Sensitization of HER2 Positive Breast Cancer Cells to Lapatinib Using Plants-Derived Isothiocyanates
Angelika Kaczyńska1, Joanna Świerczyńska, Anna Herman-Antosiewicz
1a Department of Molecular Biology, University of Gdańsk , Gdańsk , Poland.
Abstract:
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.
Insights
Combining lapatinib with plant-derived isothiocyanates like erucin shows synergistic effects against HER2-positive breast cancer cells. This novel approach enhances apoptosis and reduces cell viability, offering a promising strategy for optimizing anti-HER2 therapies.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- HER2 overexpression drives aggressive breast cancer through prosurvival pathways like Akt-mTOR-S6K.
- Current anti-HER2 therapies face resistance and side effects, necessitating novel treatment strategies.
- Targeting multiple levels of the HER2 signaling pathway may overcome treatment limitations.
Purpose of the Study:
- To investigate the synergistic efficacy of lapatinib combined with plant-derived isothiocyanates (sulforaphane, erucin, sulforaphene) against HER2-overexpressing breast cancer cells.
- To evaluate the impact of combined treatment on cell viability, apoptosis, and key signaling pathway components.
- To identify the most effective isothiocyanate combination with lapatinib for potential therapeutic optimization.
Main Methods:
- In vitro study using HER2-overexpressing breast cancer cell lines (SKBR-3, BT-474).
- Treatment with lapatinib (a tyrosine kinase inhibitor) in combination with sulforaphane, erucin, or sulforaphene.
- Assessment of cell viability, apoptosis induction, and phosphorylation levels of HER2, Akt, and S6.
Main Results:
- Combined treatment with lapatinib and isothiocyanates synergistically decreased breast cancer cell viability.
- The combination therapy led to reduced phosphorylation of HER2, Akt, and S6 signaling proteins.
- Combined treatment significantly enhanced apoptosis induction compared to individual agents, with lapatinib and erucin showing the highest efficacy.
Conclusions:
- Combination therapy targeting different levels of the HER2 pathway, specifically lapatinib with isothiocyanates, demonstrates synergistic anti-cancer effects.
- Erucin, in combination with lapatinib, emerged as a particularly effective agent for inducing apoptosis and reducing viability in HER2-positive breast cancer cells.
- These findings support the potential optimization of lapatinib-based therapies by incorporating plant-derived compounds like erucin for improved breast cancer treatment outcomes.
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