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

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Abstract

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 µM 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 µM 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 µM Dox + 5 µM Lap suppressed the observed phenotypic changes in the 0.1 µM Dox treated SKBR3 cells. There was a significant difference in the prominent F-actin filaments and the mitochondrial spread compared with the 0.1 µM Dox versus combination regimen of 0.1 µM Dox + 5 µM 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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Acknowledgements

We are most grateful to Assoc. Prof. Kathryn Tonissen for the kind gift of doxorubicin used in these studies. This work was supported by the Environmental Futures Research Institute and the School of Environment and Science, Griffith University, Australia.

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Authors and Affiliations

  1. School of Environment and Science, Nathan Campusampus, Griffith University, 170 Kessels Road, Brisbane, QLD, 4111, Australia

    Naveen Chintalaramulu & Ian Edwin Cock

  2. Queensland Micro- and Nanotechnology Centre, Nathan Campus, Griffith University, 170 Kessels Road, Brisbane, QLD, 4111, Australia

    Raja Vadivelu & Nam-Trung Nguyen

  3. Department of Chemical System Engineering, University of Tokyo, Hongo 7-3-1, Bunkyo, Tokyo, 113-8656, Japan

    Raja Vadivelu

  4. Environmental Futures Research Institute, Nathan Campus, Griffith University, 170 Kessels Road, Brisbane, QLD, 4111, Australia

    Ian Edwin Cock

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  1. Naveen Chintalaramulu
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Chintalaramulu, N., Vadivelu, R., Nguyen, NT. et al. Lapatinib inhibits doxorubicin induced migration of HER2-positive breast cancer cells. Inflammopharmacol 28, 1375–1386 (2020). https://doi.org/10.1007/s10787-020-00711-9

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