4.6 Article

Lapatinib inhibits doxorubicin induced migration of HER2-positive breast cancer cells

Journal

INFLAMMOPHARMACOLOGY
Volume 28, Issue 5, Pages 1375-1386

Publisher

SPRINGER BASEL AG
DOI: 10.1007/s10787-020-00711-9

Keywords

Cancer; Metastasis; Cytoskeleton; Therapy; Doxorubicin; Lapatinib

Funding

  1. Environmental Futures Research Institute, Griffith University, Australia
  2. School of Environment and Science, Griffith University, Australia

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Inflammatory breast cancer (IBC) is an uncommon and highly aggressive form of breast cancer. The disease is characterized by rapid progression with approximately 50% of IBC patients to have human epidermal growth factor receptor 2 (HER2) amplification. HER2-positive IBC is associated with unfavourable prognosis and increased risk of brain metastasis. Ironically, HER2-positive metastatic breast cancer is still prevalent where therapeutic targeting of HER2-receptor is well developed. In addition, the ability to accurately predict the risk of metastatic potential in these cells poses a substantial challenge. Lapatinib (Lap), a dual kinase inhibitor of HER2 and epidermal growth factor receptor is used in the treatment of advanced HER-2 positive breast cancers and is currently being evaluated in the adjuvant setting. In this study, we report the effectiveness of Lap in the suppression of low-dose response to doxorubicin (Dox) in HER2-positive SKBR3 cells. Upon treatment of SKBR3 cells with 0.1 mu M of Dox, the cell viability was significantly increased as compared to the human mammary fibroblasts, and triple-negative human breast cancer MDA-MB-231 cells. Interestingly, the effect of 0.1 mu M Dox revealed morphological changes consistent with a significant increase in the formation of prominent F-actin filaments and mitochondrial spread compared with the control SKBR3 cells. Furthermore, an enhanced migration was also evident in these cells. However, a combinational dose of 0.1 mu M Dox + 5 mu M Lap suppressed the observed phenotypic changes in the 0.1 mu M Dox treated SKBR3 cells. There was a significant difference in the prominent F-actin filaments and the mitochondrial spread compared with the 0.1 mu M Dox versus combination regimen of 0.1 mu M Dox + 5 mu M Lap. In addition, the combinational therapy showed a decrease in the percentage of wound closure when compared to the control. Hence, the combinational therapy in which Lap suppresses the low-dose effect of Dox in SKBR3 cells may provide an effective intervention strategy for reducing the risk of metastasis in HER2-positive breast cancers.

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