Combating apoptosis and multidrug resistant cancers by targeting lysosomes.
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.
Groth-Pedersen
Line
L
Pediatrics and Adolescent Medicine, The Juliane Marie Centre, University Hospital Rigshospitalet, Copenhagen, Denmark.
Jäättelä
Marja
M
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002403:Cathepsins / Q000378:metabolism; D016923:Cell Death; D002467:Cell Nucleus / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism
D000970:Antineoplastic Agents; C112980:acid sphingomyelinase-1; D013108:Sphingomyelin Phosphodiesterase; D002403:Cathepsins