The synergistic effect of combination temozolomide and chloroquine treatment is dependent on autophagy formation and p53 status in glioma cells
Authors: Hyun-Kyung Kim
Young Ae Joe
Seung Woo Lee
Na-Hyeon Lee
Hong-Sug Kim
Sung Hee Hong
Yong-Kil Hong
Hee-Yeon Yi
Journal: Cancer Letters (2015)
Discipline: CLINICAL MEDICINE
Keywords: Autophagy; Chloroquine; Glioma; Temozolomide; p53.
Affiliations: Cancer Research Institute, Department of Medical Lifescience, and Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea., Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 215-4, Gongneung-Dong, Nowon-Gu, Seoul 139-706, Republic of Korea., Department of Neuro-Surgery, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea., Cancer Research Institute, Department of Medical Lifescience, and Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea. Electronic address: .

Abstract:  Temozolomide (TMZ) is an alkylating agent used for the treatment of glioblastoma. The late autophagy inhibitor chloroquine (CQ) inhibits glioblastoma tumors in a p53-independent and p53-dependent manner. We addressed a possible beneficial effect of combination treatment with TMZ and CQ by examining the molecular and cellular mechanism of co-treatment. Combination treatment of U87 cell (wild type p53) with TMZ and CQ synergistically reduced cell proliferation and enhanced apoptosis, with increased sub-G1 hypodiploid cells and caspase activation. This effect was abolished by a pan-caspase inhibitor, Z-VAD-FMK. TMZ induced autophagy, and the addition of CQ further increased autophagic vacuoles. Inhibition of early stages of autophagy by Beclin 1 knockdown and 3-methyladenine pretreatment prevented the enhanced effect of the combination treatment. The combination treatment also upregulated p53 and phospho-p53 levels, whereas p53 knockdown or overexpression of mutant p53 abolished the combination effect. In contrast, combination therapy had no enhanced effect on U373 cell (mutant p53) proliferation and apoptosis within 3 d, although TMZ induced autophagy and co-treatment with CQ increased autophagic vacuole accumulation. However, long term combination treatment for 9-10 d effectively decreased clonal and cellular growth with increased G2-M arrest. This effect was also abolished by Beclin 1 knockdown. Our data support the beneficial effect of combination treatment with TMZ and CQ in glioma via differential autophagy-associated mechanisms, depending on p53 status. 

Retracted: No

PubPeer comments:
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 #1 This paper conforms to a style identified by [Dr Elisabeth Bik] and [Dr Jana Christopher] , among others. , 
 Retraction notice published around June 15, 2021, found here: https: www.scielo.br j bjmbr a f7kLkFP8dPYzFNv5N8DPYvL ?lang=en format=pdf It reads:  The authors would like to retract the article u201clncRNA CCAT1 promotes cell proliferation, migration, and invasion by down-regulation of miR-143 in FTC-133 thyroid carcinoma cell lineu201d that was published in volume 51 no. 6 (2018) (Epub May 21, 2018) in the Brazilian Journal of Medical and Biological Research. After the publication of this study, the corresponding author requested its retraction due to u201cthe identification of data fabrication.u201d The Editors decided to immediately retract this paper to avoid further damage to the scientific community. The Brazilian Journal of Medical and Biological Research remains vigilant to prevent misconduct and reinforces the Journalu2019s commitment to good scientific practices. We regret the unprofessional behavior of the authors involved. ,