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Updated: Feb 12, 2026
Invasive Behavior of Human Breast Cancer Cells in Embryonic Zebrafish
Published on: April 25, 2017
Sorafenib improves alkylating therapy by blocking induced inflammation, invasion and angiogenesis in breast cancer
Alfeu Zanotto-Filho1, Subapriya Rajamanickam2, Eva Loranc2
1Greehey 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.
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.
Insights
Low-dose sorafenib enhances chemotherapy by inhibiting inflammation and promoting tumor healing in breast cancer models. This targeted approach improves treatment efficacy by blocking key pathways involved in cancer progression.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Classical chemotherapy faces limitations in improving antitumor activity.
- Molecular targeted compounds offer a promising strategy to enhance chemotherapy efficacy.
- Understanding drug-induced cellular responses is crucial for optimizing combination therapies.
Purpose of the Study:
- To investigate the synergistic effect of sorafenib and cyclophosphamide in breast cancer treatment.
- To elucidate the molecular mechanisms underlying the enhanced antitumor activity.
- To explore the role of inflammatory pathways in chemotherapy response.
Main Methods:
- Utilized MDA-MB231 xenografts and 4T1-12B syngeneic metastasis models.
- Administered low-dose sorafenib in combination with cyclophosphamide.
- Performed mechanistic studies involving gene/protein expression analysis (COX-2, IL8, CXCL2, MMP1) and pathway analysis (MEK1/2-ERK1/2, NRF2, ER stress).
Main Results:
- Low-dose sorafenib significantly improved cyclophosphamide's antitumor activity by inhibiting angiogenesis and metastasis.
- Cyclophosphamide upregulated inflammatory genes (COX-2, IL8, CXCL2, MMP1) via the MEK1/2-ERK1/2 pathway, promoting invasion and angiogenesis.
- Sorafenib effectively inhibited this inflammatory pathway, mitigating cancer cell invasion and angiogenesis.
- NRF2 and ER stress pathways were unaffected by sorafenib.
- In non-invasive cells, sorafenib showed ROS-dependent cytotoxicity at higher concentrations, independent of ERK1/2.
Conclusions:
- Alkylating agents can induce inflammatory responses that contribute to malignant progression in certain breast cancer subtypes.
- Targeting these inflammation-driven pathways offers a strategy to optimize combination regimens of chemotherapy and targeted agents.
- Combined therapy with sorafenib and cyclophosphamide shows potential for improved breast cancer treatment outcomes.
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