Format

Send to

Choose Destination
Tumour Biol. 2016 Mar;37(3):3549-60. doi: 10.1007/s13277-015-4125-4. Epub 2015 Oct 10.

Inhibition of autophagy induced by quercetin at a late stage enhances cytotoxic effects on glioma cells.

Bi Y1,2, Shen C1,2, Li C3, Liu Y1,2, Gao D4, Shi C5, Peng F1,2, Liu Z1,2, Zhao B1,2, Zheng Z1,2, Wang X1,2, Hou X1,2, Liu H1,2, Wu J1,2, Zou H6, Wang K1,2, Zhong C1,2, Zhang J1,2, Shi C7, Zhao S8,9.

Author information

1
Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, People's Republic of China.
2
Institute of Brain Science, Harbin Medical University, Harbin, Heilongjiang, 150001, People's Republic of China.
3
Department of Neurosurgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, People's Republic of China.
4
Department of Endocrinology, General Hospital of HeiLongJiang Agricultural Reclamation Department, Harbin, Heilongjiang, 150001, People's Republic of China.
5
Department of Neurological Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA.
6
Department of Pain Medicine, Third Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, People's Republic of China.
7
Section of Neurosurgery, Department of Surgery, The University of Chicago Medical Center and Pritzker School of Medicine, Chicago, IL, USA.
8
Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, People's Republic of China. guangsz@hotmail.com.
9
Institute of Brain Science, Harbin Medical University, Harbin, Heilongjiang, 150001, People's Republic of China. guangsz@hotmail.com.

Abstract

Glioma is the most common primary brain tumor in the central nervous system (CNS) with high morbidity and mortality in adults. Although standardized comprehensive therapy has been adapted, the prognosis of glioma patients is still frustrating and thus novel therapeutic strategies are urgently in need. Quercetin (Quer), an important flavonoid compound found in many herbs, is shown to be effective in some tumor models including glioma. Recently, it is reported that adequate regulation of autophagy can strengthen cytotoxic effect of anticancer drugs. However, it is not yet fully clear how we should modulate autophagy to achieve a satisfactory therapeutic effect. 3-Methyladenine (3-MA) and Beclin1 short hairpin RNA (shRNA) were used to inhibit the early stage of autophage while chloroquine (CQ) to inhibit the late stage. MTT assay was implemented to determine cell viability. Transmission electron microscopy, western blot, and immunohistochemistry were adopted to evaluate autophagy. Western blot, flow cytometry, and immunohistochemistry were used to detect apoptosis. C6 glioma xenograft models were established to assess the therapeutic effect (the body weight change, the median survival time, and tumor volume) in vivo. Quercetin can inhibit cell viability and induce autophagy of U87 and U251 glioma cells in a dose-dependent manner. Inhibition of early-stage autophagy by 3-MA or shRNA against Beclin1 attenuated the quercetin-induced cytotoxicity. In contrast, suppression of autophagy at a late stage by CQ enhanced the anti-glioma efficiency of quercetin. Therapeutic effect of quercetin for malignant glioma can be strengthened by inhibition of autophagy at a late stage, not initial stage, which may provide a novel opportunity for glioma therapy.

KEYWORDS:

Apoptosis; Autophagy; Glioma; Quercetin

PMID:
26454746
DOI:
10.1007/s13277-015-4125-4
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Springer
Loading ...
Support Center