Synergistic antitumor effects of endostar in combination with oxaliplatin via inhibition of HIF and CXCR4 in the colorectal cell line SW1116.
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.
The First Hospital of Jilin University, Changchun, China.
Fengyan
F
Jin
Huifan
H
Ji
Chunshu
C
Jia
Ulf
U
Brockmeier
Dirk M
DM
Hermann
Eric
E
Metzen
Yingqiao
Y
Zhu
Baorong
B
Chi
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D002448:Cell Adhesion / Q000187:drug effects; D015687:Cell Hypoxia; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003094:Collagen; D015179:Colorectal Neoplasms / Q000473:pathology*; D004338:Drug Combinations; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D043169:Endostatins / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D007797:Laminin; D009361:Neoplasm Invasiveness / Q000473:pathology; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000494:pharmacology*; D000077150:Oxaliplatin; D011509:Proteoglycans; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D011994:Recombinant Proteins; D015398:Signal Transduction / Q000187:drug effects; D000099162:Endothelial PAS Domain-Containing Protein 1
D000970:Antineoplastic Agents; D051792:Basic Helix-Loop-Helix Proteins; D003094:Collagen; D004338:Drug Combinations; D043169:Endostatins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007797:Laminin; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D011509:Proteoglycans; D019718:Receptors, CXCR4; D011994:Recombinant Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1; C527276:CXCR4 protein, human; C497442:HIF1A protein, human; C059485:matrigel; C522911:endostar protein