Vincristine Induces Dramatic Lysosomal Changes and Sensitizes Cancer Cells to Lysosome-Destabilizing Siramesine

Groth‐Pedersen, Line; Ostenfeld, Marie Stampe; Høyer-Hansen, Maria; Nylandsted, Jesper; Jäättelä, Marja

doi:10.1158/0008-5472.can-06-3520

Cited by 186 publications

(197 citation statements)

References 45 publications

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“…The data presented above add BAMLET to the growing list of cytotoxic agents that can induce a nonapoptotic lysosomal cell death pathway (35). In light of these data, combination therapies with agents further sensitizing cells to lysosomal destabilization (such as microtubule disturbing drugs vincristine and paclitaxel) as well as with those inducing lysosomal destabilization (such as siramesine) should be experimentally tested (38,39). Given that many cancers have fundamental defects in both mitochondrial and death receptor signaling pathways, and that these apoptotic defects specifically characterize the most aggressive therapy resistant tumors, BAMLET alone or in combination therapies may provide new treatment options in aggressive cancers.…”

Section: Discussionmentioning

confidence: 99%

BAMLET Activates a Lysosomal Cell Death Program in Cancer Cells

Rammer

Groth‐Pedersen

Kirkegaard

et al. 2010

Molecular Cancer Therapeutics

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118

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A complex of human α-lactalbumin and oleic acid (HAMLET) was originally isolated from human milk as a potent anticancer agent. It kills a wide range of transformed cells of various origins while leaving nontransformed healthy cells largely unaffected both in vitro and in vivo. Importantly, purified α-lactalbumins from other mammals form complexes with oleic acid that show biological activities similar to that of HAMLET. The mechanism by which these protein-lipid complexes kill tumor cells is, however, largely unknown. Here, we show that complex of bovine α-lactalbumin and oleic acid (BAMLET), the bovine counterpart of HAMLET, kills tumor cells via a mechanism involving lysosomal membrane permeabilization. BAMLET shows potent cytotoxic activity against eight cancer cell lines tested, whereas nontransformed NIH-3T3 murine embryonic fibroblasts are relatively resistant. BAMLET accumulates rapidly and specifically in the endolysosomal compartment of tumor cells and induces an early leakage of lysosomal cathepsins into the cytosol followed by the activation of the proapoptotic protein Bax. Ectopic expression of three proteins known to stabilize the lysosomal compartment, i.e. heat shock protein 70 (Hsp70), Hsp70-2, and lens epithelium-derived growth factor, confer significant protection against BAMLET-induced cell death, whereas the antiapoptotic protein Bcl-2, caspase inhibition, and autophagy inhibition fail to do so. These data indicate that BAMLET triggers lysosomal cell death pathway in cancer cells, thereby clarifying the ability of α-lactalbumin:oleate complexes to kill highly apoptosis-resistant tumor cells. Mol Cancer Ther; 9(1); 24-32. ©2010 AACR.

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Section: Discussionmentioning

confidence: 99%

BAMLET Activates a Lysosomal Cell Death Program in Cancer Cells

Rammer

Groth‐Pedersen

Kirkegaard

et al. 2010

Molecular Cancer Therapeutics

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118

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“…Indeed, preliminary data from our laboratory, investigating the involvement of cytoskeleton components in endosomal stability and/or direct exocytosis pathway, are showing that treatment of melanoma cells with non-cytotoxic doses of microtubule-targeting drugs (paclitaxel and vinblastine) could reduce microvesicle release (M Iero, unpublished observations). Similarly, alterations of the lysosomal compartment are observed in breast cancer cells treated with additional microtubule-disturbing drugs, such as vincristine, 63 in which increased total lysosomal volume most likely results from a defective lysosome exocytosis.…”

Section: Pharmacological Modulation Of Exosome Secretion By Tumour Cellsmentioning

confidence: 93%

Tumour-released exosomes and their implications in cancer immunity

et al. 2007

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“…Cytosolic protease activity can be measured using lysosome-impermeable cathepsin substrates such as pepstatin BODIPY . Alternatively, protease activities can be monitored in cytosolic extracts with cathepsin-specific substrates such as zFR-amino-trifluoromethylcoumarin (Groth-Pedersen et al, 2007). Cytosolic cathepsin translocation can also be visualized by transfecting cells with fusion constructs encoding cathepsins that have been coupled to fluorescent proteins (Werneburg et al, 2002Broker et al, 2005).…”

Section: Lysosomal Membrane Permeabilization: Its Detectionmentioning

confidence: 99%

“…This applies to microtubule destabilizing vinca alkaloids such as vincristine, vinorelbine and vinblastine (Groth-Pedersen et al, 2007), as well as to compounds that stabilize microtubules such as paclitaxel, epothilone B and dicodermoliede. All these agents reportedly induce LMP-and CB-dependent apoptosis (Broker et al, 2004;Groth-Pedersen et al, 2007). The general applicability of these findings, however, remains to be confirmed.…”

Section: Inducers Of Lmpmentioning

confidence: 99%

Lysosomal membrane permeabilization in cell death

2008

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Mitochondrial outer membrane permeabilization (MOMP) constitutes one of the major checkpoint(s) of apoptotic and necrotic cell death. Recently, the permeabilization of yet another organelle, the lysosome, has been shown to initiate a cell death pathway, in specific circumstances. Lysosomal membrane permeabilization (LMP) causes the release of cathepsins and other hydrolases from the lysosomal lumen to the cytosol. LMP is induced by a plethora of distinct stimuli including reactive oxygen species, lysosomotropic compounds with detergent activity, as well as some endogenous cell death effectors such as Bax. LMP is a potentially lethal event because the ectopic presence of lysosomal proteases in the cytosol causes digestion of vital proteins and the activation of additional hydrolases including caspases. This latter process is usually mediated indirectly, through a cascade in which LMP causes the proteolytic activation of Bid (which is cleaved by the two lysosomal cathepsins B and D), which then induces MOMP, resulting in cytochrome c release and apoptosome-dependent caspase activation. However, massive LMP often results in cell death without caspase activation; this cell death may adopt a subapoptotic or necrotic appearance. The regulation of LMP is perturbed in cancer cells, suggesting that specific strategies for LMP induction might lead to novel therapeutic avenues.

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Vincristine Induces Dramatic Lysosomal Changes and Sensitizes Cancer Cells to Lysosome-Destabilizing Siramesine

Cited by 186 publications

References 45 publications

BAMLET Activates a Lysosomal Cell Death Program in Cancer Cells

BAMLET Activates a Lysosomal Cell Death Program in Cancer Cells

Tumour-released exosomes and their implications in cancer immunity

Lysosomal membrane permeabilization in cell death

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