Synergistic effects of gemcitabine and gefitinib in the treatment of head and neck carcinoma

University of Michigan, Ann Arbor, Michigan, United States
Cancer Research (Impact Factor: 9.28). 02/2006; 66(2):981-8. DOI: 10.1158/0008-5472.CAN-05-2665
Source: PubMed

ABSTRACT Although the combination of gemcitabine and radiation produces a high frequency of complete responses in the treatment of locally advanced head and neck cancer, substantial toxicity suggests that an improvement in the therapeutic index is required. The purpose of this study was to determine if gefitinib could improve the efficacy of gemcitabine and if drug schedule is important. We hypothesized that gemcitabine followed by gefitinib would be superior to the opposite order because of both cell cycle and growth factor signaling interactions. Using UMSCC-1 cells in vitro, we confirmed that gefitinib arrested cells in G(1) and suppressed phospho-epidermal growth factor receptor (p(Y845)EGFR) and that gemcitabine arrested cells in S phase and stimulated p(Y845)EGFR. The schedule of gemcitabine followed by gefitinib caused arrest of cells in S phase. Gefitinib suppressed gemcitabine-mediated p(Y845)EGFR stimulation. This schedule caused decreased p(S473)AKT, increased poly(ADP-ribose) polymerase cleavage, and increased apoptosis compared with gemcitabine alone. The schedule of gefitinib followed by gemcitabine also caused suppression of p(Y845)EGFR but arrested cells in G(1). This schedule in which gefitinib was used first was associated with stable levels of p(S473)AKT and minimal poly(ADP-ribose) polymerase cleavage and apoptosis. These results were reflected in experiments in nude mice bearing UMSCC-1 xenografts, in which there was greater tumor regression and apoptosis when animals received gemcitabine followed by gefitinib during the first week of therapy. These findings suggest that the schedule of gemcitabine followed by gefitinib may increase the therapeutic index over gemcitabine alone and, combined with clinical data, encourage exploration of combination of gemcitabine, EGFR inhibitors, and radiation.

  • Source
    • "This is consistent with another in vitro study that showed a reversal of drug resistance by gefitinib in breast and lung cancer cells expressing MDR proteins (Yang et al., 2005). Although synergistic effects of gefitinib and chemotherapeutic agents have been reported in previous studies in vivo (Sirotnak et al., 2000; Chun et al., 2006), no such effect has been observed in clinical trials (Giaccone et al., 2004; Herbst et al., 2004). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Pancreatic cancer is a devastating malignancy, characterized by intrinsic or acquired resistance to conventional chemotherapies. Recent evidences suggest an involvement of tyrosine kinase pathway in the regulation of multidrug resistance (MDR) protein gene expression. The aim of this study was to test whether gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor could regulate the MDR protein gene expression and sensitize the resistant cancer cells to chemotherapy. The gene expression of MDR proteins (MRP1, MRP2, MRP3, and PGP) were evaluated by quantitative RT-PCR, and expression levels of various tyrosine kinases were investigated by quantitative RT-PCR and Western Blot in pancreatic cancer cell line. MTT assay was used for evaluating the effect of chemotherapeutic agents. Chemotherapeutics induced drug resistance by regulating the gene expression of MDR proteins (MRP1, MRP2, and MRP3), and increased the gene expression of RAF1/ERK and the phosphorylation of ERK in pancreatic cancer Bxpc-3 cells. Gefitinib caused an inhibition of p-ERK tyrosine kinase activation in a dose-dependent manner, and reversed gemcitabine-induced RAF1/ERK gene expression and p-ERK activation. In addition, a reversal of MDR proteins gene expression was achieved by gefitinib, which sensitized resistant cells to gemcitabine. This study demonstrated that MDR of Bxpc-3 cell is involved in the RAF1/ERK tyrosine kinase pathway. Gefitinib reverses the MDR protein gene expression and restores sensitivity of resistant cells to gemcitabine via RAF1/ERK signaling pathway. Combination of gefitinib with conventional chemotherapeutic agents may offer a new approach for the treatment of patients with pancreatic cancer. Anat Rec, 2012. © 2012 Wiley Periodicals, Inc.
    The Anatomical Record Advances in Integrative Anatomy and Evolutionary Biology 12/2012; 295(12). DOI:10.1002/ar.22552 · 1.53 Impact Factor
  • Source
    • "Epidermal growth factor receptor (EGFR) overexpression is a common occurrence in human malignancies of epithelial origin including lung and head and neck cancers and has been correlated with poor prognosis [1] [2] [3], and small molecules directed at EGFR kinase activity have provided definite but limited success [4] [5] [6]. We have shown that therapies causing EGFR degradation, as opposed to simple inhibition of its kinase activity, are far more potent both in killing cancer cells and in sensitizing tumor cells to chemotherapy than simply inhibiting EGFR kinase activity [7] [8] [9]. We, therefore, hypothesized that, instead of simply inhibiting EGFR kinase function, degrading EGFR may improve the clinical outcome of already-existing strategies to control tumor cell growth. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Epidermal growth factor receptor (EGFR) is overexpressed in a variety of epithelial tumors and is considered to be an important therapeutic target. Although gene amplification is responsible for EGFR overexpression in certain human malignancies including lung and head and neck cancers, additional molecular mechanisms are likely. Here, we report a novel interaction of EGFR with an HECT-type ubiquitin ligase SMURF2, which can ubiquitinate, but stabilize EGFR by protecting it from c-Cbl-mediated degradation. Conversely, small interfering RNA (siRNA)-mediated knockdown of SMURF2 destabilized EGFR, induced an autophagic response and reduced the clonogenic survival of EGFR-expressing cancer cell lines, with minimal effects on EGFR-negative cancer cells, normal fibroblasts, and normal epithelial cells. UMSCC74B head and neck squamous cancer cells, which form aggressive tumors in nude mice, significantly lost in vivo tumor-forming ability on siRNA-mediated SMURF2 knockdown. Gene expression microarray data from 443 lung adenocarcinoma patients, and tissue microarray data from 67 such patients, showed a strong correlation of expression between EGFR and SMURF2 at the messenger RNA and protein levels, respectively. Our findings suggest that SMURF2-mediated protective ubiquitination of EGFR may be responsible for EGFR overexpression in certain tumors and support targeting SMURF2-EGFR interaction as a novel therapeutic approach in treating EGFR-addicted tumors.
    Neoplasia (New York, N.Y.) 07/2011; 13(7):570-8. DOI:10.1593/neo.11632 · 5.40 Impact Factor
  • Source
    • "Gefitinib achieved a 50% growth inhibition (IC 50 ) at concentrations of <1 μM in only one cell line JHU-029 (Supplementary Table S2 and data not shown). This is consistent with an earlier report that most HNSCC lines are relatively resistant to gefitinib, with IC 50 s between 10–15 μM (Chun et al., 2006). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Overexpression of epidermal growth factor receptor (EGFR) is found in over 80% of head and neck squamous cell carcinomas (HNSCC) and associated with poor clinical outcomes. EFGR selective tyrosine kinase inhibitors (TKIs) or antibodies have recently emerged as promising treatments for solid tumors, including HNSCC, though the response rate to these agents is low. p53 upregulated modulator of apoptosis (PUMA), a BH3-only Bcl-2 family protein, is required for apoptosis induced by p53 and various chemotherapeutic agents. In this study, we show that PUMA induction is correlated with EGFR-TKI sensitivity, and is mediated through the p53 family protein p73beta and inhibition of the PI3K/AKT pathway. In some HNSCC cells, the gefitinib-induced degradation of oncogenic Delta Np63 seems to facilitate p73-mediated PUMA transcription. Inhibiting PUMA expression by small hairpin RNA (shRNA) impairs gefitinib-induced apoptosis. Furthermore, PUMA or BH3 mimetics sensitize HNSCC cells to gefitinib-induced apoptosis. Our results suggest that PUMA induction through p73 represents a new mechanism of EGFR inhibitor-induced apoptosis, and provide potential ways for enhancing and predicting the sensitivity to EGFR-targeted therapies in HNSCC.
    Oncogene 06/2009; 28(24):2348-57. DOI:10.1038/onc.2009.108 · 8.56 Impact Factor
Show more


Available from