Journal
CANCER LETTERS
Volume 332, Issue 2, Pages 265-274Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2010.05.021
Keywords
Lysosome; Cell death; Multidrug resistance; Cathepsins; Acid sphingomyelinase
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Funding
- Danish Cancer Society
- Danish Medical Research Council
- Danish National Research Foundation
- European Commission FP7 APO-SYS network
- Meyer Foundation
- Novo Nordisk Foundation
- M.L. Jorgensen & G. Hansen Foundation
- Lundbeck Foundation
- Alfred Benzon Foundation
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Acquired therapy resistance is one of the prime obstacles for successful cancer treatment. Partial resistance is often acquired already during an early face of tumor development when genetic changes causing defects in classical caspase-dependent apoptosis pathway provide transformed cells with a growth advantage by protecting them against various apoptosis inducing stimuli including transforming oncogenes themselves and host immune system. Apoptosis defective cells are further selected during tumor progression and finally by apoptosis inducing treatments. Another form of resistance, multidrug resistance, arises during cancer treatment when cancer cells with effective efflux of cytotoxic agents escape the therapy. Remarkably, induction of lysosomal membrane permeabilization has recently emerged as an effective way to kill apoptosis resistant cancer cells and some lysosome targeting drugs can also re-sensitize multidrug resistant cells to classical chemotherapy. In this review, we highlight recent data on lysosomal cell death pathways and their implications for the future treatment of apoptosis defective and multidrug resistant aggressive tumors. (C) 2010 Elsevier Ireland Ltd. All rights reserved.
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