Chloroquine-induced autophagic vacuole accumulation and cell death in glioma cells is p53 independent.
Glioblastoma (GBM) is a high-grade central nervous system malignancy and despite aggressive treatment strategies, GBM patients have a median survival time of just 1 year. Chloroquine (CQ), an antimalarial lysosomotropic agent, has been identified as a potential adjuvant in the treatment regimen of GBMs. However, the mechanism of CQ-induced tumor cell death is poorly defined. We and others have shown that CQ-mediated cell death may be p53-dependent and at least in part due to the intrinsic apoptotic death pathway. Here, we investigated the effects of CQ on 5 established human GBM lines, differing in their p53 gene status. CQ was found to induce a concentration-dependent death in each of these cell lines. Although CQ treatment increased caspase-3-like enzymatic activity in all 5 cell lines, a broad-spectrum caspase inhibitor did not significantly attenuate death. Moreover, CQ caused an accumulation of autophagic vacuoles in all cell lines and was found to affect the levels and subcellular distribution of cathepsin D, suggesting that altered lysosomal function may also play a role in CQ-induced cell death. Thus, CQ can induce p53-independent death in gliomas that do not require caspase-mediated apoptosis. To potentially identify more potent chemotherapeutics, various CQ derivatives and lysosomotropic compounds were tested on the GBM cells. Quinacrine and mefloquine were found to be more potent than CQ in killing GBM cells in vitro and given their superior blood-brain barrier penetration compared with CQ may prove more efficacious as chemotherapeutic agents for GBM patients.
Geng
Ying
Y
Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294-0017, USA.
Kohli
Latika
L
Klocke
Barbara J
BJ
Roth
Kevin A
KA
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects / Q000235:genetics*; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002738:Chloroquine / Q000494:pharmacology*; D005910:Glioma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D015767:Mefloquine / Q000494:pharmacology; D011796:Quinacrine / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D014617:Vacuoles / Q000187:drug effects / Q000235:genetics / Q000473:pathology
D000970:Antineoplastic Agents; D016159:Tumor Suppressor Protein p53; D002738:Chloroquine; D011796:Quinacrine; D015767:Mefloquine
Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6242-4
10841526
Nat Rev Cancer. 2005 Sep;5(9):726-34
16148885
Oncogene. 2007 Jan 11;26(2):186-97
16819506
Mol Pharmacol. 2006 Apr;69(4):1125-36
16391239
J Neuropathol Exp Neurol. 2001 Oct;60(10):937-45
11589424
Mol Pharmacol. 1980 Nov;18(3):468-75
7464813
Cancer Res. 2001 Jan 15;61(2):439-44
11212227
Toxicol Lett. 2008 Apr 21;178(1):52-60
18359172
Cell Death Differ. 2004 Apr;11(4):448-57
14713959
Int J Parasitol. 1992 Apr;22(2):243-5
1316884
Exp Cell Res. 1994 Apr;211(2):314-21
8143779
Br J Cancer. 2008 Apr 22;98(8):1431-3
18349850
Brain Pathol. 1999 Jul;9(3):469-79
10416987
Ann Intern Med. 2006 Mar 7;144(5):337-43
16520474
Am J Trop Med Hyg. 1985 Nov;34(6):1028-36
3879657
Brain Tumor Pathol. 2006 Apr;23(1):29-34
18095116
J Neurosurg. 2003 Feb;98(2):378-84
12593626
Biochem Pharmacol. 1991 Dec 11;42 Suppl:S225-7
1768282
Free Radic Biol Med. 2008 Jun 15;44(12):2034-42
18397762
Oncogene. 2003 Jun 19;22(25):3927-36
12813466
Nat Rev Mol Cell Biol. 2007 Sep;8(9):741-52
17717517
Cancer Biol Ther. 2005 Aug;4(8):893-8
16177561
Antimicrob Agents Chemother. 2008 Feb;52(2):684-93
17999964
J Cell Biol. 1981 Sep;90(3):665-9
6169733
Br J Neurosurg. 2007 Oct;21(5):496-500
17852105
Mol Cell Biol. 2005 Feb;25(3):1025-40
15657430
Pathol Biol (Paris). 1982 Jun;30(6 Pt 2):589-92
6750530
Neurosurg Focus. 2003 Feb 15;14(2):e3
15727424
Nat Rev Cancer. 2005 Nov;5(11):886-97
16239905
Cell. 2005 Jan 28;120(2):237-48
15680329
Cell Death Differ. 2007 Mar;14(3):548-58
16946731
Nat Rev Cancer. 2004 Aug;4(8):592-603
15286739
EMBO J. 2000 Nov 1;19(21):5720-8
11060023
Oncologist. 2007 Dec;12(12):1395-403
18165616
J Clin Invest. 2007 Feb;117(2):326-36
17235397