scholarly journals Selenium inhibits growth of trastuzumab-resistant human breast cancer cells via downregulation of Akt and beclin-1

PLoS ONE ◽  
2021 ◽  
Vol 16 (9) ◽  
pp. e0257298
Author(s):  
Joohyun Woo ◽  
Jong Bin Kim ◽  
Taeeun Cho ◽  
Eun Hye Yoo ◽  
Byung-In Moon ◽  
...  

The response rate to treatment with trastuzumab (Tz), a recombinant humanized anti-HER2 monoclonal antibody, is only 12–34% despite demonstrated effectiveness on improving the survival of patients with HER2-positive breast cancers. Selenium has an antitumor effect against cancer cells and can play a cytoprotective role on normal cells. This study investigated the effect of selenium on HER2-positive breast cancer cells and the mechanism in relation to the response of the cells to Tz. HER2-positive breast cancer cell lines, SK-BR-3 as trastuzumab-sensitive cells, and JIMT-1 as Tz-resistant cells were treated with Tz and sodium selenite (selenite). Cell survival rates and expression of Her2, Akt, and autophagy-related proteins, including LC3B and beclin 1, in both cell lines 72 h after treatment were evaluated. Significant cell death was induced at different concentrations of selenite in both cell lines. A combined effect of selenite and Tz at 72 h was similar to or significantly greater than each drug alone. The expression of phosphorylated Akt (p-Akt) was decreased in JIMT-1 after combination treatment compared to that after only Tz treatment, while p-Akt expression was increased in SK-BR-3. The expression of beclin1 increased particularly in JIMT-1 after only Tz treatment and was downregulated by combination treatment. These results showed that combination of Tz and selenite had an antitumor effect in Tz-resistant breast cancer cells through downregulation of phosphorylated Akt and beclin1-related autophagy. Selenite might be a potent drug to treat Tz-resistant breast cancer by several mechanisms.

2020 ◽  
Author(s):  
Jianing Yi ◽  
Pingyong Yi ◽  
Shuai Chen ◽  
Qian Li ◽  
Runzhang Wu ◽  
...  

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.


2020 ◽  
Vol 16 (3) ◽  
pp. 4485-4495
Author(s):  
Gulcan Bulut ◽  
Harika Atmaca ◽  
Burcak Karaca

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.


2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e11501-e11501 ◽  
Author(s):  
Senem Demirci Alanyali ◽  
Emir Bozkurt ◽  
Hilmi Alanyali ◽  
Burcak Karaca ◽  
Ruchan Uslu

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.


2021 ◽  
Vol 21 ◽  
Author(s):  
Chuansheng Yang ◽  
Hongbo Zhu ◽  
Yeru Tan ◽  
Renjie Zhu ◽  
Xiaoping Wu ◽  
...  

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.


2021 ◽  
Vol 12 ◽  
Author(s):  
Min Ye ◽  
Wei Huang ◽  
Rui Liu ◽  
Yingli Kong ◽  
Yang Liu ◽  
...  

Lapatinib is an FDA-approved EGFR and HER2 tyrosine kinase inhibitor for the treatment of HER2-positive breast cancer patients. However, its therapeutic efficacy is limited by primary or acquired resistance. In the present study, we established breast cancers cells with acquired lapatinib resistance and investigated the antitumor activity of the second-generation HSP90 inhibitor ganetespib in association with lapatinib in lapatinib-sensitive and -resistant cells. The combination treatment showed synergistic inhibition of HER and the downstream PI3K/Akt and Ras/MEK/ERK pathways, in addition to enhancing induction of early apoptotic cell death and G1 arrest in both parent and lapatinib-resistant cells in vitro. The joint administration of ganetespib and lapatinib depleted the aberrant nuclear transcription factor STAT3, a mediator of the cell cycle and apoptosis-related pathways that is probably involved in the lapatinib resistance of HER2-positive breast cancer cells. In conjunctive with the augmented inhibition of tumor growth observed in both SKBR3 and SKBR3-L xenografts compared to monotherapy, our data provide a sound preclinical basis for combination treatment with lapatinib and ganetespib for refractory HER2-positive breast cancer.


2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e14573-e14573
Author(s):  
Z. Qadir ◽  
J. Crown ◽  
M. R. Jensen ◽  
M. Clynes ◽  
D. Slamon ◽  
...  

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]


2021 ◽  
Vol 22 (17) ◽  
pp. 9621
Author(s):  
Balsam Rizeq ◽  
Ishita Gupta ◽  
Hadeel Kheraldine ◽  
Dana Elkhalifa ◽  
Halema F. Al-Farsi ◽  
...  

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.


2021 ◽  
Vol 10 (1) ◽  
pp. 744-753
Author(s):  
Zahra Rahimzadeh ◽  
Seyed Morteza Naghib ◽  
Esfandyar Askari ◽  
Fatemeh Molaabasi ◽  
Ali Sadr ◽  
...  

Abstract In this paper, we use a simple and cheap approach for the synthesis of herceptin-conjugated graphene biosensor to detect the HER2-positive breast cancer cells. The bifunctional graphene-herceptin nanosheets are prepared from graphite by a simple ultrasonic-mediated technique. The prepared protein-mediated graphene is fully characterized. The results show the exfoliation of graphene layers in herceptin solution. Moreover, herceptin is effectively conjugated into the surface of graphene nanosheets. The synthesized herceptin-conjugated graphene is applied for breast cancer detection. The linear range of this biosensor is 1–80 cells, which is significant. The biosensor shows an excellent selectivity performance for detection of HER2-positive cancer cells. Likewise, the stability and functionality of the biosensor is about 40 days. Based on the results, this device is a promising candidate for rapid and selective detection of cancer cells.


Author(s):  
Jun Hua ◽  
Zhe Zhang ◽  
Lili Zhang ◽  
Yan Sun ◽  
Yuan Yuan

Abstract Purpose This study aimed to investigate the possibility of UCP-2 inhibitor in reducing acquired resistance of trastuzumab to improve the outcome of patients receiving trastuzumab therapy by exploring the relationship between UCP-2 expression and HER2 signaling pathway and examining whether UCP-2 expression was modulated by trastuzumab treatment. Methods 32 women diagnosed with primary HER2-positive breast cancer were recruited in this study. Needle biopsy was obtained from patients before they received at least four cycles neoadjuvant therapy containing trastuzumab in combination with chemotherapy. Surgical tumor biopsy was obtained during surgical procedure after the neoadjuvant therapy. Levels of HER2 phosphorylation and UCP-2 expression were detected by immunohistochemistry (IHC) and compared between tumor needle biopsy tissue and surgical tumor samples of these patients, as well as in BT474 breast cancer cells before and after trastuzumab treatment. HER2-selective phosphorylation/kinase activity inhibitor ONT-380 was used to identify the correlation between HER2 phosphorylation level and UCP-2 expression. UCP-2 inhibitor Genipin was then used to evaluate the apoptosis index in BT474 cells treated with trastuzumab. Results UCP-2 expression was significantly elevated in surgical tumor samples from breast cancer patients receiving trastuzumab in a neoadjuvant setting. We further confirmed our findings in HER2-positive BT474 cell line and found that trastuzumab treatment induced phosphorylation of HER2 and the overexpression of UCP-2, and the latter can be reversed by HER2 selective kinase inhibitor ONT-380. Moreover, UCP-2 inhibitor Genipin significantly enhanced the proliferation suppression effects of trastuzumab and markedly promoted apoptosis. Conclusion Taken together, our study identified UCP-2 as a novel therapeutic target for HER2 positive breast cancer and UCP-2 inhibitor may have great potential to enhance the response rate and efficacy of trastuzumab therapy.


2017 ◽  
Vol 50 (6) ◽  
pp. 2221-2228 ◽  
Author(s):  
Martina S.J. Mcdermott ◽  
Alexandra Canonici ◽  
Laura Ivers ◽  
Brigid C. Browne ◽  
Stephen F. Madden ◽  
...  

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