Blockade of EGFR and ErbB2 by the Novel Dual EGFR and ErbB2 Tyrosine Kinase Inhibitor GW572016 Sensitizes Human Colon Carcinoma GEO Cells to Apoptosis

Zhou, Yunfei; Li, Song; Hu, Yi; Wang, Jing; Hauser, Jennie; Conway, Alexis; Vinci, Michelle; Humphrey, Lisa E.; Zborowska, Elizabeth; Willson, James K.V.; Brattain, Michael G.

doi:10.1158/0008-5472.can-05-2506

Cited by 88 publications

(57 citation statements)

References 45 publications

(52 reference statements)

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“…This suggests that either NTRK3 signaling is important for maintaining oocyte viability, or that AG 879 has a cytotoxic affect on oocytes in particular that is independent of its actions on the NTRK3 receptor. AG 879 has been shown to also inhibit signaling through the ERBB2 (neu) receptor (Levitzki & Gazit 1995, Zhou et al 2006, and ERBB2 receptor mRNA levels have been shown to be regulated during follicle development (Kezele et al 2005b). Therefore, it is possible that signaling through pathways other than that of NT3/NTRK3 are mediating this effect of oocyte loss.…”

Section: Discussionmentioning

confidence: 99%

Neurotrophin Nt3 Promotes Ovarian Primordial to Primary Follicle Transition.

Nilsson

Dole²,

Skinner³

2009

Biology of Reproduction

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Neurotrophins are growth factors that are known to have a role in promoting cell survival and differentiation. The focus of the current study is to examine the role of neurotrophins in regulating ovarian primordial follicle development. Ovaries from 4-day old rats were placed into organ culture and cultured for 10 days in the absence or presence of neurotrophin-3 (NT3), brain-derived neurotrophic factor (BDNF), or nerve growth factor (NGF). Treatment of ovaries with NT3 resulted in a significant (P<0.01) increase in primordial follicle development (i.e. primordial to primary follicle transition). Treatment with BDNF at high doses of 100-250 ng/ml also significantly (P<0.01) increased primordial follicle development, but NGF had no effect. Immunohistochemical studies determined that NT3 was present in granulosa cells, interstitial tissue, and in the oocytes of primordial and primary follicles. The NT3 receptor NTRK3 was present in oocytes at all stages of development. Analysis of ovaries that contain predominantly primordial follicles demonstrated the transcripts for NT3, NTRK3, NGF, and the BDNF/ neurotrophin-4 (NT4) receptor NTRK2 are expressed, while BDNF, NT4, and the NGF receptor NTRK1 are not detectable. Inhibition of the NTRK3 receptor with the tyrphostin AG 879 resulted in oocyte death and a significant (P<0.01) reduction in follicle pool size. Inhibition of the NTRK receptors with K252a slowed primordial to primary follicle transition. A microarray analysis demonstrated that a small number of genes were differentially expressed after NT3 treatment. Observations indicate that the neurotrophin NT3, acting through the NTRK3 receptor in oocytes, promotes the primordial to primary follicle transition.

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Section: Discussionmentioning

confidence: 99%

Neurotrophin Nt3 Promotes Ovarian Primordial to Primary Follicle Transition.

Nilsson

Dole²,

Skinner³

2009

Biology of Reproduction

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“…Regarding colon cancer, Zhou et al reported that lapatinib (200 mg/kg daily) had significant antitumor activity compared to vehicle control. There was <10% weight loss compared to the vehicle control (41). These reports indicated that lapatinib at a dose of 200 mg/kg daily had a significant antitumor effect, but this dose seems to have severe drug toxicity.…”

Section: -------------------------------------------------mentioning

confidence: 95%

Antitumor effects of lapatinib (GW572016), a dual inhibitor of EGFR and HER-2, in combination with cisplatin or paclitaxel on head and neck squamous cell carcinoma

et al. 2010

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Abstract. The epidermal growth factor receptor (EGFR) and a related family member, HER-2, are often overexpressed simultaneously in patients with a variety of malignant tumors, and the combination may cooperatively promote cancer cell growth and survival. Heterodimerization of EGFR and HER-2 has been known to create intense proliferative signals. Lapatinib (GW572016) is a small molecule that is administrated orally and functions as a reversible inhibitor of both EGFR and HER-2 tyrosine kinases. In the present study, we evaluated the antitumor effect of lapatinib on head and neck squamous cell carcinoma (HNSCC) cell lines in vitro and in vivo. In vivo we examined the antitumor effects of combined treatment with lapatinib and either cisplatin or paclitaxel. In vitro lapatinib displayed antiproliferative effects on HNSCC cells. The IC 50 of lapatinib ranged between 13.6 and 60.2 μM after 24-h exposure to lapatinib. A correlation was not observed between results of in vitro proliferation assays for lapatinib and the expression of EGFR or HER-2. In vivo lapatinib displayed antitumor activity, and induced apoptosis in nude mice bearing an established xenograft of YCU-H891 cells. Lapatinib did not significantly inhibit angiogenesis. Combination treatment of lapatinib with cisplatin or paclitaxel enhanced antitumor activity mainly by inducing apoptosis. Inhibition of antiangiogenesis was observed only for combination treatment of lapatinib with paclitaxel (compared to vehicle control). These results suggest that: i) lapatinib has antitumor effects in vitro and in vivo; ii) lapatinib may be more effective in combination with cisplatin or paclitaxel; and iii) lapatinib might provide useful clinical benefits to HNSCC patients.

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“…Heterodimers composed of ErbB-3 and a breast cancer-specific truncated form of ErbB-2 are also effectively inhibited by lapatinib (25). Lapatinib-mediated inhibition of ErbB-regulated signalling pathways in cell lines and in tumour xenografts resulted in partial cell cycle arrest and apoptosis (22,26,27). We and others have found that the effect of lapatinib on cell growth in various tumour cell lines is independent of ErbB-1/-2 expression levels (7,28,29).…”

Section: Introductionmentioning

confidence: 95%

Lapatinib, a dual inhibitor of ErbB-1/-2 receptors, enhances effects of combination chemotherapy in bladder cancer cells

et al. 2009

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Abstract. Survival rate of patients diagnosed with the invasive form of bladder cancer is low suggesting an urgent need to implement novel treatments. GTC (gemcitabine, paclitaxel and cisplatin) is a new chemotherapeutic regimen, which has shown promise in clinical trials. Given that receptor tyrosine kinases of the ErbB family are overexpressed in a high proportion of metastatic bladder tumours, approaches involving small-molecule inhibitors of ErbB receptors in combination with conventional cytostatic drugs are of potential interest. Here, we show that the dual inhibitor of ErbB receptors, lapatinib, enhances cytostatic and induces cytotoxic effects of GTC in two bladder cancer cell lines which differ with regard to expression levels of proteins taking part in the ErbB pathway. Lapatinib inhibited phosphorylation of ErbB receptors and also reduced the level of phosphorylated AKT. Flow cytometry analysis demonstrated that GTC treatment affects cell cycle distribution differently in the presence or absence of lapatinib. In RT112 cells, which express high levels of ErbB receptors and harbour wild-type p53, combined GTC/lapatinib treatment resulted in the phosphorylation of p53 at Ser46 and accumulation of sub-G 1 cell populations. Our data indicate that a combinatorial approach involving GTC and lapatinib may have therapeutic potential in a subset of bladder tumours depending on the genetic context. IntroductionBladder cancer is a worldwide disease with poor clinical outcome, especially among patients with the muscle invasive form of the disease (1). Several combinations of chemotherapeutic agents are used in treatment of metastatic transitional cell carcinoma (TCC) of the bladder. The combination of methotrexate, vinblastine, doxorubicin and cisplatin was previously considered the 'gold standard' chemotherapy treatment of TCC, although the median survival was only one year (2). Administration of the gemcitabine and cisplatin regimen has resulted in decreased toxicity, but has not improved survival rates (3). At present, a combination of gemcitabine, paclitaxel (taxol) and cisplatin (GTC) with median survival of 22 months is considered as a promising approach (4). In view of the continuing modest survival rates, novel targeted therapies for the treatment of advanced TCC of the bladder are urgently required. Much interest currently centres on modifying the activity of epidermal growth factor receptor (EGFR) family members (5-7). This family, which has been implicated in human cancers, comprises four receptors, ErbB-1 (HER1, EGFR), ErbB-2 (HER2), ErbB-3 (HER3) and ErbB-4 (HER4) (8). High expression of ErbB-1/ErbB-2, which has been described in TCC of the bladder, is an independent predictor of reduced survival (9-12). In contrast, high expression of ErbB-3/ErbB-4 is associated with favourable clinical outcome in TCC patients (13,14).The ErbB receptors are composed of an extracellular ligand-binding region, transmembrane domain, and a cytoplasmic region containing a tyrosine kinase domain and autophosphorylation sit...

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Blockade of EGFR and ErbB2 by the Novel Dual EGFR and ErbB2 Tyrosine Kinase Inhibitor GW572016 Sensitizes Human Colon Carcinoma GEO Cells to Apoptosis

Cited by 88 publications

References 45 publications

Neurotrophin Nt3 Promotes Ovarian Primordial to Primary Follicle Transition.

Neurotrophin Nt3 Promotes Ovarian Primordial to Primary Follicle Transition.

Antitumor effects of lapatinib (GW572016), a dual inhibitor of EGFR and HER-2, in combination with cisplatin or paclitaxel on head and neck squamous cell carcinoma

Lapatinib, a dual inhibitor of ErbB-1/-2 receptors, enhances effects of combination chemotherapy in bladder cancer cells

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