Bortezomib induces G2-M arrest in human colon cancer cells through ROS-inducible phosphorylation of ATM-CHK1

International Journal of Oncology
Yong Sang HongTae Won Kim

Abstract

Colorectal cancer (CRC) is one of the most common cancers; however, the development of drugs to treat the condition has reached a plateau. Bortezomib (PS-341, Velcade®) is a proteasome inhibitor approved for the treatment of hematological malignancies, including multiple myeloma. A few trials of bortezomib, alone or in combination chemotherapy, for CRC patients have been reported; however, the results were largely inconclusive. This may be related to a lack of understanding of the drug's mechanism of action. Although bortezomib is reported to induce apoptosis and cell cycle arrest in various human cancer cells, the inhibitory mechanism involved is not clear. In this study, the effect of bortezomib as a treatment for human CRC was examined in vitro using three CRC cell lines. Bortezomib induced G2-M arrest in CRC cells. Investigation of G2-M phase-related cell cycle proteins involved in the response to bortezomib revealed that the ataxia telangiectasia mutated (ATM)-cell cycle checkpoint kinase 1 (CHK1) pathway, but not ATM and Rad3-related (ATR), was activated, resulting in the inactivation of cdc2. Bortezomib caused an increase in intracellular reactive oxygen species (ROS) and treatment with the ROS scavenger NAC inhibited ph...Continue Reading

Citations

Jul 15, 2015·Toxicology in Vitro : an International Journal Published in Association with BIBRA·Lanhai LüHongzhang Huang
Dec 22, 2014·Molecular and Cellular Endocrinology·Jerry Vriend, Russel J Reiter
May 28, 2013·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·Hsin-Yu FangBing-Hung Chen
Mar 13, 2016·The Journal of Investigative Dermatology·Kimberley A BeaumontNikolas K Haass
Nov 22, 2016·International Journal of Molecular Sciences·Bingqian XieWeiliang Zhu
Apr 1, 2015·Molecular & Cellular Oncology·Florine ObristLorenzo Galluzzi
May 18, 2018·Oxidative Medicine and Cellular Longevity·Pierpaola DavalliDomenico D'Arca

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