sulphoraphene and erucin

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.. 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.. 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.. 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.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Cell Survival; Drug Resistance, Neoplasm; Female; Humans; Isothiocyanates; Lapatinib; Quinazolines; Receptor, ErbB-2; Signal Transduction; Sulfides; Sulfoxides; Thiocyanates

Nearly 25% of all breast cancer is characterized by overexpression of HER2 (human epidermal growth factor receptor 2) which leads to overactivation of prosurvival signal transduction pathways, especially through Akt-mTOR-S6K kinases, and results in enhanced proliferation, migration, induction of angiogenesis, and apoptosis inhibition. Anti-HER2 targeted therapies, such as specific monoclonal antibodies or small-molecule tyrosine kinase inhibitors, even in combination, still seem to be insufficient due to incidence of primary or acquired resistance and prevalence of serious side-effects of these drugs. We assumed that combination of compounds that target different levels of the above-mentioned signal transduction pathway might be more effective in eradication of breast cancer cells. In our in vitro research we used a commercially available drug, lapatinib, acting at the level of the receptor in combination with 1 of the plant-derived isothiocyanates: sulforaphane, erucin, or sulforaphene, as it has been shown previously that sulforaphane inhibits Akt-mTOR-S6K1 pathway in breast cancer cells. We used 2 HER2 overexpressing breast cancer cell lines, SKBR-3 and BT-474. Combinations of the drug and isothiocyanates considerably decreased their viability. This action was synergistic and was accompanied by a decrease in phosphorylation of HER2, Akt, and S6. Combined treatment induced apoptosis more efficiently than either agent alone; however the most effective was a combination of lapatinib with erucin. These findings might support the optimization of therapy based on lapatinib treatment.

Topics: Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Female; Gene Expression Regulation, Neoplastic; Humans; Isothiocyanates; Lapatinib; Proto-Oncogene Proteins c-akt; Quinazolines; Receptor, ErbB-2; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Sulfides; Sulfoxides; Thiocyanates; TOR Serine-Threonine Kinases