Next Article in Journal
Mast Cells May Regulate The Anti-Inflammatory Activity of IL-37
Next Article in Special Issue
The Protective Effect of Insulin on Rat Cortical Neurons in Oxidative Stress and Its Dependence on the Modulation of Akt, GSK-3beta, ERK1/2, and AMPK Activities
Previous Article in Journal
Cell Autonomous Dysfunction and Insulin Resistance in Pancreatic α Cells
Previous Article in Special Issue
Pitavastatin Exerts Potent Anti-Inflammatory and Immunomodulatory Effects via the Suppression of AP-1 Signal Transduction in Human T Cells
Open AccessArticle

Co-Inhibition of the DNA Damage Response and CHK1 Enhances Apoptosis of Neuroblastoma Cells

Department of Clinical Diagnostic Oncology, Showa University Clinical Research Institute for Clinical Pharmacology and Therapeutics, 6-11-11 kita-karasuyama, setagaya-ku, Tokyo 157-8577, Japan
Department of Biomedical Sciences, Division of Biochemistry, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan
Chiba Cancer Center Research Institute, Chiba 260-8717, Japan
Division of Molecular Medicine, Life Science Research Institute, Saga Medical Center Koseikan, Saga 840-8571, Japan
SAGA HIMAT Foundation, Saga 841-0071, Japan
Department of Pediatric Surgery, Nihon University School of Medicine, Tokyo 173-8610, Japan
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(15), 3700;
Received: 1 July 2019 / Revised: 22 July 2019 / Accepted: 23 July 2019 / Published: 29 July 2019
(This article belongs to the Special Issue Kinase Signal Transduction 2019)
Checkpoint kinase 1 (CHK1) is a central mediator of the DNA damage response (DDR) at the S and G2/M cell cycle checkpoints, and plays a crucial role in preserving genomic integrity. CHK1 overexpression is thought to contribute to cancer aggressiveness, and several selective inhibitors of this kinase are in clinical development for various cancers, including neuroblastoma (NB). Here, we examined the sensitivity of MYCN-amplified NB cell lines to the CHK1 inhibitor PF-477736 and explored mechanisms to increase its efficacy. PF-477736 treatment of two sensitive NB cell lines, SMS-SAN and CHP134, increased the expression of two pro-apoptotic proteins, BAX and PUMA, providing a mechanism for the effect of the CHK1 inhibitor. In contrast, in NB-39-nu and SK-N-BE cell lines, PF-477736 induced DNA double-strand breaks and activated the ataxia telangiectasia mutated serine/threonine kinase (ATM)-p53-p21 axis of the DDR pathway, which rendered the cells relatively insensitive to the antiproliferative effects of the CHK1 inhibitor. Interestingly, combined treatment with PF-477736 and the ATM inhibitor Ku55933 overcame the insensitivity of NB-39-nu and SK-N-BE cells to CHK1 inhibition and induced mitotic cell death. Similarly, co-treatment with PF-477736 and NU7441, a pharmacological inhibitor of DNA-PK, which is also essential for the DDR pathway, rendered the cells sensitive to CHK1 inhibition. Taken together, our results suggest that synthetic lethality between inhibitors of CHK1 and the DDR drives G2/M checkpoint abrogation and could be a novel potential therapeutic strategy for NB. View Full-Text
Keywords: CHK1; ATM; DNA-PK; neuroblastoma; checkpoint abrogation CHK1; ATM; DNA-PK; neuroblastoma; checkpoint abrogation
Show Figures

Graphical abstract

MDPI and ACS Style

Ando, K.; Nakamura, Y.; Nagase, H.; Nakagawara, A.; Koshinaga, T.; Wada, S.; Makishima, M. Co-Inhibition of the DNA Damage Response and CHK1 Enhances Apoptosis of Neuroblastoma Cells. Int. J. Mol. Sci. 2019, 20, 3700.

AMA Style

Ando K, Nakamura Y, Nagase H, Nakagawara A, Koshinaga T, Wada S, Makishima M. Co-Inhibition of the DNA Damage Response and CHK1 Enhances Apoptosis of Neuroblastoma Cells. International Journal of Molecular Sciences. 2019; 20(15):3700.

Chicago/Turabian Style

Ando, Kiyohiro; Nakamura, Yohko; Nagase, Hiroki; Nakagawara, Akira; Koshinaga, Tsugumichi; Wada, Satoshi; Makishima, Makoto. 2019. "Co-Inhibition of the DNA Damage Response and CHK1 Enhances Apoptosis of Neuroblastoma Cells" Int. J. Mol. Sci. 20, no. 15: 3700.

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

Search more from Scilit
Back to TopTop