Abstract
Combination treatment with endostar, a novel modified endostatin, and cytotoxic chemotherapies showed a survival benefit in Chinese clinical trials. However, the exact mechanism for this synergism remains unclear. In this study, we report for the first time that the chemokine receptor CXCR4 and the hypoxia-inducible transcription factors (HIF)-1α and HIF-2α are involved in these synergistic antitumor effects in human colorectal cancer SW1116 cells in vitro when endostar treatment is combined with the cytotoxic drug oxaliplatin. Under normoxia, we demonstrate that endostar and oxaliplatin treatments synergize to inhibit SW1116 cell proliferation, Matrigel adhesion and invasion by reduction of CXCR4 expression. Consistently, these antitumor abilities of endostar and oxaliplatin were markedly reduced by silencing of CXCR4 in SW1116 cells. Under low oxygen conditions (hypoxia, 1% oxygen), enhanced proliferation of SW1116 cells exposed to oxaliplatin was observed due to the emergence of drug resistance. Strikingly, endostar overcame oxaliplatin-resistance, most likely as a consequence of reduced HIF-2α and CXCR4 levels. CXCR4, is only dependent on HIF-2α, which promotes more aggressive phenotype and more significant for oxaliplatin resistance in SW1116 cells. Our data not only provide clues to aid understanding of the mechanism of the synergism of endostar and chemotherapy under either normoxia or hypoxia, but also suggests a new strategy of combination endostar and chemotherapy treatments which might potentiate therapeutic efficacies and/or counteract chemotherapy resistance.
Highlights
Even though 5-year-survival rates of localized colorectal cancer (CRC) approach 90%, 50% of patients have developed distant metastasis at the time of diagnosis [1]
To evaluate whether endostar in combination with chemotherapy exerts antitumor effects synergistically, we administered various concentrations of endostar alone or in combination with oxaliplatin which was kept at a constant IC25 and performed proliferation, Matrigel adhesion and invasion assay
In SW1116 cells treated with 200 mg/ml or 400 mg/ml of endostar, colony formation was inhibited by 22.8% or 37.9%, respectively
Summary
Even though 5-year-survival rates of localized colorectal cancer (CRC) approach 90%, 50% of patients have developed distant metastasis at the time of diagnosis [1]. Despite new chemotherapeutic regimens and target therapies, CRC remains one of the three leading causes of cancer-related death in the worldwide [2,3]. Metastasis and drug resistance are major problems in CRC chemotherapy. Looking for the predictors for recurrence and effective therapy counteracting drug resistance is a particular challenge for CRC. Recent studies indicate that expression levels of the chemokine receptor CXCR4 may predict early relapse, and influence occurrence of drug resistance [4,5,6,7,8]. CXCR4, a seven-transmembrane G-protein-coupled receptor, acts through its specific ligand, CXCL12, leading to intracellular signaling cascades. The CXCL12/CXCR4 axis plays the critical role in HIV infection [9], B-cell development [10], stem cell mobilization and homing [11] and angiogenesis [12,13]
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