title: Combination of lapatinib with isothiocyanates overcomes drug resistance and inhibits migration of HER2 positive breast cancer cells.
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.
authors.affiliation: Department of Molecular Biology, Faculty of Biology, University of Gdańsk, Wita Stwosza 59, 80-308, Gdańsk, Poland.
authors.forename: Angelika
authors.initials: A
authors.lastname: Kaczyńska
authors.affiliation: Department of Molecular Biology, Faculty of Biology, University of Gdańsk, Wita Stwosza 59, 80-308, Gdańsk, Poland. anna.herman-antosiewicz@biol.ug.edu.pl.
authors.forename: Anna
authors.initials: A
authors.lastname: Herman-Antosiewicz
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006801:Humans; D017879:Isothiocyanates / Q000008:administration & dosage; D000077341:Lapatinib; D011799:Quinazolines / Q000008:administration & dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013440:Sulfides / Q000008:administration & dosage; D013454:Sulfoxides; D013861:Thiocyanates / Q000008:administration & dosage
chemical_list: D017879:Isothiocyanates; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D013440:Sulfides; D013454:Sulfoxides; D013861:Thiocyanates; C073539:erucin; C508053:ERBB2 protein, human; C016766:sulforaphane; C473643:sulphoraphene
keywords: Erucin; HER2; Isothiocyanates; Lapatinib resistance