1, 9-Pyrazoloanthrones downregulate HIF-1α and sensitize cancer cells to cetuximab-mediated anti-EGFR therapy

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1, 9-Pyrazoloanthrones downregulate HIF-1α and sensitize cancer cells to cetuximab-mediated anti-EGFR therapy
著者: Lu, Yang ; Li, Xinqun ; Lu, Haiquan ; Fan, Zhen
Gullberg, Donald
主題: AKT protein ; Androgens ; Angiogenesis ; Anthracenes - chemistry ; Anthracenes - pharmacology ; Antibodies, Monoclonal - pharmacology ; Antibodies, Monoclonal, Humanized ; Antineoplastic Agents - pharmacology ; Apoptosis ; Biology ; Breast cancer ; c-Jun protein ; Cancer ; Cancer therapies ; Cell Line, Tumor ; Cetuximab ; Clinical outcomes ; Colorectal cancer ; Degradation ; Down-Regulation ; Epidermal growth factor ; Epidermal growth factor receptors ; Extracellular signal-regulated kinase ; Gene expression ; Gene Expression Regulation, Neoplastic ; Head & neck cancer ; Humans ; Hypoxia ; Hypoxia-inducible factor 1 ; Hypoxia-Inducible Factor 1 - metabolism ; Hypoxia-inducible factor 1a ; Hypoxia-inducible factors ; Immunoglobulins ; Immunotherapy ; Inhibition ; Kinases ; MAP Kinase Kinase 4 - metabolism ; Medicine ; Metastasis ; Monoclonal antibodies ; Mutation ; Oxygen ; Patients ; Phosphorylation ; Prolyl hydroxylase ; Prostate cancer ; Proteasomes ; Protein biosynthesis ; Protein synthesis ; Proteins ; Pyrazoles - chemistry ; Pyrazoles - pharmacology ; Receptor, Epidermal Growth Factor - antagonists & inhibitors ; Signaling ; Solid tumors ; Synergistic effect ; Targeted cancer therapy ; TOR protein ; Transcription factors ; Tumors ; Ubiquitin - chemistry ; Vascular Endothelial Growth Factor A - metabolism
所屬期刊: PloS one, 2010-12, Vol.5 (12), p.e15823-e15823
描述: Cetuximab, a monoclonal antibody that blocks the epidermal growth factor receptor (EGFR), is currently approved for the treatment of several types of solid tumors. We previously showed that cetuximab can inhibit hypoxia-inducible factor-1 alpha (HIF-1α) protein synthesis by inhibiting the activation of EGFR downstream signaling pathways including Erk, Akt, and mTOR. 1, 9-pyrazoloanthrone (1, 9 PA) is an anthrapyrazolone compound best known as SP600125 that specifically inhibits c-jun N-terminal kinase (JNK). Here, we report 1, 9 PA can downregulate HIF-1α independently of its inhibition of JNK. This downregulatory effect was abolished when the oxygen-dependent domain (ODD) of HIF-1α (HIF-1α-ΔODD, the domain responsible for HIF-1α degradation) was experimentally deleted or when the activity of HIF-1α prolyl hydroxylase (PHD) or the 26S proteasomal complex was inhibited, indicating that the 1, 9 PA downregulates HIF-1α by promoting PHD-dependent HIF-1α degradation. We found that the combination of 1, 9 PA and cetuximab worked synergistically to induce apoptosis in cancer cells in which cetuximab or 1, 9 PA alone had no or only weak apoptotic activity. This synergistic effect was substantially decreased in cancer cells transfected with HIF-1α-ΔODD, indicating that downregulation of HIF-1α was the mechanism of this synergistic effect. More importantly, 1, 9 PA can downregulate HIF-1α in cancer cells that are insensitive to cetuximab-induced inhibition of HIF-1α expression due to overexpression of oncogenic Ras (RasG12V). Our findings suggest that 1, 9 PA is a lead compound of a novel class of drugs that may be used to enhance the response of cancer cells to cetuximab through a complementary effect on the downregulation of HIF-1α.
出版者: United States: Public Library of Science
語言: 英文
識別號: ISSN: 1932-6203
EISSN: 1932-6203
DOI: 10.1371/journal.pone.0015823
PMID: 21209911
資源來源: Publicly Available Content Database
EBSCOhost Academic Search Premier
Agricultural & Environmental Science Collection
DOAJ Directory of Open Access Journals

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1, 9-Pyrazoloanthrones downregulate HIF-1α and sensitize cancer cells to cetuximab-mediated anti-EGFR therapy

Lu, Yang ; Li, Xinqun ; Lu, Haiquan ; Fan, Zhen Gullberg, Donald

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