Combining Celecoxib with Sorafenib Synergistically Inhibits Hepatocellular Carcinoma Cells In Vitro

Anticancer Res, 2013 33:1387-96.

TAKASHI MORISAKI1, MASAYO UMEBAYASHI1, AKIFUMI KIYOTA1, NORIHIRO KOYA1, HIROTO TANAKA1, HIDEYA ONISHI2, MITSUO KATANO2

1Fukuoka General Cancer Clinic, Hakata-ku, Fukuoka, Japan;

2Departments of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

Contact:Dr. Takashi Morisaki, Fukuoka General Cancer Clinic, 3-1-1 Sumiyoshi, Hakata-ku, Fukuoka 812-0018, Japan. Tel: +81 922827696, Fax: +81 924056376, e-mail: tmorisaki@cancer-clinic.jp

 

Abstract

Sorafenib is a promising treatment for hepatocellular carcinoma (HCC) but recent toxicity concerns suggest that new strategies for its use are needed. One approach for reducing toxicity is to use lower doses of sorafenib in combination with other complementary mechanisms. Celecoxib, a cyclooxygenase 2 inhibitor, has been shown to inhibit HCC, and we hypothesized that low-dose sorafenib co-administered with celecoxib could act synergistically in the inhibition of HCC. In this study, the effect of sorafenib was tested in combination with celecoxib on the growth of human HCC cells in vitro. Two human HCC cell lines, HepG2 and Huh7, were treated with sorafenib and celecoxib, alone and in combination, and the effect of these treatments on growth, apoptosis, and expression of phospho-AKT was evaluated by WST-8, DNA content, and immunocytochemical assays, respectively. When compared to the actions of either agent alone, the combination of low concentrations of soerafenib (<5 mM) and celecoxib (< 20mM) resulted in enhanced inhibition of both cell growth and AKT activation, and increased the induction of apoptosis. Combination index (CI) analysis showed that the growth inhibition effect was synergistic. This study shows that celecoxib synergistically potentiates the sorafenib-mediated antitumor effect. This finding establishes the foundation for clinical trials evaluating the efficacy of co-administration of soerafenib and celecoxib as a treatment for HCC.

Key Words: Celecoxib, sorafenib, AKT, apoptosis, hepatocellular carcinoma, synergism, HCC.

PMID: 23564777

 

Supplement :

Sorafenib is a small molecule that inhibits tumor-cell proliferation and tumor angiogenesis and increases the rate of apoptosis in a wide range of tumor models including HCC.Limitation of sorafenib use is its toxicity. One approach to overcome this toxicity is to use lower doses of sorafenib in combination with other complementary agents. However, success requires the identification of agents that can potentiate the sorafenib-mediated tumor inhibition without significant systemic toxicity.

Non-steroidal anti-inflammatory drugs (NSAIDs) appear to reduce the risk of developing cancer. One mechanism through which NSAIDs act to reduce carcinogenesis is to inhibit the activity of cyclooxygenase-2 (COX-2), an enzyme that is overexpressed in various cancer tissues. Recently, selective COX-2 inhibitors have been shown to act additionally through COX-2-independent mechanisms. Several reports have demonstrated that combination of celecoxib with other agents has synergistic anti-proliferative and pro-apoptotic effects in various types of cancers.

Takashi Morisaki-fig1

Although anti-HCC activity has been shown for both sorafenib and celecoxib, the effect on HCC of these drugs in combination has not, to our knowledge, been reported. We hypothesized that these drugs may synergize to be more effective than either agents administered alone.

In the present study, we have provided evidence that the combination of sorafenib and celecoxib leads to potentiated cytotoxicity in the HCC cell lines, HepG2 and Huh7, via increased apoptosis. It appears that in this context, celecoxib is acting on the phosphorylation of AKT downstream of PI3K rather than via COX-2 inhibitory activity. These findings collectively suggest that celecoxib enhances sorafenib-mediated antitumor effects by inhibiting PI3K/AKT signaling in HCC. The synergy between sorafenib and celecoxib in HCC cells is clinically significant, because it would be a more cost-effective way of using sorafenib and, perhaps more importantly, because it would lower the potential for adverse events. Sorafenib at clinically effective doses is expensive and causes adverse effects that reduce quality of life, including high rates of diarrhea and HFSR. Although the cost-effectiveness of sorafenib compares favorably with the best supportive care available, it is still unacceptably high when taking into account the cost of treating the adverse events that it causes. Reducing the required dose of sorafenib by combining it with celecoxib may diminish both the cost and side-effects associated with its use.

In conclusion, our data show that low-dose sorafenib in combination with celecoxib synergistically inhibits cell viability via actions on the antiapoptotic AKT and RAS/RAF signaling pathways. Celecoxib potentiates the antiproliferative action of sorafenib, promoting HCC cell apoptosis and allowing the use of lower doses of sorafenib than are currently used. It may thus have potential in treating HCC in patients, a finding that demands further clinical testing.

Takashi Morisaki-fig2

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