scholarly journals Therapeutic Mechanism of Lapatinib Combined with Sulforaphane on Gastric Cancer

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Huixing Yi ◽  
Zheming Li ◽  
Xiaoxi Liu ◽  
Shijie Dai ◽  
Shouye Li
Keyword(s):  
Gastric Cancer ◽  
Cell Viability ◽  
Western Blotting ◽  
Kinase Inhibitor ◽  
Boyden Chamber ◽  
G1 Arrest ◽  
Therapeutic Effects ◽  
Her2 Positive ◽  
Thiazolyl Blue Tetrazolium Bromide ◽  
Her 2

Background. Lapatinib is a small-molecule tyrosine kinase inhibitor that plays important roles in cell proliferation and survival. Administration of lapatinib with capecitabine is an effective treatment for HER2-positive metastatic BC. However, the effects of lapatinib on gastric cancer (GC) remain to be clear. In this study, we aimed to investigate the therapeutic effects of lapatinib combined with sulforaphane on GC and its underlying mechanisms. Methods. SGC-7901 and lapatinib-resistant SGC-7901 cells were treated with lapatinib (0.2 μM), sulforaphane (5 μM), or their combinations. Cell viability, invasion, cycle, and apoptosis of SGC-7901 and lapatinib-resistant SGC-7901 cells were evaluated by thiazolyl blue tetrazolium bromide (MTT), Boyden chamber assay, and flow cytometer. The protein expressions of HER-2, p-HER-2, AKT, p-AKT, ERK, and p-ERK were detected by Western blotting. Results. We observed that lapatinib combined with sulforaphane significantly decreased cell viability and inhibited cell migration of drug-sensitive and drug-resistant cells. Lapatinib sulforaphane also remarkably induced cell apoptosis with G0/G1 arrest. In addition, Western blotting revealed that the expressions of HER-2, p-HER-2, AKT, p-AKT, ERK, and p-ERK were downregulated by lapatinib-sulforaphane treatment. Conclusion. Combination of lapatinib and sulforaphane might be a novel and promising therapeutic treatment for lapatinib-sensitive or lapatinib-resistant GC patients.

The dual EGFR/HER-2 tyrosine kinase inhibitor lapatinib sensitizes colon and gastric cancer cells to the irinotecan active metabolite SN-38

2009 ◽  
Vol 125 (12) ◽  
pp. 2957-2969 ◽  
Author(s):  
Melissa J. LaBonte ◽  
Philipp C. Manegold ◽  
Peter M. Wilson ◽  
Will Fazzone ◽  
Stan G. Louie ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Cancer Cells ◽  
Active Metabolite ◽  
Kinase Inhibitor ◽  
Gastric Cancer Cells ◽  
Her 2

Effect of neratinib (N) alone and in combination with trastuzumab (T) in HER2-positive breast cancer (BC) cell lines.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 632-632
Author(s):  
Alexandra Canonici ◽  
Kasper Pedersen ◽  
Naomi Walsh ◽  
John Crown ◽  
Norma O'Donovan
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Cell Lines ◽  
Kinase Inhibitor ◽  
Combined Treatment ◽  
Clinical Problem ◽  
Resistant Cell ◽  
Her2 Positive ◽  
Her 2 ◽  
Resistant Cells

632 Background: HER-2, a member of the transmembrane receptor tyrosine kinase ErbB family, is over-expressed in approximately 25% of BC. HER-2 targeted therapies, in particular, T, a monoclonal antibody targeting HER-2, and lapatinib (L), a reversible HER-2 tyrosine kinase inhibitor, have been shown to significantly improve the prognosis for HER-2 positive BC patients. However, resistance to T and/or L is a significant clinical problem. The aim of this study is to assess the activity of N (HKI-272), an irreversible HER-2 tyrosine kinase inhibitor, in HER-2 overexpressing BC cell lines, including T and/or L resistant cells. Methods: Using proliferation assays, the effect of N was assessed alone and in combination with T in HER-2 positive BC cell lines, including T and/or L resistant cell lines. The effect of N on HER-2 and downstream signalling molecules, Erk and Akt, was determined by immunoblotting. Results: HER-2 positive BC cell lines, including T and/or L resistant cells, are sensitive to N alone with IC50 values (concentration which inhibits 50% of growth) ranging from 1 to 280 nM. The combination of N and T has additive effects in SkBR3 and BT474 which are sensitive to T and also in SKBR3-Lwhich are resistant to L. In the cell lines HCC1954, HCC1954-L, MDA-MB-453, JIMT1 and SKBR3-HL which are resistant to T, combined treatment with T and N showed no enhancement compared to N alone. Finally, N decreased phosphorylation of HER-2, Erk and Akt in all cell lines tested. Conclusions: Our results suggest that N should be studied in patients with HER-2 positive BC, including patients with T and/or L resistant BC. We also demonstrate that N in combination with T may be more effective than either agent alone in T sensitive cells.

scholarly journals GDC-0980, a novel PI3K/mTOR kinase inhibitor, is effective in HER2 positive gastric cancer (GC) cell lines resistant to Trastuzumab

2016 ◽  
Vol 27 ◽  
pp. iv22
Author(s):  
J. Ventriglia ◽  
M.M. laterza ◽  
A. Capasso ◽  
V. Belli ◽  
B. Savastano ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Lines ◽  
Kinase Inhibitor ◽  
Her2 Positive ◽  
Mtor Kinase

scholarly journals Antimetastatic and Antitumor Activities of Orally Administered NAX014 Compound in a Murine Model of HER2-Positive Breast Cancer

2021 ◽  
Vol 22 (5) ◽  
pp. 2653
Author(s):  
Elisa Pierpaoli ◽  
Francesco Piacenza ◽  
Gaetano Fiorillo ◽  
Paolo Lombardi ◽  
Fiorenza Orlando ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Transgenic Mice ◽  
Tumor Infiltrating Lymphocytes ◽  
Mammary Tumors ◽  
Cell Senescence ◽  
Therapeutic Effects ◽  
Her2 Positive ◽  
Anticancer Efficacy ◽  
Her 2

The natural isoquinoline alkaloid Berberine (BBR) has been shown to possess several therapeutic effects, including anticancer activity. Different BBR derivatives have been designed and synthesized in order to obtain new compounds with enhanced anticancer efficacy. We previously showed that intraperitoneal (IP) administration of the BBR-derived NAX014 compound was able to counteract HER-2 overexpressing mammary tumors onset and progression in transgenic mice. However, the IP administration was found to induce organ toxicity at doses higher than 2.5 mg/Kg. In this study, we evaluated the effect of intragastric (IG) administration of 20 mg/kg of NAX014 on both safety and anticancer efficacy in HER-2/neu transgenic mice. Furthermore, cancer cell dissemination and migration, tumor cell senescence and immunological changes were examined. Our results demonstrated that IG NAX014 administration delayed the onset of mammary tumors with no negative effects on health and survival. NAX014 reduced HER-2 overexpressing BC cells migration in vitro and the frequency of lung metastasis in HER-2/neu transgenic mice. A statistically significant increase of senescence-associated p16 expression was observed in tumors from NAX014-treated mice, and the induction of cell senescence was observed in HER-2 overexpressing BC cells after in vitro treatment with NAX014. Although NAX014 did not modulate the presence of tumor-infiltrating lymphocytes, the level of circulating TNF-α and VEGF was found to be reduced in NAX014-treated mice. The overall results address the NAX014 compound as potential tool for therapeutic strategies against HER-2 overexpressing breast cancer.

scholarly journals A Comparative Proteomic Analysis of Erinacine A’s Inhibition of Gastric Cancer Cell Viability and Invasiveness

2017 ◽  
Vol 43 (1) ◽  
pp. 195-208 ◽  
Author(s):  
Hsing-Chun Kuo ◽  
Yur-Ren Kuo ◽  
Kam-Fai Lee ◽  
Meng-Chiao Hsieh ◽  
Cheng-Yi Huang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Viability ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Gastric Cancer Cell ◽  
Boyden Chamber ◽  
Human Gastric Cancer ◽  
Gastric Cancer Cells ◽  
Induction Of Apoptosis ◽  
Erinacine A

Background / Aims: Erinacine A, isolated from the ethanol extract of the Hericium erinaceus mycelium, has been demonstrated as a new alternative anticancer medicine. Drawing upon current research, this study presents an investigation of the molecular mechanism of erinacine A inhibition associated with gastric cancer cell growth. Methods: Cell viability was determined by Annexin V–FITC/propidium iodide staining and migration using a Boyden chamber assay to determine the effects of erinacine A treatment on the proliferation capacity and invasiveness of gastric cancer cells. A proteomic assay provided information that was used to identify the differentially-expressed proteins following erinacine A treatment, as well as the mechanism of its targets in the apoptotic induction of erinacine A. Results: Our results demonstrate that erinacine A treatment of TSGH 9201 cells increased cytotoxicity and the generation of reactive oxygen species (ROS), as well as decreased the invasiveness. Treatment of TSGH 9201 cells with erinacine A resulted in the activation of caspases and the expression of TRAIL. Erinacine A induction of apoptosis was accompanied by sustained phosphorylation of FAK/AKT/p70S6K and the PAK1 pathways, as well as the generation of ROS. Furthermore, the induction of apoptosis and anti-invasion properties by erinacine A could involve the differential expression of the 14-3-3 sigma protein (1433S) and microtubule-associated tumor suppressor candidate 2 (MTUS2), with the activation of the FAK/AKT/p70S6K and PAK1 signaling pathways. Conclusions: These results lead us to speculate that erinacine A may generate an apoptotic cascade in TSGH 9201 cells by activating the FAK/AKT/p70S6K/PAK1 pathway and upregulating proteins 1433S and MTUS2, providing a new mechanism underlying the anti-cancer effects of erinacine A in human gastric cancer cells.

How many biopsy fragments will be necessary to assess HER2 status for gastric cancer?

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 40-40 ◽  
Author(s):  
Eiji Shinozaki ◽  
Noriko Yamamoto ◽  
Keisho Chin ◽  
Mariko Ogura ◽  
Mitsukuni Suenaga ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Survival Benefit ◽  
Study Data ◽  
Her2 Status ◽  
Her2 Positive ◽  
Her2 Protein ◽  
Positive Group ◽  
Biopsy Specimens ◽  
Her 2 ◽  
Overall Survival Benefit

40 Background: Trastuzumab (T) has been shown to confer overall survival benefit adding to capecitabine or 5-FU and CDDP in HER2-positive advanced gastric cancer in ToGA study. Data from the study, overexpression of HER2 according to immunohistochemistry (IHC) has been confirmed as potential responders. HER2 scoring is essential to decide the strategy of the personalized therapy with T. There are some differences in details to assess HER2 score between surgically resected materials and the biopsy fragments. Moreover it is not unclear how many biopsy fragments will be necessary to assess HER2 status. In this study we attemped to prove the optimal biopsy for HER2 scoring of gastric cancer. Methods: HER2 status was evaluated in 30 cases who were scored HER2 as 3+ and 44 cases who were selected for reference as HER2 score of 2+, 1+, 0 in previous tests of surgical specimens. In total 74 cases of 232 biopsies we investigated HER2 protein expression by IHC using HercepTest (DAKO) and assessed according to Gastric Cancer Scoring System. We analyzed the concordance of HER2 score between surgically specimens and the biopsy fragments. Results: Average numbers of biopsy fragments were 3.13(1-6)/case. The concordances between surgical specimens and biopsy specimens were 80.0% in HER2 3+ group of surgical specimens, 47.8% and 47.6% in HER2 2+ and 1+ or 0. The concordances per each biopsy were 73.5%, 34.7% and 69.1%, respectively. Both concordances in HER2 positive group were significant higher than those in HER 2 negative or equivocal groups. There were not statistic differences of the concordances between 3 or less fragments of biopsy and 4 or more. Conclusions: Our data suggested in HER2 score 3+ according to surgical materials, the concordance of HER2 scoring between surgically resected materials and the prior biopsy specimens was high and at least 3 fragments were seemed enough to assess whether IHC HER2 is positive in biopsy. Other hands in HER 2 negative or equivocal groups, the concordances were low.

Multicenter phase II study of trastuzumab with S-1 alone in elderly patients with HER-2 positive advanced gastric cancer (JACCRO GC-06).

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 106-106 ◽  
Author(s):  
Toshiki Masuishi ◽  
Tomono Kawase ◽  
Kazuhiro Nishikawa ◽  
Chikara Kunisaki ◽  
Satoshi Matsusaka ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Antitumor Activity ◽  
Adverse Events ◽  
Elderly Patients ◽  
Advanced Gastric Cancer ◽  
Statistical Power ◽  
Her2 Positive ◽  
Standard Regimen ◽  
End Point ◽  
Her 2

106 Background: S-1 plus cisplatin (SP) is a standard regimen for advanced gastric cancer (AGC) in East Asia. In patients with HER2-positive AGC, ToGA trial showed survival benefit with the addition of trastuzumab to capecitabine plus cisplatin or fluorouracil plus cisplatin and HERBIS-1 trial demonstrated promising antitumor activity with the addition of trastuzumab to SP. However, cisplatin has several important drawbacks, including nausea, vomiting, and renal toxicity. And these disadvantages of cisplatin are noticeable in elderly patients. We evaluated the efficacy and safety of trastuzumab combined with S-1 alone in elderly patients with HER-2 positive AGC. Methods: Patients, 65 years or older, with HER2-positive AGC received S-1 (80–120mg per day) orally on days 1–28 of a 42-day cycle and trastuzumab (course 1, 8 mg/kg; course 2 onward, 6 mg /kg) intravenously on day 1 of a 21-day cycle. The primary end point was response rate (RR); secondary endpoints were overall survival (OS), progression free survival (PFS), time to treatment failure (TTF) and adverse events. The sample size was 40 to 60 patients estimated on the basis of threshold RR=20%, expected RR=35%, alpha=0.1 (one-sided) and power=80 to 90%. Results: A total of 51 patients were enrolled. One patient was ineligible, therefore in the full analysis set of 50 patients (actual statistical power = 87.5%), the median age was 71 years (range=65-85), male: female was 37:13 and ECOG PS was 0/1/2= 33/14/3. The confirmed RR (CR/PR/SD/PD=3/17/23/7) was 40.0% (80% confidence interval (CI); 31.1-48.9%, 95% CI; 26.4-53.6%), and the null hypothesis was rejected. The disease control rate was 86.0% (95% CI; 76.4-95.6%). Median OS, PFS, and TTF were immature. Major grade 3 or 4 adverse events included neutropenia (10.0%), anemia (24.0%), diarrhea (10.0%) and anorexia (12.0%). There was one treatment-related death. Conclusions: The primary end point was met. Trastuzumab in combination with S-1 alone demonstrated promising antitumor activity and manageable toxic effects in elderly patients with HER2-positive AGC. Clinical trial information: UMIN000007368.

Individual Approach In Treatment Of Advanced Stomach Cancer

2010 ◽  
Vol 1 ◽  
Author(s):  
D Juraev ◽  
M Egamberdiev ◽  
S Khudayorov ◽  
N Tuyev
Keyword(s):  
Gastric Cancer ◽  
Advanced Gastric Cancer ◽  
Target Therapy ◽  
Combined Treatment ◽  
Control Group ◽  
Her2 Positive ◽  
Remission Duration ◽  
Her 2 ◽  
Gastric Cancer Patients ◽  
High Level

Background: To study efficiency of the combined treatment of advanced gastric cancer with inclusion Trastuzumab.Material: We present the intermediate analysis of the use of target therapy with Trastuzumab in patients with a HER2-positive gastric cancer. Up to 01.10.2009y 118 patients have been tested for HER-2 expression, and in 24 gastric cancer patients it is revealed HER2-positive status of tumor. It is lead chemotherapy to all patients by the PLF regimen and Herceptin in doze 6 mg/kg once in 3 weeks (6 cycles). In control group in 26 patients it is lead only chemotherapy by the PLF regimen once in 3 weeks without addition Trastuzumab (6 cycles).Results:  At the moment of the analysis of preliminary data, the median remission duration in compared groups has made 8.3 months, and 5.2 months, accordingly.Conclusion: At advanced gastric cancer with high level HER-2 expression Trastuzumab increases frequency of objective effect and the median remission duration.

scholarly journals Lapatinib, a Dual-Targeted Small Molecule Inhibitor of EGFR and HER2, in HER2-Amplified Breast Cancer: From Bench to Bedside

2011 ◽  
Vol 3 ◽  
pp. CMT.S3783 ◽  
Author(s):  
Roger Y. Tsang ◽  
Saeed Sadeghi ◽  
Richard S. Finn
Keyword(s):  
Breast Cancer ◽  
Tyrosine Kinase ◽  
Small Molecule ◽  
Clinical Data ◽  
Transmembrane Domain ◽  
Kinase Inhibitor ◽  
Extracellular Domain ◽  
Type I ◽  
Her2 Positive ◽  
Her 2

The HER-2/neu gene product is a 185 kDa Type I receptor tyrosine kinase which consists of an extracellular domain, transmembrane domain, kinase domain, and cytoplasmic tail. The initial discovery that amplification and subsequent overexpression of the HER-2/neu oncogene plays a pivotal role in the pathogenesis of 20%–25% of breast cancers has since led to significant clinical advances in the management of this subtype of breast cancer. The first approved HER2-targeted therapy, trastuzumab, is a humanized monoclonal antibody against the extracellular domain of HER2 and has demonstrated survival benefits in both the metastatic and adjuvant settings. Lapatinib, a small molecule tyrosine kinase inhibitor of both the epidermal growth factor receptor (EGFR) and HER2 is now also approved for advanced HER2-amplified breast cancer and is currently being evaluated in the adjuvant setting. Importantly, lapatinib has been shown to have activity in women with HER2-amplified breast cancer that is refractory to trastuzumab. In addition, it has been shown to extend survival in the front-line setting in combination with letrozole for estrogen receptor (ER) positive, HER2-positive breast cancer. Here we will review the biologic rationale and pre-clinical data that drove its initial clinical development as well as current clinical data and ongoing studies.

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