7272P (Cyclophosphamide); 9ZOQ3TZI87 (Sorafenib) |
| Entry Date(s): | Date Created: 20180403 Date Completed: 20190611 Latest Revision: 20240223 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC5930000 |
| DOI: | 10.1016/j.canlet.2018.03.037 |
| PMID: | 29608984 |
| Database: | MEDLINE |
Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.