Synergistic Antitumor Effects of Endostar in Combination with Oxaliplatin via Inhibition of HIF and CXCR4 in the Colorectal Cell Line SW1116

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.

Overexpression of HIF-2α, TWIST, and CXCR4 Is Associated with Lymph Node Metastasis in Papillary Thyroid Carcinoma

“…While highly homologous, HIF-1 α and HIF-2 α have unique tissue distributions and play critical but nonoverlapping roles in tumor progression [ 5 , 6 ]. HIF-2 α promotes metastasis through regulation of critical factors controlling tumor cell metastatic potential, such as CXCR4 and TWIST [ 7 – 9 ]. To date, studies have shown that HIF-2 α , TWIST, and CXCR4 are overexpressed in several human tumors such as clear cell renal carcinoma (ccRCC) [ 23 ], nonsmall cell lung cancer (NSCLC) [ 24 ], neuroblastoma [ 25 ], and breast, prostate, gastric, hepatocellular, colon, and bladder cancers [ 11 – 18 ].…”

“…Although highly homologous, HIF-1 α and HIF-2 α play critical but nonoverlapping roles in tumor progression [ 5 , 6 ]. Recent studies have shown that TWIST and CXCR4 are two direct target genes of HIF-2 α , HIF-2 α can activate the expression of TWIST and CXCR4, which subsequently promote invasion and metastasis of tumor cells [ 7 – 9 ].…”

Combined chemotherapy plus endostar with sequential stereotactic radiotherapy as salvage treatment for recurrent esophageal cancer with severe dyspnea: A case report and review of the literature

“…Endostar combined with radiation or chemotherapy has proven effective in treating other cancers, including nasopharyngeal carcinoma, colorectal, non-small cell lung and cervical cancers (23–25). In addition, Chang et al (26) investigated the efficacy of endostar combined with chemotherapy on human esophageal squamous cell carcinoma Eca-109 cells in mice, and demonstrated that the tumor volumes and weight were significantly lower in the treatment group compared with the control.…”

The Difference of Hypoxia Inducible Factor 2α mRNA Expression in High-Grade and Low-Grade Glioma Tissue

“…Some grade III and grade IV glioma samples that expressed relatively low HIF-2α levels also might indicate a better prognosis towards the patients. Some publications have stated that HIFs, including HIF-2α, correlate with the perception of chemotherapy resistance in several other cancers such as liver [22], lung [23], renal [24], and colorectal [25] cancer. According to those papers, HIF-2 is responsible for allowing a vigorous proliferation of the cancerous cells that further impede the drug's efficacy.…”