LY294002 and LY303511 Sensitize Tumor Cells to Drug-Induced Apoptosis via Intracellular Hydrogen Peroxide Production Independent of the Phosphoinositide 3-Kinase-Akt Pathway

The tumor suppressor p53 and the phosphoinositide 3-kinase (PI3K)-Akt pathway have fundamental roles in regulating cell growth, apoptosis and are frequently mutated in cancer. Here, we show that genotoxic stress induces nuclear Akt activation by a p53-dependent mechanism that is independent from the canonical membrane-localized PI3K-Akt pathway. Upon genotoxic stress a nuclear p53-PI3,4,5P3 complex is generated in regions devoid of membranes by a nuclear PI3K, and this complex recruits all the kinases required to activate Akt and phosphorylate FOXOs, inhibiting DNA damage-induced apoptosis. Wild-type p53 activates nuclear Akt in an on/off fashion upon stress, whereas mutant p53 stimulates high basal Akt activity, indicating a fundamental difference. The nuclear p53-phosphoinositide signalosome is distinct from the canonical membrane-localized pathway and insensitive to PI3K inhibitors currently in the clinic, underscoring its therapeutic relevance.

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Hydrogen peroxide level in tumor cells during cisplatin-induced apoptosis

Medical Laser Applications and Laser-Tissue Interactions IX ◽

10.1117/12.2527195 ◽

2019 ◽

Author(s):

Anastasiya S. Nerush ◽

Kseniya M. Shсhukina ◽

Irina V. Balalaeva ◽

Anna G. Orlova

Keyword(s):

Hydrogen Peroxide ◽

Tumor Cells ◽

Induced Apoptosis

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Cross-Resistance of CD95- and Drug-Induced Apoptosis as a Consequence of Deficient Activation of Caspases (ICE/Ced-3 Proteases)

Blood ◽

10.1182/blood.v90.8.3118 ◽

1997 ◽

Vol 90 (8) ◽

pp. 3118-3129 ◽

Cited By ~ 123

Author(s):

Marek Los ◽

Ingrid Herr ◽

Claudia Friesen ◽

Simone Fulda ◽

Klaus Schulze-Osthoff ◽

...

Keyword(s):

Cell Death ◽

Drug Treatment ◽

Tumor Cells ◽

Anticancer Drugs ◽

Ex Vivo ◽

Resistant Cell ◽

Cross Resistance ◽

Strong Increase ◽

Drug Induced ◽

Induced Apoptosis

Abstract The cytotoxic effect of anticancer drugs has been shown to involve induction of apoptosis. We report here that tumor cells resistant to CD95 (APO-1/Fas) -mediated apoptosis were cross-resistant to apoptosis-induced by anticancer drugs. Apoptosis induced in tumor cells by cytarabine, doxorubicin, and methotrexate required the activation of ICE/Ced-3 proteases (caspases), similarly to the CD95 system. After drug treatment, a strong increase of caspase activity was found that preceded cell death. Drug-induced activation of caspases was also found in ex vivo-derived T-cell leukemia cells. Resistance to cell death was conferred by a peptide caspase inhibitor and CrmA, a poxvirus-derived serpin. The peptide inhibitor was effective even if added several hours after drug treatment, indicating a direct involvement of caspases in the execution and not in the trigger phase of drug action. Drug-induced apoptosis was also strongly inhibited by antisense approaches targeting caspase-1 and -3, indicating that several members of this protease family were involved. CD95-resistant cell lines that failed to activate caspases upon CD95 triggering were cross-resistant to drug-mediated apoptosis. Our data strongly support the concept that sensitivity for drug-induced cell death depends on intact apoptosis pathways leading to activation of caspases. The identification of defects in caspase activation may provide molecular targets to overcome drug resistance in tumor cells.

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