Chloroquine prevents hypoxic accumulation of HIF-1α by inhibiting ATR kinase: implication in chloroquine-mediated chemosensitization of colon carcinoma cells under hypoxia.

Abstract

BACKGROUND:

Chloroquine (CQ) is an effective and safe antimalarial drug that is also used as a disease-modifying antirheumatic drug. Recent studies have shown that CQ can sensitize cancer cells to anti-cancer therapies.

METHODS:

In this study, we investigated the molecular mechanisms underlying CQ-mediated chemosensitization in human colon carcinoma cells.

RESULTS:

CQ prevented hypoxia-inducible factor (HIF)-1α protein induction in human colon carcinoma cells. CQ also suppressed HIF-1 activity, as represented by CQ inhibition of HIF-1-dependent luciferase activity and reduced induction of vascular endothelial growth factor. Under hypoxia, CQ restricted HIF-1α synthesis but did not affect HIF-1α transcription and protein stability. The hypoxic state activated ataxia telangiectasia and Rad3-related (ATR) kinase and increased the level of phosphorylated checkpoint kinase 1, a substrate of ATR kinase; however, this was prevented by CQ. An ATR kinase inhibitor suppressed the hypoxic induction of HIF-1α protein and was as effective as CQ. The cytotoxicity of 5-fluorouracil (5-FU), the first choice for the treatment of colorectal cancer, was attenuated under hypoxia. CQ enhanced the cytotoxicity of 5-FU treatment, which was mimicked by the transient transfection with HIF-1α siRNA.

CONCLUSIONS:

Under hypoxia, CQ-mediated sensitization of colon carcinoma HCT116 cells to 5-FU involves HIF-1 inhibition via ATR kinase suppression.

• Authors: Changyu Kang, Sanghyun Ju, Jaejeong Kim, Yunjin Jung
• Journal: Pharmacological reports : PR (Pharmacol Rep) Vol. 75 Issue 1 Pg. 211-221 (Feb 2023) ISSN: 2299-5684 [Electronic] Switzerland
• PMID: 36508076 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s) under exclusive licence to Maj Institute of Pharmacology Polish Academy of Sciences.

Chemical References

• Ataxia Telangiectasia Mutated Proteins
• ATR protein, human
• Chloroquine
• Fluorouracil
• Vascular Endothelial Growth Factor A
• HIF1A protein, human

Topics

• Humans
• Ataxia Telangiectasia Mutated Proteins (metabolism)
• Carcinoma
• Cell Hypoxia
• Cell Line, Tumor
• Chloroquine (pharmacology)
• Colonic Neoplasms (metabolism)
• Fluorouracil
• Hypoxia (metabolism)
• Vascular Endothelial Growth Factor A (metabolism)