Doxorubicin-induced apoptosis in caspase-8-deficient neuroblastoma cells is mediated through direct action on mitochondria

Rebbaa, Abdelhadi; Chou, Pauline M.; Emran, Mohammad A.; Mirkin, Bernard L.

doi:10.1007/s002800100375

Cited by 35 publications

(24 citation statements)

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“…Its main activity is related to the inhibition of topoisomerase II, free radical formation and oxidative DNA damage (2,3). It is believed that DOX induces apoptosis through cytochrome c release and activation of caspase-3 (4,5). However, in our previous study we observed the occurrence of cells not only with apoptotic features, but those characteristic of mitotic catastrophe (6).…”

Section: Introductionmentioning

confidence: 77%

Actin reorganization in CHO AA8 cells undergoing mitotic catastrophe and apoptosis induced by doxorubicin

Grzanka¹

2010

Oncol Rep

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Abstract. Doxorubicin (DOX) is a drug widely used in cancer chemotherapy. Although it has been proven that DOX kills tumor cells, the triggered modes of cell death are not fully understood. There is some evidence that, depending on the dose of DOX, the treated cells undergo senescence, mitotic catastrophe, apoptosis or necrosis. The aim of this study was to assess the type of CHO AA8 cell death induced with different DOX doses. In this context, we also assessed organization and distribution of F-actin, which integrity was suggested to be indispensable for apoptosis. Following treatment with 0.5 and 1 μM DOX, the giant multinucleated cells with extended network of fine microfilaments appeared. Notably, in the nuclei of the enlarged cells microscopy and cytometric analysis showed the presence of F-actin. DOX (2.5 μM) caused the appearance of the giant cells and with apoptotic features and signs of autophagy vacuolization. Flow cytometric studies indicated a dose-dependent increase in the number of TUNELpositive cells and cells stained with both Annexin V and PI. Cell cycle analysis revealed the increase in the hyperploid DNA content. Our results suggest that treatment of CHO AA8 cells with different DOX doses caused mitotic catastrophe that was followed by apoptosis with signs of autophagy. The increase in F-actin content in the nuclei of the dying cells was evident. We hypothesize that in CHO AA8 cells F-actin may be involved in chromatin reorganization undergoing cell death.

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Section: Introductionmentioning

confidence: 77%

Actin reorganization in CHO AA8 cells undergoing mitotic catastrophe and apoptosis induced by doxorubicin

Grzanka¹

2010

Oncol Rep

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“…Unfortunately, despite its potent antitumor effects, DOXO is not a safe drug and its use is associated with unwanted side effects, especially a cardiac toxicity which is common to most anthracycline derivatives (Zucchi and Danesi, 2003). DOXO induces mitochondria-dependent apoptosis in heart and cardiomyocytes (Arola et al, 2000;Rebbaa et al, 2001;Green and Leeuwenburgh, 2002) and it is assumed that cardiomyocytes apoptosis is responsible, at least in part, for DOXO-induced cardiotoxicity.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial proliferation during apoptosis induced by anticancer agents: effects of doxorubicin and mitoxantrone on cancer and cardiac cells

et al. 2004

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“…Like LCL-30, doxorubicin is a lipophilic cationic molecule that may compromise mitochondrial integrity (33). There is strong evidence that doxorubicin increases endogenous ceramide levels in cancer cells by either activation of neutral sphingomyelinase and/or induction of the de novo pathway of ceramide metabolism (2, 34 -38).…”

Section: Does the Coadministration Of Doxorubicin Enhance Cell Toxicimentioning

confidence: 99%

Cationic long-chain ceramide LCL-30 induces cell death by mitochondrial targeting in SW403 cells

Dindo

Dahm

Szulc

et al. 2006

Molecular Cancer Therapeutics

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Ceramides are sphingolipid second messengers that are involved in the mediation of cell death. There is accumulating evidence that mitochondria play a central role in ceramide-derived toxicity. We designed a novel cationic long-chain ceramide [W-pyridinium bromide D-erythro -C 16 -ceramide (LCL-30)] targeting negatively charged mitochondria. Our results show that LCL-30 is highly cytotoxic to SW403 cells (and other cancer cell lines) and preferentially accumulates in mitochondria, resulting in a decrease of the mitochondrial membrane potential, release of mitochondrial cytochrome c, and activation of caspase-3 and caspase-9. Ultrastructural analyses support the concept of mitochondrial selectivity. Interestingly, levels of endogenous mitochondrial C 16 -ceramide decreased by more than half, whereas levels of sphingosine-1-phosphate increased dramatically and selectively in mitochondria after administration of LCL-30, suggesting the presence of a mitochondrial sphingosine kinase. Of note, intracellular long-chain ceramide levels and sphingosine-1-phosphate remained unaffected in the cytosolic and extramitochondrial (nuclei/cellular membranes) cellular fractions. Furthermore, a synergistic effect of cotreatment of LCL-30 and doxorubicin was observed, which was not related to alterations in endogenous ceramide levels.Cationic long-chain pyridinium ceramides might be promising new drugs for cancer therapy through their mitochondrial preference. [Mol Cancer Ther 2006;5(6):1520 -9]

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Doxorubicin-induced apoptosis in caspase-8-deficient neuroblastoma cells is mediated through direct action on mitochondria

Cited by 35 publications

References 0 publications

Actin reorganization in CHO AA8 cells undergoing mitotic catastrophe and apoptosis induced by doxorubicin

Actin reorganization in CHO AA8 cells undergoing mitotic catastrophe and apoptosis induced by doxorubicin

Mitochondrial proliferation during apoptosis induced by anticancer agents: effects of doxorubicin and mitoxantrone on cancer and cardiac cells

Cationic long-chain ceramide LCL-30 induces cell death by mitochondrial targeting in SW403 cells

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