Antisense oligonucleotides targeting the epidermal growth factor receptor inhibit proliferation, induce apoptosis, and cooperate with cytotoxic drugs in human cancer cell lines

Ciardiello, Fortunato; Caputo, Romualdo; Troiani, Teresa; Borriello, G; Kandimalla, Ekambar R.; Agrawal, Sudhir; Mendelsohn, John; Bianco, Angelo Raffaele; Tortora, Giampaolo

doi:10.1002/ijc.1335

Cited by 78 publications

(36 citation statements)

References 26 publications

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“…To date, several preclinical studies have reported EGFR inhibitors to have an additive or synergistic antitumor effect when administered in combination with chemotherapeutic agents in a variety of cancer models, including HNSCC. (32)(33)(34)(35) Consistent with these reports, we demonstrated that the downregulation of EGFR expression by siRNA significantly enhanced the growthinhibitory effects and chemosensitivity of cisplatin, 5-FU and docetaxel in HNSCC cells (Fig. 3).…”

Section: Discussionsupporting

confidence: 87%

“…Several reports have shown that EGFR activation regulates apoptosis in different experimental systems, and the inhibition of EGFR was associated with a reduction in tumor cell growth and an induction of apoptosis. (35,36) In contrast, other reports have shown that siRNA directed against wild-type EGFR had no effect on cell growth or apoptosis. (37) Chemotherapeutic agents are likely to induce a complex cascade of molecular and biochemical changes in the expression of myriad genes associated with cellular protection or cell death response.…”

Section: Discussionmentioning

confidence: 87%

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Small interfering RNA targeting epidermal growth factor receptor enhances chemosensitivity to cisplatin, 5‐fluorouracil and docetaxel in head and neck squamous cell carcinoma

et al. 2006

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Overexpression of epidermal growth factor receptor (EGFR) has been found in various epithelial malignancies, including head and neck squamous cell carcinoma (HNSCC), and is associated with increased tumor growth, metastasis, resistance to chemotherapeutic agents and poor prognosis. As such, EGFR is a potential target for antitumor therapy and several EGFR inhibitors have been investigated in preclinical or clinical settings. In the present study, we used small interfering RNA (siRNA) to downregulate EGFR expression while evaluating the effect of EGFR siRNA on cell proliferation, and the combined effects with cisplatin, 5-fluorouracil (5-FU) and docetaxel in HNSCC. Furthermore, HNSCC xenografts were treated with EGFR siRNA alone or in combination with cisplatin, and tumor growth was examined. EGFR expression, proliferation, angiogenesis and apoptosis index were evaluated by immunohistochemistry. The results showed that EGFR siRNA efficiently downregulated EGFR expression and inhibited cell growth of HNSCC. Treatment with EGFR siRNA in combination with cisplatin, 5-FU and docetaxel enhanced chemosensitivity with a significant increase in apoptosis. EGFR siRNA delivered by atelocollagen enhanced the antitumor effect of cisplatin in the HNSCC xenograft model. These cumulative results suggest that EGFR siRNA combined with cisplatin, 5-FU and docetaxel may be a feasible strategy to enhance the effects of chemotherapy in patients with HNSCC.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 87%

Small interfering RNA targeting epidermal growth factor receptor enhances chemosensitivity to cisplatin, 5‐fluorouracil and docetaxel in head and neck squamous cell carcinoma

et al. 2006

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“…For colon cancer, several apoptosis-related targets for AS oligonucleotide approaches have already been tested. Treatment with EGFR AS oligonucleotides showed an inhibition of human colon cancer cell growth with potentiation of inhibitory cell growth effects in combination with cytotoxic drugs (Ciardiello et al, 2001). p21 AS oligonucleotides sensitised colon cancer cells in vivo by downregulation of IR induced p21 expression and increased apoptotic cell death (Tian et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Bcl-xL antisense oligonucleotides radiosensitise colon cancer cells

et al. 2003

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Advanced colon cancer is a malignancy with poor response to various treatment modalities including ionising radiation (IR) and chemotherapy. Both IR and chemotherapeutic agents have been shown to act by inducing apoptosis, a type of cell death antagonised by the Bcl-x L gene product. Since approximately 60% of human colon cancers express Bcl-x L , it was the aim of this study to explore the potential of Bcl-x L antisense oligonucleotides as a novel radiosensitisation strategy. Caco-2 colon cancer cells were treated with Bcl-x L antisense oligonucleotides in combination with IR or cisplatin, and Bcl-x L protein expression, apoptosis, cell viability and clonogenic survival were examined. Bcl-x L antisense oligonucleotide specifically reduced the Bcl-x L protein level by almost 50% in Caco-2 cells. The decreased threshold for the induction of apoptosis resulted in a 300% increase of apoptosis after IR or cisplatin treatment and led to a 60% reduction of cell proliferation beyond response rates achieved with IR. These data suggest that Bcl-x L is an important factor contributing to the treatment resistance of human colon cancer. Specific reduction of Bcl-x L protein levels by antisense oligonucleotides qualifies as a promising therapeutic strategy for colon cancer that may help overcome resistance and improve clinical outcome in this malignancy.

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“…Preclinical studies demonstrated that downregulation of specific gene products with antisense oligonucleotides sensitizes breast cancer cells to chemotherapeutic agents, resulting in an additive or synergistic anticancer effect. In preclinical trials, these antisense targets include mouse double minutes 2 (MDM2), 185 erbb2, 186 PKC-a, 187 and Bcl-2. 188 In addition, clinical trials have tested antisense oligonucleotides in combination with chemotherapeutic agents.…”

Section: Rationale For Combination Therapymentioning

confidence: 99%