Sorafenib induces preferential apoptotic killing of a drug- and radio-resistant hep G2 cells through a mitochondria-dependent oxidative stress mechanism

Chiou, Jeng Fong; Tai, Ching Tai; Wang, Yu Huei; Liu, Tsan Zon; Jen, Yee‐Min; Shiau, Chia Yang

doi:10.4161/cbt.8.20.9436

Cited by 65 publications

(62 citation statements)

References 59 publications

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“…Sorafenib-induced apoptosis of nucleated cells was previously shown to be modulated by oxidative stress [45,46]. The present observations reveal that exposure of erythrocytes to sorafenib indeed enhances oxidative stress and that the antioxidant N-acetyl-L-cysteine signi�icantly blunts eryptosis induced by sorafenib.…”

Section: Discussionsupporting

confidence: 54%

Enhanced Erythrocyte Membrane Exposure of Phosphatidylserine Following Sorafenib Treatment: Anin vivoandin vitroStudy

Lupescu

Shaik

Jilani

et al. 2012

Cell Physiol Biochem

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Background: Sorafenib (Nexavar^®), a polytyrosine kinase inhibitor, stimulates apoptosis and is thus widely used for chemotherapy in hepatocellular carcinoma (HCC). Hematological side effects of Nexavar^® chemotherapy include anemia. Erythrocytes may undergo apoptosis-like suicidal death or eryptosis, which is characterized by cell shrinkage and phosphatidylserine-exposure at the cell surface. Signaling leading to eryptosis include increase in cytosolic Ca²⁺activity ([Ca²⁺]_i), formation of ceramide, ATP-depletion and oxidative stress. The present study explored, whether sorafenib triggers eryptosis in vitro and in vivo. Methods: [Ca²⁺]_iwas estimated from Fluo3-fluorescence, cell volume from forward scatter, phosphatidylserine-exposure from annexin-V-binding, hemolysis from hemoglobin release, ceramide with antibody binding-dependent fluorescence, cytosolic ATP with a luciferin–luciferase-based assay, and oxidative stress from 2’,7’ dichlorodihydrofluorescein diacetate (DCFDA) fluorescence. Results: A 48 h exposure of erythrocytes to sorafenib (≥0.5 µM) significantly increased Fluo 3 fluorescence, decreased forward scatter, increased annexin-V-binding and triggered slight hemolysis (≥5 µM), but did not significantly modify ceramide abundance and cytosolic ATP. Sorafenib treatment significantly enhanced DCFDA-fluorescence and the reducing agents N-acetyl-L-cysteine and tiron significantly blunted sorafenib-induced phosphatidylserine exposure. Nexavar^® chemotherapy in HCC patients significantly enhanced the number of phosphatidylserine-exposing erythrocytes. Conclusions: The present observations disclose novel effects of sorafenib, i.e. stimulation of suicidal erythrocyte death or eryptosis, which may contribute to the pathogenesis of anemia in Nexavar^®-based chemotherapy.

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Section: Discussionsupporting

confidence: 54%

Enhanced Erythrocyte Membrane Exposure of Phosphatidylserine Following Sorafenib Treatment: Anin vivoandin vitroStudy

Lupescu

Shaik

Jilani

et al. 2012

Cell Physiol Biochem

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“…It has been reported that sorafenib can rapidly provoke the production of reactive oxygen species (ROS) and induce apoptotic death of cells through a mitochondria-dependent oxidative stress mechanism 22. The significance of this finding was further highlighted by Coriat et al .,23 who found that the effectiveness of sorafenib in HCC cell lines in vitro is mediated by ROS production.…”

Section: Resultsmentioning

confidence: 94%

“…However, the role of additional pathways involved in the cytostatic and cytotoxic effects of sorafenib has obtained much attention in the last years. It has been reported that mitochondrial and endoplasmic reticulum stress induced by sorafenib is relevant for its effect on cell death 22,23,26. The mitochondria-dependent oxidative stress leads to the production of ROS and intracellular glutathione (an antioxidant) depletion.…”

Section: Discussionmentioning

confidence: 99%

Sorafenib synergizes with metformin in NSCLC through AMPK pathway activation

Groenendijk

Mellema

Burg

et al. 2014

Intl Journal of Cancer

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The multikinase inhibitor sorafenib is under clinical investigation for the treatment of many solid tumors, but in most cases, the molecular target responsible for the clinical effect is unknown. Furthermore, enhancing the effectiveness of sorafenib using combination strategies is a major clinical challenge. Here, we identify sorafenib as an activator of AMP-activated protein kinase (AMPK), in a manner that involves either upstream LKB1 or CAMKK2. We further show in a phase II clinical trial in KRAS mutant advanced non-small cell lung cancer (NSCLC) with single agent sorafenib an improved disease control rate in patients using the antidiabetic drug metformin. Consistent with this, sorafenib and metformin act synergistically in inhibiting cellular proliferation in NSCLC in vitro and in vivo. A synergistic effect of both drugs is also seen on phosphorylation of the AMPKα activation site. Our results provide a rationale for the synergistic antiproliferative effects, given that AMPK inhibits downstream mTOR signaling. These data suggest that the combination of sorafenib with AMPK activators could have beneficial effects on tumor regression by AMPK pathway activation. The combination of metformin or other AMPK activators and sorafenib could be tested in prospective clinical trials.

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“…[39][40][41][42][43] Subsequent events include the depletion of glutathione and other antioxidants and the formation of oxidized proteins. 40,41 Pretreatment with the superoxide dismutase mimetic manganese (III) tetrakis (4-benzoic acid)-porphyrin chloride was found to decrease the extent of SRF-induced liver cell lysis. 41 SRF may also elicit direct actions on the mitochondrion, including rapid fragmentation due to deregulation of mitochondrial fusion-related proteins OPA1, Mfn1, and…”

Section: Srf (10 µM 24 H) Strongly Decreased the Proportion Of Hepg2mentioning

confidence: 99%

Cytochrome P450-Mediated Biotransformation of Sorafenib and Its N-Oxide Metabolite: Implications for Cell Viability and Human Toxicity

Gillani

Rawling

Murray

2014

Chem. Res. Toxicol.

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The multikinase inhibitor sorafenib (SRF) is approved for the treatment of renal and hepatic carcinomas and is also undergoing evaluation in therapeutic combinations with other anticancer agents. SRF is generally well tolerated but produces severe toxicities in a significant proportion of patients by mechanisms that are largely unknown. It has been shown that cytochrome P450 (CYP) 3A4 has a major role in SRF biotransformation to the pharmacologically active N-oxide (SRF-Nox) and two other metabolites. In this study, we prepared the major metabolites of SRF and evaluated their further biotransformation by CYPs in relation to their capacity to produce cellular toxicity. CYP3A4 was also found to be the principal enzyme that mediated the secondary oxidation of SRF metabolites. However, the reduction of SRF-Nox to SRF was also found to be a significant reaction mediated by several CYPs, especially CYPs 2B6 and 1A1. In human liver-derived HepG2 cells, SRF effectively decreased ATP production to an extent greater than that of its metabolites. SRF also markedly altered the cell cycle distribution in HepG2 cells by decreasing the proportion in G0/G1 phase and increasing that in S and G2/M phases. In comparison, SRF metabolites minimally affected HepG2 cell cycle progression. These findings suggest that SRF, but not its metabolites, prevents cells from entering the cell cycle and also inhibits cycling cells from completing mitosis. Reduction of the major metabolite SRF-Nox back to SRF may mediate decreased cellular viability and contribute to adverse reactions in some individuals.

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Sorafenib induces preferential apoptotic killing of a drug- and radio-resistant hep G2 cells through a mitochondria-dependent oxidative stress mechanism

Cited by 65 publications

References 59 publications

Enhanced Erythrocyte Membrane Exposure of Phosphatidylserine Following Sorafenib Treatment: Anin vivoandin vitroStudy

Enhanced Erythrocyte Membrane Exposure of Phosphatidylserine Following Sorafenib Treatment: Anin vivoandin vitroStudy

Sorafenib synergizes with metformin in NSCLC through AMPK pathway activation

Cytochrome P450-Mediated Biotransformation of Sorafenib and Its N-Oxide Metabolite: Implications for Cell Viability and Human Toxicity

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