Synergistic antitumor effects of celecoxib with 5‐fluorouracil depend on IFN‐γ

Irie, Takanobu; Tsujii, Masahiko; Tsuji, S.; Yoshio, Toshiyuki; Ishii, Shuji; Shinzaki, Shinichiro; Egawa, Satoshi; Kakiuchi, Yohei; Nishida, Tsutomu; Yasumaru, Masakazu; Iijima, Hideki; Murata, Hiroaki; Takehara, Tetsuo; Kawano, Seiji; Hayashi, Norio

doi:10.1002/ijc.22720

Cited by 38 publications

(29 citation statements)

References 22 publications

(22 reference statements)

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“…In addition, drugs are combined having different effects, and each drug can be used at its optimal dose, without intolerable side effects (34). Currently, growing evidence suggests that the anticancer activity of standard chemotherapeutic agents can be enhanced by using CXB (35). For instance, Zhang et al showed that the combination of low concentrations of sorafenib (SOR) and CXB in A549 tumor cells significantly suppressed the proliferation in vitro and suppressed tumor growth in vivo compared to the actions of either agent alone (23).…”

Section: Discussionmentioning

confidence: 99%

Combined cetuximab and celecoxib treatment exhibits a synergistic anticancer effect on human oral squamous cell carcinoma in vitro and in vivo

Qian¹,

Qian²,

Jing³

et al. 2014

Oncology Reports

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Abstract. The aim of the present study was to evaluate the potency of epidermal growth factor receptor (EGFR) pathway inhibition achieved by combining cetuximab (CET), an anti-EGFR monoclonal antibody, and celecoxib (CXB), a cyclooxygenase-2 (COX-2) inhibitor, in oral squamous cell carcinoma (OSCC) in vitro and in vivo. The OSCC cell line, HSC3, was treated with CET (0-400 µg/ml), CXB (0-40 µM), or a combination of both at a range of concentrations. Cell proliferation, apoptosis, migration and invasion were determined to assess the anticancer effects in vitro. The in vivo effects of CET and CXB on tumor cell growth were examined using an OSCC xenograft nude mouse model. In addition, downstream protein expression levels of EGFR, p-EGFR, PI3K, p-PI3K, AKT and p-Akt were evaluated by western blot analysis. It was found that the combination of low concentrations of CET and CXB significantly suppressed the proliferation, migration and invasion of the HSC3 tumor cells and decreased PEG2 production and VEGF expression in vitro, and inhibited tumor growth in vivo compared to the action of either agent alone. The results also showed that this combination significantly induced apoptosis and increased caspase-3 and caspase-8 activity compared to the action of either agent alone (P<0.01). Furthermore, the combination treatment significantly reduced the expression of p-EGFR, p-PI3K and p-Akt in the HSC3 cell line, which may contribute to the inhibition of tumor growth. Taken together, our findings revealed that the additive combination of CET and CXB is a potential drug candidate for the treatment of OSCC. IntroductionOral squamous cell carcinoma (OSCC) accounts for approximately 4% of all carcinomas in men and 2% in women worldwide, with geographical variation in frequency (1). Although advances in early diagnosis and multimodal treatments, including surgery, chemotherapy and irradiation have been achieved, the 5-year survival rate of OSCC patients has remained at 50-60% due to recurrence and metastasis (2). Since conventional cytotoxic therapies act upon rapidly dividing normal cells as well as malignant cells, which results in the significant morbidity in patients with solid tumors including OSCC, this method is of limited benefit for survival (3). Therefore, the development of improved anticancer therapies that effectively and specifically target epithelial tumor cells while minimizing the toxic side effects commonly associated with conventional cytotoxic therapies is urgently needed.With the enhanced understanding of key cellular pathways involved in tumor growth, progression and cell death, molecular targeted therapies have been exploited (4). Recently, novel treatments aimed to target specific molecules, such as epidermal growth factor receptor (EGFR), aberrantly expressed in OSCC, have been investigated and tested in clinical trials at several research centers with promising results (5). For many years, the EGFR has been investigated as a major target for the treatment of uncontrolled tumor growth (6). The EGFR, a gl...

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Section: Discussionmentioning

confidence: 99%

Combined cetuximab and celecoxib treatment exhibits a synergistic anticancer effect on human oral squamous cell carcinoma in vitro and in vivo

Qian¹,

Qian²,

Jing³

et al. 2014

Oncology Reports

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“…Although the suppression of angiogenesis that occurs with NSAID treatment alone may not be sufficient to inhibit tumour growth, NSAIDs may enhance the antiangiogenic and antiproliferative effects of certain antitumour drugs (123,125,127). As shown by Irie et al (125), celecoxib alone did not significantly inhibit tumour growth, although it did exhibit a certain antiangiogenic activity. However, in combination with 5-FU, celecoxib enhanced the antitumour effect of 5-FU and significantly suppressed angiogenesis and tumour growth, likely via the inhibition of VEGF and the induction of IFN-γ (125).…”

Section: Combination Of Nsaids With Chemotherapeutic Drugs In Vivomentioning

confidence: 93%

“…Certain studies demonstrated the ability of NSAIDs, particularly selective COX-2 inhibitors, to suppress tumour growth by inhibiting angiogenesis and cell proliferation (131,132). Although the suppression of angiogenesis that occurs with NSAID treatment alone may not be sufficient to inhibit tumour growth, NSAIDs may enhance the antiangiogenic and antiproliferative effects of certain antitumour drugs (123,125,127). As shown by Irie et al (125), celecoxib alone did not significantly inhibit tumour growth, although it did exhibit a certain antiangiogenic activity.…”

Section: Combination Of Nsaids With Chemotherapeutic Drugs In Vivomentioning

confidence: 99%

Potency of non-steroidal anti-inflammatory drugs in chemotherapy

Hiľovská

Jendželovský

Fedoročko

2014

Molecular and Clinical Oncology

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“…Administration of sulindac or celecoxib to mice with gastric cancer xenografts decreased levels of both FGF and VEGF, effectively reducing microvessel density within the tumor [76]. Celecoxib in conjunction with chemotherapy reduced VEGF in mice implanted with a colon cancer cell line and also increased IFN-gamma, which is important for antitumor immunity [77]. Zhou et al reported that post-operative gastric cancer patients given celecoxib had reduced VEGF levels in cancerous tissue compared to those that received surgical intervention alone [78].…”

Section: Cox-2/pge 2 Promotes Angiogenesis and Metastasismentioning

confidence: 99%

Targeting Cyclooxygenase-2 in Hematological Malignancies: Rationale and Promise

Bernard¹,

Bancos²,

Sime³

et al. 2008

CPD

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There is much interest in the potential use of Cox-2 selective inhibitors in combination with other cancer therapeutics. Malignancies of hematopoietic and non-hematopoietic origin often have increased expression of cyclooxygenase-2 (Cox-2), a key modulator of inflammation. For example, hematological malignancies such as chronic lymphocytic leukemia, chronic myeloid leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma and multiple myeloma often highly express Cox-2, which correlates with poor patient prognosis. Expression of Cox-2 enhances survival and proliferation of malignant cells, while negatively influencing anti-tumor immunity. Hematological malignancies expressing elevated levels of Cox-2 potentially avoid immune responses by producing factors that enhance angiogenesis and metastases. Cellular immune responses regulated by natural killer cells, cytotoxic T lymphocytes, and T regulatory cells are also influenced by Cox-2 expression. Therefore, Cox-2 selective inhibitors have promising therapeutic potential in patients suffering from certain hematological malignancies.

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Synergistic antitumor effects of celecoxib with 5‐fluorouracil depend on IFN‐γ

Cited by 38 publications

References 22 publications

Combined cetuximab and celecoxib treatment exhibits a synergistic anticancer effect on human oral squamous cell carcinoma in vitro and in vivo

Combined cetuximab and celecoxib treatment exhibits a synergistic anticancer effect on human oral squamous cell carcinoma in vitro and in vivo

Potency of non-steroidal anti-inflammatory drugs in chemotherapy

Targeting Cyclooxygenase-2 in Hematological Malignancies: Rationale and Promise

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