Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Breast Cancer
Published in: Breast Cancer 2/2017

Open Access 01-03-2017 | Original Article

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

Authors: Angelika Kaczyńska, Anna Herman-Antosiewicz

Published in: Breast Cancer | Issue 2/2017

Login to get access

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.
Literature
1.
Da Silva L, Simpson PT, Smart CE, Cocciardi S, Waddell N, et al. HER3 and downstream pathways are involved in colonization of brain metastases from breast cancer. Breast Cancer Res. 2010;12:R46.CrossRefPubMedPubMedCentral
2.
Hicks DG, Short SM, Prescott NL, Tarr SM, Coleman KA, et al. Breast cancers with brain metastases are more likely to be estrogen receptor negative, express the basal cytokeratin CK5/6, and overexpress HER2 or EGFR. Am J Surg Pathol. 2006;30:1097–104.CrossRefPubMed
3.
4.
Rana P, Sridhar SS. Efficacy and tolerability of lapatinib in the management of breast cancer. Breast Cancer (Auckl). 2012;6:67–77.
5.
Yin W, Jiang Y, Shen Z, Shao Z, Lu J. Trastuzumab in the adjuvant treatment of HER2-positive early breast cancer patients: a meta-analysis of published randomized controlled trials. PLoS One. 2011;6:e21030.CrossRefPubMedPubMedCentral
6.
Montemurro F, Redana S, Viale G, Sanna G, Donadio M, et al. Retrospective evaluation of clinical outcomes in patients with HER2-positive advanced breast cancer progressing on trastuzumab-based therapy in the pre-lapatinib era. Clin Breast Cancer. 2008;8:436–42.CrossRefPubMed
7.
Franklin MC, Carey KD, Vajdos FF, Leahy DJ, de Vos AM, et al. Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell. 2004;5:317–28.CrossRefPubMed
8.
Baselga J, Cortes J, Kim SB, Im SA, Hegg R, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109–19.CrossRefPubMed
9.
10.
Bartsch R, Berghoff AS, Vogl U, Rudas M, Bergen E, et al. Activity of T-DM1 in Her2-positive breast cancer brain metastases. Clin Exp Metastasis. 2015;32:729–37.CrossRefPubMed
11.
Wang YC, Morrison G, Gillihan R, Guo J, Ward RM, et al. Different mechanisms for resistance to trastuzumab versus lapatinib in HER2-positive breast cancers—role of estrogen receptor and HER2 reactivation. Breast Cancer Res. 2011;13:R121.CrossRefPubMedPubMedCentral
12.
Chen FL, Xia W, Spector NL. Acquired resistance to small molecule ErbB2 tyrosine kinase inhibitors. Clin Cancer Res. 2008;14:6730–4.CrossRefPubMed
13.
Formisano L, Nappi L, Rosa R, Marciano R, D’Amato C, et al. Epidermal growth factor-receptor activation modulates Src-dependent resistance to lapatinib in breast cancer models. Breast Cancer Res. 2014;16:R45.CrossRefPubMedPubMedCentral
14.
O’Brien NA, Browne BC, Chow L, Wang Y, Ginther C, et al. Activated phosphoinositide 3-kinase/AKT signaling confers resistance to trastuzumab but not lapatinib. Mol Cancer Ther. 2010;9:1489–502.CrossRefPubMed
15.
Falchook GS, Moulder SL, Wheler JJ, Jiang Y, Bastida CC, et al. Dual HER2 inhibition in combination with anti-VEGF treatment is active in heavily pretreated HER2-positive breast cancer. Ann Oncol. 2013;24:3004–11.CrossRefPubMedPubMedCentral
16.
17.
Ghosh S, Basu M, Roy SS. ETS-1 protein regulates vascular endothelial growth factor-induced matrix metalloproteinase-9 and matrix metalloproteinase-13 expression in human ovarian carcinoma cell line SKOV-3. J Biol Chem. 2012;287:15001–15.CrossRefPubMedPubMedCentral
18.
Kaczyńska A, Świerczyńska J, Herman-Antosiewicz A. Sensitization of HER2 positive breast cancer cells to lapatinib using plants-derived isothiocyanates. Nutr Cancer. 2015;67:976–86.CrossRefPubMed
19.
Munday R, Munday CM. Induction of phase II detoxification enzymes in rats by plant-derived isothiocyanates: comparison of allyl isothiocyanate with sulforaphane and related compounds. J Agric Food Chem. 2004;52:1867–71.CrossRefPubMed
20.
Barcelo S, Gardiner JM, Gescher A, Chipman JK. CYP2E1-mediated mechanism of anti-genotoxicity of the broccoli constituent sulforaphane. Carcinogenesis. 1996;17:277–82.CrossRefPubMed
21.
22.
Suppipat K, Park CS, Shen Y, Zhu X, Lacorazza HD. Sulforaphane induces cell cycle arrest and apoptosis in acute lymphoblastic leukemia cells. PLoS One. 2012;7:e51251.CrossRefPubMedPubMedCentral
23.
Pawlik A, Wiczk A, Kaczyńska A, Antosiewicz J, Herman-Antosiewicz A. Sulforaphane inhibits growth of phenotypically different breast cancer cells. Eur J Nutr. 2013;52:1949–58.CrossRefPubMedPubMedCentral
24.
Tseng E, Scott-Ramsay EA, Morris ME. Dietary organic isothiocyanates are cytotoxic in human breast cancer MCF-7 and mammary epithelial MCF-12A cell lines. Exp Biol Med (Maywood). 2004;229:835–42.
25.
Sakao K, Singh SV. D, L-sulforaphane-induced apoptosis in human breast cancer cells is regulated by the adapter protein p66Shc. J Cell Biochem. 2012;113:599–610.CrossRefPubMedPubMedCentral
26.
Wu X, Zhu Y, Yan H, Liu B, Li Y, et al. Isothiocyanates induce oxidative stress and suppress the metastasis potential of human non-small cell lung cancer cells. BMC Cancer. 2010;10:269.CrossRefPubMedPubMedCentral
27.
Shankar S, Ganapathy S, Srivastava RK. Sulforaphane enhances the therapeutic potential of TRAIL in prostate cancer orthotopic model through regulation of apoptosis, metastasis, and angiogenesis. Clin Cancer Res. 2008;14:6855–66.CrossRefPubMed
28.
Gupta SC, Kim JH, Prasad S, Aggarwal BB. Regulation of survival, proliferation, invasion, angiogenesis, and metastasis of tumor cells through modulation of inflammatory pathways by nutraceuticals. Cancer Metastasis Rev. 2010;29:405–34.CrossRefPubMedPubMedCentral
29.
Bertl E, Bartsch H, Gerhauser C. Inhibition of angiogenesis and endothelial cell functions are novel sulforaphane-mediated mechanisms in chemoprevention. Mol Cancer Ther. 2006;5:575–85.CrossRefPubMed
30.
31.
32.
Rusnak DW, Lackey K, Affleck K, Wood ER, Alligood KJ, et al. The effects of the novel, reversible epidermal growth factor receptor/ErbB-2 tyrosine kinase inhibitor, GW2016, on the growth of human normal and tumor-derived cell lines in vitro and in vivo. Mol Cancer Ther. 2001;1:85–94.PubMed
33.
Leung WY, Roxanis I, Sheldon H, Buffa FM, Li JL, et al. Combining lapatinib and pertuzumab to overcome lapatinib resistance due to NRG1-mediated signalling in HER2-amplified breast cancer. Oncotarget. 2015;6:5678–94.CrossRefPubMedPubMedCentral
34.
Nelson MH, Dolder CR. A review of lapatinib ditosylate in the treatment of refractory or advanced breast cancer. Ther Clin Risk Manag. 2007;3:665–73.PubMedPubMedCentral
35.
Mukohara T. Role of HER2-targeted agents in adjuvant treatment for breast cancer. Chemother Res Pract. 2011;2011:730360.PubMedPubMedCentral
36.
Xia W, Bacus S, Hegde P, Husain I, Strum J, et al. A model of acquired autoresistance to a potent ErbB2 tyrosine kinase inhibitor and a therapeutic strategy to prevent its onset in breast cancer. Proc Natl Acad Sci USA. 2006;103:7795–800.CrossRefPubMedPubMedCentral
37.
Davis NM, Sokolosky M, Stadelman K, Abrams SL, Libra M, et al. Deregulation of the EGFR/PI3K/PTEN/Akt/mTORC1 pathway in breast cancer: possibilities for therapeutic intervention. Oncotarget. 2014;5:4603–50.CrossRefPubMedPubMedCentral
38.
Ren W, Liu Y, Wan S, Fei C, Wang W, et al. BMP9 inhibits proliferation and metastasis of HER2-positive SK-BR-3 breast cancer cells through ERK1/2 and PI3K/AKT pathways. PLoS One. 2014;9:e96816.CrossRefPubMedPubMedCentral
39.
Khotskaya YB, Goverdhan A, Shen J, Ponz-Sarvise M, Chang SS, et al. S6K1 promotes invasiveness of breast cancer cells in a model of metastasis of triple-negative breast cancer. Am J Transl Res. 2014;6:361–76.PubMedPubMedCentral
40.
Klos KS, Wyszomierski SL, Sun M, Tan M, Zhou X, et al. ErbB2 increases vascular endothelial growth factor protein synthesis via activation of mammalian target of rapamycin/p70S6K leading to increased angiogenesis and spontaneous metastasis of human breast cancer cells. Cancer Res. 2006;66:2028–37.CrossRefPubMed
Metadata
Title
Combination of lapatinib with isothiocyanates overcomes drug resistance and inhibits migration of HER2 positive breast cancer cells
Authors
Angelika Kaczyńska
Anna Herman-Antosiewicz
Publication date
01-03-2017
Publisher
Springer Japan
Published in
Breast Cancer / Issue 2/2017
Print ISSN: 1340-6868
Electronic ISSN: 1880-4233
DOI
https://doi.org/10.1007/s12282-016-0700-9

Other articles of this Issue 2/2017

Breast Cancer 2/2017 Go to the issue

Original Article

Different patterns of change in bone turnover markers during treatment with bone-modifying agents for breast cancer patients with bone metastases

Review Article

Systematic review of ixabepilone for treating metastatic breast cancer

Original Article

Pretreatment quality of life, performance status and their relation to treatment discontinuation and treatment changes in high-risk breast cancer patients receiving chemotherapy: results from the prospective randomized ADEBAR trial

Original Article

A unique hypofractionated radiotherapy schedule with 51.3 Gy in 18 fractions three times per week for early breast cancer: outcomes including local control, acute and late skin toxicity

Rapid Communication

Patterns of clinical practice for sentinel lymph node biopsy in women with node-negative breast cancer: the results of a national survey in Japan

Original Article

Anticancer effects of synthetic hexahydrobenzo [g]chromen-4-one derivatives on human breast cancer cell lines
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits