Combination of lapatinib with isothiocyanates overcomes drug resistance and inhibits migration of HER2 positive breast cancer cells

Angelika Kaczyńska , Anna Herman-Antosiewicz

Abstract

Background: Lapatinib is a commonly used drug that interrupts signaling from the epidermal growth factor receptors, EGFR and HER2/neu. Long-term exposure to lapatinib during therapy eliminates cells that are sensitive to the drug; however, at the same time it increases probability of lapatinib-resistant cell selection. The aim of this study was to verify whether combinations of lapatinib with one of isothiocyanates (sulforaphane, erucin or sulforaphene), targeting different levels of HER2 signaling pathway, exert stronger cytotoxic effect than therapy targeting the receptor only, using heterogeneous populations consisting of lapatinib-sensitive and lapatinib-resistant breast cancer cells. Methods: Lapatinib-sensitive HER2 overproducing SKBR-3 breast cancer cells and their lapatinib-resistant derivatives were combined at different proportions to simulate enrichment of cancer cell population in a drug-resistant fraction during lapatinib therapy. Effects of treatments on cell survival (MTT), apoptosis induction (PARP cleavage), prosurvival signaling (p-Akt, p-S6) as well as cell motility (wound healing assay) and invasion (Boyden chamber assay) were investigated. Results: Combination of lapatinib with any of isothiocyanates significantly decreased cell viability and inhibited migration of populations consisting of different amounts of drug-sensitive and drug-resistant cells. In case of population entirely composed of lapatinib-resistant cells the most effective was combination of lapatinib with erucin which decreased cell viability and motility, phosphorylation of Akt, S6 and VEGF level more efficiently than each agent alone. Conclusions: Combination of lapatinib and isothiocyanates, especially erucin, might be considered as an effective treatment reducing metastatic potential of breast cancer cells, even these with the drug resistance phenotype.
Author Angelika Kaczyńska KBM
Angelika Kaczyńska,,
- Department of Molecular Biology
, Anna Herman-Antosiewicz KBM
Anna Herman-Antosiewicz,,
- Department of Molecular Biology
Journal seriesBreast Cancer-Tokyo, ISSN 1340-6868
Issue year2017
Vol24
No2
Pages271-280
Publication size in sheets0.5
Keywords in EnglishHER2, isothiocyanates, erucin, lapatinib resistance
DOIDOI:10.1007/s12282-016-0700-9
URL http://link.springer.com/article/10.1007%2Fs12282-016-0700-9
Languageen angielski
LicenseOther; published final; Uznanie Autorstwa (CC-BY); with publication
Score (nominal)20
ScoreMinisterial score = 20.0, 20-12-2017, ArticleFromJournal
Ministerial score (2013-2016) = 20.0, 20-12-2017, ArticleFromJournal
Publication indicators WoS Impact Factor: 2016 = 1.572 (2) - 2016=1.561 (5)
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