HSP90 inhibition in HER2-positive breast cancer cells

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e14573-e14573
Author(s):  
Z. Qadir ◽  
J. Crown ◽  
M. R. Jensen ◽  
M. Clynes ◽  
D. Slamon ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Breast Cancer Cells ◽  
Hsp90 Inhibitor ◽  
Breast Cancer Cell Lines ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer Cell ◽  
Positive Breast Cancer

e14573 Background: HSP90 is required for the stability and activity of HER2 and downstream proteins, such as Akt, which play a key role in survival. We aimed to assess the anti-tumor effect of the HSP90 inhibitor NVP-AUY922 in HER-2 positive breast cancer cell lines. Methods: HER2 positive breast cancer cell lines with varied sensitivity to trastuzumab (Sensitive: BT474, SKBR3; acquired resistance: BT474Res, SKBR3Res; innate resistance: HCC1419, HCC1954, MDA-MB-453) were treated with the HSP90 inhibitor NVP-AUY922 (Novartis) and trastuzumab. IC50s were determined using the acid phosphatase assay. HER2, Akt and HSP90 levels were determined by immunoblotting after treatment with NVP-AUY922. Combinations of NVP-AUY922 with docetaxel, cisplatin and 5'-deoxy-5-fluorouridine (5-DFUR) were tested in BT474 and SKBR3 cells. Results: All of the HER2 positive cells were sensitive to NVP-AUY922, with IC50s ranging from 5.5 to 16.4 nM. Combined treatment with NVP-AUY922 (10 nM) and trastuzumab (10 nM) showed significantly greater inhibition of growth than either trastuzumab or NVP-AUY922 alone in BT474 and BT474Res cell lines (p<0.005). In SKBR3 and SKBR3Res cells, dual treatment with NVP-AUY922 and trastuzumab did not significantly increase response compared to NVP-AUY922 alone ( Table 1 ). Treatment with NVP-AUY922 resulted in a dose-dependent decrease in HER2 and Akt levels in trastuzumab-sensitive and -resistant cells. Combinations of docetaxel, cisplatin or 5-DFUR with NVP- AUY922 were antagonistic in both BT474 and SKBR3 cells (CI values >1). Conclusions: This study demonstrates that NVP-AUY922 has anti-tumor activity in trastuzumab-sensitive, and in both innate and acquired trastuzumab-resistant HER2 positive breast cancer cells. The antagonistic interactions observed for combinations of NVP-AUY922 with chemotherapy do not favour clinical evaluation of such combinations. However, combinations with other targeted therapies, such as trastuzumab, warrant further investigation. [Table: see text] [Table: see text]

scholarly journals Trastuzumab in combination with AT-101 induces cytotoxicity and apoptosis in Her2 positive breast cancer cells

2020 ◽  
Vol 16 (3) ◽  
pp. 4485-4495
Author(s):  
Gulcan Bulut ◽  
Harika Atmaca ◽  
Burcak Karaca
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Breast Cancer Cells ◽  
Breast Cancer Cell Lines ◽  
Her2 Positive ◽  
Protein Levels ◽  
Her2 Positive Breast Cancer ◽  
Synergistic Cytotoxicity ◽  
Positive Breast Cancer

Aim: AT-101 is a polyphenolic compound with potent anti-apoptotic effects in various cancers. In this study, the possible synergistic cytotoxic and apoptotic effect of trastuzumab/AT-101 combination was investigated in HER2-positive breast cancer cell lines. Materials & methods: SKBR-3, MDA-MB-453 and MCF-10A cell lines were treated with a trastuzumab/AT-101 combination. Synergistic cytotoxicity and apoptosis effects were shown and then PI3K and Akt protein levels were studied. Result: The trastuzumab/AT-101 combination induced synergistic cytotoxicity and apoptosis in both breast cancer cells but not in MCF-10A cells. Combination treatment induced cytotoxicity via inhibiting PI3K/AKT but not the MAPK/ERK pathway. Conclusion: The trastuzumab/AT-101 combination may be a good candidate for patients with trastuzumab-resistant Her2-positive breast cancer and inhibition of the PI3K/AKT pathway may be one of the underlying mechanisms.

Radiosensitization of HER2-positive breast cancer cell lines with trastuzumab.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e11501-e11501 ◽  
Author(s):  
Senem Demirci Alanyali ◽  
Emir Bozkurt ◽  
Hilmi Alanyali ◽  
Burcak Karaca ◽  
Ruchan Uslu
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Cancer Cells ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer Cell ◽  
Positive Breast Cancer

e11501 Background: HER2 is a member of the human epidermal growth factor (EGF) receptor family that is blocked by a monoclonal antibody, Trastuzumab (Herceptin). In daily clinical practice, Trastuzumab is being used concurrently with radiotherapy (RT) in breast cancer patients. Administration of Trastuzumab with RT appear to be safe in regard to cardiac morbidity and mortality in patients with relatively modest follow-up duration (less than 5 years). In this study we aimed to determine the possible interactions between RT and Trastuzumab in HER2 positive breast cancer cell line MDA-MB-453. Methods: MDA-MB-453 cells were treated with increased dose of Trastuzumab (10 – 200 µg/mL, 72 hours) and irradiation (0-8 Gy, 4 Gy/min, 48 hours). XTT (Roche) viability assay was used to measure the cytotoxicity of Trastuzumab, and trypan blue method was used to measure the cytotoxicity of irradiation. The sensitization of MDA-MB-453 cell lines was done by IC50 of Trastuzumab with 24 hours treatment followed by 6 and 8 Gy irradiation. Results: Cytotoxicity was increased in a dose and time dependent manner by Trastuzumab and irradiation treatment in MDA-MB-453 cell lines. IC50 values of Trastuzumab and irradiation were found to be 167 µg/mL and 8 Gy, at 48 hours, respectively.Cells were pretreated with IC25 and IC50 doses of Trastuzumab for 24 hours and then irradiated with 6 and 8 Gy doses. The cell viability at 24 and 48 hours were significantly decreased (p=0.0012) compared to single exposures (Trastuzumab or irradiation), indicating that Trastuzumab sensitizes HER2 positive breast cancer cells to irradiation. Conclusions: This preliminary study showed the sensitization effect of Trastuzumab to irradiation in HER2 positive breast cancer cells. Further studies are warranted for the optimal dosing and normal tissue toxicity of this combination.

scholarly journals Novel Nitrogen-Based Chalcone Analogs Provoke Substantial Apoptosis in HER2-Positive Human Breast Cancer Cells via JNK and ERK1/ERK2 Signaling Pathways

2021 ◽  
Vol 22 (17) ◽  
pp. 9621
Author(s):  
Balsam Rizeq ◽  
Ishita Gupta ◽  
Hadeel Kheraldine ◽  
Dana Elkhalifa ◽  
Halema F. Al-Farsi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Cell Lines ◽  
Breast Cancer Cells ◽  
Chorioallantoic Membrane ◽  
Breast Cancer Cell Lines ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

Natural chalcones possess antitumor properties and play a role as inducers of apoptosis, antioxidants and cytotoxic compounds. We recently reported that novel nitrogen chalcone-based compounds, which were generated in our lab, have specific effects on triple-negative breast cancer cells. However, the outcome of these two new compounds on human epidermal growth factor receptor 2 (HER2)-positive breast cancer remains nascent. Thus, we herein investigated the effects of these compounds (DK-13 and DK-14) on two HER2-positive breast cancer cell lines, SKBR3 and ZR75. Our data revealed that these compounds inhibit cell proliferation, deregulate cell-cycle progression and significantly induce cell apoptosis in both cell lines. Furthermore, the two chalcone compounds cause a significant reduction in the cell invasion ability of SKBR3 and ZR75 cancer cells. In parallel, we found that DK-13 and DK-14 inhibit colony formation of both cell lines in comparison to their matched controls. On the other hand, we noticed that these two compounds can inhibit angiogenesis in the chorioallantoic membrane model. The molecular pathway analysis of chalcone compounds exposed cells revealed that these compounds inhibit the expression of both JNK1/2/3 and ERK1/2, the major plausible molecular pathways behind these events. Our findings implicate that DK-13 and DK-14 possess effective chemotherapeutic outcomes against HER2-positive breast cancer via the ERK1/2 and JNK1/2/3 signaling pathways.

Pyrotinib sensitizes 5‑fluorouracil‑resistant HER2-positive breast cancer cells to 5‑fluorouracil

2020 ◽  
Author(s):  
Jianing Yi ◽  
Pingyong Yi ◽  
Shuai Chen ◽  
Qian Li ◽  
Runzhang Wu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Combination Treatment ◽  
Breast Cancer Cells ◽  
Continuous Exposure ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Her2 Breast Cancer ◽  
Positive Breast Cancer

Abstract BACKGROUND: Clinical trials have shown that pyrotinib+ capecitabine significantly improved efficacy of patients with human epidermal growth factor receptor 2(HER2) +breast cancer. However, whether pyrotinib sensitizes 5‑Fluorouracil(5‑FU)‑resistant breast cancer cells to 5‑FU is unknown. This study aimed to investigate the effects of pyrotinib on HER2+breast cancer cells with resistance to 5‑FU and provide new clues for the pyrotinib treatment in 5-FU-resistant breast cancer.METHODS: the 5‑FU‑resistant breast cancer cell lines SK-BR-3/FU and MAD-MB-453/FU were established by continuous exposure of the parental cells to 5‑FU.The effects of pyrotinib on these cell lines were examined by growth inhibitory activity assay, reverse transcription‑quantitative polymerase chain reaction, Western blot analysis, high-performance liquid chromatography and animal experiments.RESULTS: Pyrotinib inhibited the proliferation of 5-FU-resistant and parental HER2-positive breast cancer cells and re-sensitized resistant cells to 5-FU by decreasing the expression of thymidylate synthase(TS) and ABC transporter subfamily G member 2(ABCG2). In a xenograft model, combination treatment with 5-FU and pyrotinib showed greater antitumor activity than either agent alone. CONCLUSIONS: Our results offer a preclinical rationale for clinical investigations of combination treatment with pyrotinib and 5-FU for 5-FU-resistant HER2-positive breast cancer.

MALAT1 Promotes Tumorigenesis and Increases Cellular Sensitivity to Herceptin in HER2-positive Breast Cancer

2021 ◽  
Vol 21 ◽  
Author(s):  
Chuansheng Yang ◽  
Hongbo Zhu ◽  
Yeru Tan ◽  
Renjie Zhu ◽  
Xiaoping Wu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Breast Cancer Cells ◽  
Her2 Positive ◽  
Mouse Xenograft ◽  
Her2 Positive Breast Cancer ◽  
Potential Biomarker ◽  
Mouse Xenograft Model ◽  
Positive Breast Cancer

Background: The function of MALAT1, a kind of long non-coding RNAs (lncRNA), in HER2-positive breast cancer remains largely unexplored. Therefore, there is a need investigate the effect of MALAT1 on tumor development in HER2-positive breast cancer. Objectives: We detected MALAT1 expression in HER2-positive breast cancer cells and tissues and analyzed the effects of MALAT1 on cell proliferation in HER2-positive breast cancer cell lines (BT-474 and SKBR3). Methods: A mouse xenograft model was established for detecting the function of MALAT1 in HER2-positive breast cancer. Results amp; Discussion: As a result, MALAT1 was remarkably up-regulated in HER2-positive breast cancer both in cells and tissues. In addition, the silence of MALAT1 inhibited the proliferation of HER2-positive breast cancer cells both in vitro and in vivo. Furthermore, the knockdown of MALAT1 by shRNA down-regulated DNMT1, DNMT3a, and DNMT3b, while up-regulated BRCA1 and PTEN in HER2-positive breast cancer both in cell lines and mouse xenograft models. Conclusion: In short, MALAT1 might be a potential biomarker and therapeutic target for HER2-positive breast cancer therapy.

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