Chloroquine activates the p53 pathway and induces apoptosis in human glioma cells

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Abstract

Glioblastoma is the most common malignant brain tumor in adults. The currently available treatments offer only a palliative survival advantage and the need for effective treatments remains an urgent priority. Activation of the p53 growth suppression/apoptotic pathway is one of the promising strategies in targeting glioma cells. We show that the quinoline derivative chloroquine activates the p53 pathway and suppresses growth of glioma cells in vitro and in vivo in an orthotopic (U87MG) human glioblastoma mouse model. Induction of apoptosis is one of the mechanisms underlying the effects of chloroquine on suppressing glioma cell growth and viability. siRNA-mediated downregulation of p53 in wild-type but not mutant p53 glioblastoma cells substantially impaired chloroquine-induced apoptosis. In addition to its p53-activating effects, chloroquine may also inhibit glioma cell growth via p53-independent mechanisms. Our results clarify the mechanistic basis underlying the antineoplastic effect of chloroquine and reveal its therapeutic potential as an adjunct to glioma chemotherapy.

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Most cited references 46

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Genetic pathways to primary and secondary glioblastoma.

Hiroko Ohgaki, Paul Kleihues (2007)

Glioblastoma is the most frequent and most malignant human brain tumor. The prognosis remains very poor, with most patients dying within 1 year after diagnosis. Primary and secondary glioblastoma constitute distinct disease subtypes, affecting patients of different age and developing through different genetic pathways. The majority of cases (>90%) are primary glioblastomas that develop rapidly de novo, without clinical or histological evidence of a less malignant precursor lesion. They affect mainly the elderly and are genetically characterized by loss of heterozygosity 10q (70% of cases), EGFR amplification (36%), p16(INK4a) deletion (31%), and PTEN mutations (25%). Secondary glioblastomas develop through progression from low-grade diffuse astrocytoma or anaplastic astrocytoma and manifest in younger patients. In the pathway to secondary glioblastoma, TP53 mutations are the most frequent and earliest detectable genetic alteration, already present in 60% of precursor low-grade astrocytomas. The mutation pattern is characterized by frequent G:C-->A:T mutations at CpG sites. During progression to glioblastoma, additional mutations accumulate, including loss of heterozygosity 10q25-qter ( approximately 70%), which is the most frequent genetic alteration in both primary and secondary glioblastomas. Primary and secondary glioblastomas also differ significantly in their pattern of promoter methylation and in expression profiles at RNA and protein levels. This has significant implications, particularly for the development of novel, targeted therapies, as discussed in this review.

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Genetic pathways to glioblastoma: a population-based study.

Hiroko Ohgaki, Pierre Dessen, Benjamin Jourde … (2004)

We conducted a population-based study on glioblastomas in the Canton of Zurich, Switzerland (population, 1.16 million) to determine the frequency of major genetic alterations and their effect on patient survival. Between 1980 and 1994, 715 glioblastomas were diagnosed. The incidence rate per 100,000 population/year, adjusted to the World Standard Population, was 3.32 in males and 2.24 in females. Observed survival rates were 42.4% at 6 months, 17.7% at 1 year, and 3.3% at 2 years. For all of the age groups, younger patients survived significantly longer, ranging from a median of 8.8 months ( 80 years). Loss of heterozygosity (LOH) 10q was the most frequent genetic alteration (69%), followed by EGFR amplification (34%), TP53 mutations (31%), p16(INK4a) deletion (31%), and PTEN mutations (24%). LOH 10q occurred in association with any of the other genetic alterations and was predictive of shorter survival. Primary (de novo) glioblastomas prevailed (95%), whereas secondary glioblastomas that progressed from low-grade or anaplastic gliomas were rare (5%). Secondary glioblastomas were characterized by frequent LOH 10q (63%) and TP53 mutations (65%). Of the TP53 mutations in secondary glioblastomas, 57% were in hotspot codons 248 and 273, whereas in primary glioblastomas, mutations were more equally distributed. G:C-->A:T mutations at CpG sites were more frequent in secondary than primary glioblastomas (56% versus 30%; P = 0.0208). This suggests that the acquisition of TP53 mutations in these glioblastoma subtypes occurs through different mechanisms.

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Disruption of p53 in human cancer cells alters the responses to therapeutic agents.

F Bunz, P M Hwang, C Torrance … (1999)

We have examined the effects of commonly used chemotherapeutic agents on human colon cancer cell lines in which the p53 pathway has been specifically disrupted by targeted homologous recombination. We found that p53 had profound effects on drug responses, and these effects varied dramatically depending on the drug. The p53-deficient cells were sensitized to the effects of DNA-damaging agents as a result of the failure to induce expression of the cyclin-dependent kinase inhibitor p21. In contrast, p53 disruption rendered cells strikingly resistant to the effects of the antimetabolite 5-fluorouracil (5-FU), the mainstay of adjuvant therapy for colorectal cancer. The effects on 5-FU sensitivity were observed both in vitro and in vivo, were independent of p21, and appeared to be the result of perturbations in RNA, rather than DNA, metabolism. These results have significant implications for future efforts to maximize therapeutic efficacy in patients with defined genetic alterations.

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Author and article information

Journal

Journal ID (nlm-ta): Neuro Oncol

Journal ID (publisher-id): neuonc

Journal ID (hwp): neuonc

Title: Neuro-Oncology

Publisher: Oxford University Press

ISSN (Print): 1522-8517

ISSN (Electronic): 1523-5866

Publication date (Print): April 2010

Publication date (Electronic): 27 January 2010

Volume: 12

Issue: 4

Pages: 389-400

Affiliations

The Translational Neurooncology Research Group, Department of Neurosurgery, simpleGeorg-August University Göttingen , Göttingen, Germany(E.L.K., A.R., C.S.-S., E.-M.B., N.P., V.R., A.G.); Medical School University of Schleswig-Holstein, Campus Lübeck, Lübeck, Germany (R.W.); Heinrich-Pette-Institute, Hamburg, Germany (G.W., W.D.); Cell Transformation Unit, Children's Medical Research Institute, Westmead, New South Wales, Australia (D.S.); Department of Neuropathology, Georg-August University Göttingen, Göttingen, Germany (W.S.-S.)

Author notes

Corresponding Author: Alf Giese, MD, The Translational Neurooncology Research Group, Department of Neurosurgery, simpleGeorg-August University Göttingen , Robert-Koch-Strasse 40, 37075 Göttingen, Germany ( alf.giese@ 123456med.uni-goettingen.de ). Ella Kim, PhD, The Translational Neurooncology Research Group, Department of Neurosurgery, Georg-August University Göttingen, Robert-Koch-Strasse 40, 37075 Göttingen, Germany ( ella.kim@ 123456med.uni-goettingen.de ).

Article

Publisher ID: nop046

DOI: 10.1093/neuonc/nop046

PMC ID: 2940600

PubMed ID: 20308316

SO-VID: 5fac8dbb-57da-461e-b24b-d778e61c29a3

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This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/2.5/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Chloroquine activates the p53 pathway and induces apoptosis in human glioma cells

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Most cited references 46

Genetic pathways to primary and secondary glioblastoma.

Genetic pathways to glioblastoma: a population-based study.

Disruption of p53 in human cancer cells alters the responses to therapeutic agents.

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