Effective tumor cell death by σ-2 receptor ligand siramesine involves lysosomal leakage and oxidative stress

被引:203
作者
Ostenfeld, MS
Fehrenbacher, N
Hoyer-Hansen, M
Thomsen, C
Farkas, T
Jäättelä, M
机构
[1] Danish Canc Soc, Inst Canc Biol, Apoptosis Dept, DK-2100 Copenhagen, Denmark
[2] H Lundbeck & Co AS, Mol Pharmacol & Neurochem, Valby, Denmark
关键词
D O I
10.1158/0008-5472.CAN-05-0269
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Acquired resistance to classic caspase-mediated apoptosis is a common problem for the treatment of human cancer. Here, we show that siramesine, a novel sigma-2 receptor ligand, effectively induces caspase-independent programmed cell death in immortalized and transformed cells of various origins. Siramesine-treated tumor cells displayed increased levels of reactive oxygen species, lysosomal membrane permeabilization, chromatin condensation, and shrinkage and detachment of cells. Lipid antioxidants (alpha-tocopherol and gamma-tocopherol), but not other tested antioxidants (butylated hydroxyanisol or N-acetyl cysteine), effectively inhibited siramesine-induced morphologic changes and cell death. Cathepsin B inhibitors (CA-074-Me and R-2525) conferred similar, but less pronounced protection, whereas ectopic expression of antiapoptotic protein Bcl-2, lack of wild-type p53 as well as pharmacologic inhibitors of caspases (zVAD-fmk, DEVD-CHO, and LEHD-CHO), calpains (PD150606), and serine proteases (N-tosyl-L-phenylaianine chloromethyl ketone and pefabloc) failed to protect cells against siramesme-induced death. Importantly, transformation of murine embryonic fibroblasts with activated c-src or v-Ha-ras oncogenes greatly sensitized them to siramesine-induced cytotoxicity. Furthermore, p.o. administration of well-tolerated doses of siramesine had a significant antitumorigenic effect in orthotopic breast cancer and s.c. fibrosarcoma models in mice. These results present siramesine as a promising new drug for the treatment of tumors resistant to traditional therapies.
引用
收藏
页码:8975 / 8983
页数:9
相关论文
共 43 条
[1]   Effect of ploidy, recruitment, environmental factors, and tamoxifen treatment on the expression of sigma-2 receptors in proliferating and quiescent tumour cells [J].
Al-Nabulsi, I ;
Mach, RH ;
Wang, LM ;
Wallen, CA ;
Keng, PC ;
Sten, K ;
Childers, SR ;
Wheeler, KT .
BRITISH JOURNAL OF CANCER, 1999, 81 (06) :925-933
[2]   Sigma receptors and cancer: Possible involvement of ion channels [J].
Aydar, E ;
Palmer, CP ;
Djamgoz, MBA .
CANCER RESEARCH, 2004, 64 (15) :5029-5035
[3]   Non-antioxidant molecular functions of α-tocopherol (vitamin E) [J].
Azzi, A ;
Ricciarelli, R ;
Zingg, JM .
FEBS LETTERS, 2002, 519 (1-3) :8-10
[4]   Anisamide-targeted stealth liposomes: A potent carrier for targeting doxorubicin to human prostate cancer cells [J].
Banerjee, R ;
Tyagi, P ;
Li, S ;
Huang, L .
INTERNATIONAL JOURNAL OF CANCER, 2004, 112 (04) :693-700
[5]  
Behl C, 1995, NEUROREPORT, V7, P360, DOI 10.1097/00001756-199512000-00085
[6]   SIGMA-BINDING SITE LIGANDS INHIBIT CELL-PROLIFERATION IN MAMMARY AND COLON-CARCINOMA CELL-LINES AND MELANOMA-CELLS IN CULTURE [J].
BRENT, PJ ;
PANG, GT .
EUROPEAN JOURNAL OF PHARMACOLOGY, 1995, 278 (02) :151-160
[7]   The Bcl-2 family: roles in cell survival and oncogenesis [J].
Cory, S ;
Huang, DCS ;
Adams, JM .
ONCOGENE, 2003, 22 (53) :8590-8607
[8]   σ2 receptors regulate changes in sphingolipid levels in breast tumor cells [J].
Crawford, KW ;
Coop, A ;
Bowen, WD .
EUROPEAN JOURNAL OF PHARMACOLOGY, 2002, 443 (1-3) :207-209
[9]  
Crawford KW, 2002, CANCER RES, V62, P313
[10]   Induction of lysosomal membrane permeabilization by compounds that activate p53-independent apoptosis [J].
Erdal, H ;
Berndtsson, M ;
Castro, J ;
Brunk, U ;
Shoshan, MC ;
Linder, S .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (01) :192-197