Inhibition of PGE 2 /EP4 receptor signaling enhances oxaliplatin efficacy in resistant colon cancer cells through modulation of oxidative stress

The platinum-based chemotherapeutic agent, oxaliplatin, is used to treat advanced colorectal cancer (CRC). Unfortunately, nearly all patients acquire resistance to oxaliplatin after long-term use, limiting its therapeutic efficacy. Since COX-2 and PGE signaling can impact colon cancer cell prolifera...

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Veröffentlicht in:	Scientific reports 2019-12, Vol.9 (1), p.4954
Hauptverfasser:	Huang, Huakang, Aladelokun, Oladimeji, Ideta, Takayasu, Giardina, Charles, Ellis, Lee M, Rosenberg, Daniel W
Format:	Artikel
Sprache:	eng
Schlagworte:	Antineoplastic Combined Chemotherapy Protocols - pharmacology Antineoplastic Combined Chemotherapy Protocols - therapeutic use Colonic Neoplasms - drug therapy Colonic Neoplasms - pathology Cyclooxygenase 2 - genetics Cyclooxygenase 2 - metabolism Dinoprostone - metabolism Drug Resistance, Neoplasm - drug effects Drug Synergism Gene Knockdown Techniques HT29 Cells Humans Oxaliplatin - pharmacology Oxaliplatin - therapeutic use Oxidative Stress - drug effects Reactive Oxygen Species - metabolism Receptors, Prostaglandin E, EP4 Subtype - antagonists & inhibitors Receptors, Prostaglandin E, EP4 Subtype - metabolism RNA, Small Interfering - metabolism Signal Transduction - drug effects Signal Transduction - genetics Thiophenes - pharmacology Thiophenes - therapeutic use Triazoles - pharmacology Triazoles - therapeutic use
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Zusammenfassung:	The platinum-based chemotherapeutic agent, oxaliplatin, is used to treat advanced colorectal cancer (CRC). Unfortunately, nearly all patients acquire resistance to oxaliplatin after long-term use, limiting its therapeutic efficacy. Since COX-2 and PGE signaling can impact colon cancer cell proliferation and survival, we examined how this pathway was affected in an oxaliplatin resistant colon cancer cell line. PGE levels were significantly elevated in oxaliplatin-resistant HT29 cells (OXR) compared to naïve parental HT29 cells (PAR). This increase was associated with elevated COX-2 (17.9-fold; P = 0.008) and reduced 15-hydroxyprostaglandin dehydrogenase (2.9-fold; P
ISSN:	2045-2322
DOI:	10.1038/s41598-019-40848-4