Cytotoxicity and Mitochondrial Apoptosis Induced by Etoposide in Melanoma Cells

Rudolf, Kamil; Červinka, Miroslav; Rudolf, Emil

doi:10.1080/07357900802653480

Cited by 10 publications

(8 citation statements)

References 32 publications

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“…Apoptosome cleaves apical caspase-9, which in turn induces the activation of caspases -3 and -7 to execute the dismantling of the cells (reviewed in [37]) through proteolysis of its target proteins such as poly ADP ribose polymerase (PARP) [38]. In etoposide-treated human melanoma cells, cytochrome c release was observed along with upregulation of caspases -9 and -3 [39]. Because TCTP inhibits cytochrome c release from the mitochondria, effects on caspase activity by TCTP were investigated by specifically detecting the cleaved form of caspases.…”

Section: Resultsmentioning

confidence: 99%

Interaction of translationally controlled tumor protein with Apaf-1 is involved in the development of chemoresistance in HeLa cells

et al. 2014

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BackgroundTranslationally controlled tumor protein (TCTP), alternatively called fortilin, is believed to be involved in the development of the chemoresistance of tumor cells against anticancer drugs such as etoposide, taxol, and oxaliplatin, the underlying mechanisms of which still remain elusive.MethodsCell death analysis of TCTP-overexpressing HeLa cells was performed following etoposide treatment to assess the mitochondria-dependent apoptosis. Apoptotic pathway was analyzed through measuring the cleavage of epidermal growth factor receptor (EGFR) and phospholipase C-γ (PLC-γ), caspase activation, mitochondrial membrane perturbation, and cytochrome c release by flow cytometry and western blotting. To clarify the role of TCTP in the inhibition of apoptosome, in vitro apoptosome reconstitution and immunoprecipitation was used. Pull-down assay and silver staining using the variants of Apaf-1 protein was applied to identify the domain that is responsible for its interaction with TCTP.ResultsIn the present study, we confirmed that adenoviral overexpression of TCTP protects HeLa cells from cell death induced by cytotoxic drugs such as taxol and etoposide. TCTP antagonized the mitochondria-dependent apoptotic pathway following etoposide treatment, including mitochondrial membrane damage and resultant cytochrome c release, activation of caspase-9, and -3, and eventually, the cleavage of EGFR and PLC-γ. More importantly, TCTP interacts with the caspase recruitment domain (CARD) of Apaf-1 and is incorporated into the heptameric Apaf-1 complex, and that C-terminal cleaved TCTP specifically associates with Apaf-1 of apoptosome in apoptosome-forming condition thereby inhibiting the amplification of caspase cascade.ConclusionsTCTP protects the cancer cells from etoposide-induced cell death by inhibiting the mitochondria-mediated apoptotic pathway. Interaction of TCTP with Apaf-1 in apoptosome is involved in the molecular mechanism of TCTP-induced chemoresistance. These findings suggest that TCTP may serve as a therapeutic target for chemoresistance in cancer treatment.

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Section: Resultsmentioning

confidence: 99%

Interaction of translationally controlled tumor protein with Apaf-1 is involved in the development of chemoresistance in HeLa cells

et al. 2014

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“…Caspase-2 is a critical initiator caspase in apoptotic pathways activated by a number of cell stresses, including nutrient depletion, heat shock, DNA damage, and spindle disruption (Robertson et al 2002;Nutt et al 2005;Tu et al 2006;Rudolf et al 2009). In some of these situations, caspase-2 is controlled through posttranslational modification.…”

Section: Caspase-2mentioning

confidence: 99%

Cellular Mechanisms Controlling Caspase Activation and Function

Parrish

Freel

Kornbluth

2013

Cold Spring Harbor Perspectives in Biology

501

367

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Caspases are the primary drivers of apoptotic cell death, cleaving cellular proteins that are critical for dismantling the dying cell. Initially translated as inactive zymogenic precursors, caspases are activated in response to a variety of cell death stimuli. In addition to factors required for their direct activation (e.g., dimerizing adaptor proteins in the case of initiator caspases that lie at the apex of apoptotic signaling cascades), caspases are regulated by a variety of cellular factors in a myriad of physiological and pathological settings. For example, caspases may be modified posttranslationally (e.g., by phosphorylation or ubiquitylation) or through interaction of modulatory factors with either the zymogenic or active form of a caspase, altering its activation and/or activity. These regulatory events may inhibit or enhance enzymatic activity or may affect activity toward particular cellular substrates. Finally, there is emerging literature to suggest that caspases can participate in a variety of cellular processes unrelated to apoptotic cell death. In these settings, it is particularly important that caspases are maintained under stringent control to avoid inadvertent cell death. It is likely that continued examination of these processes will reveal new mechanisms of caspase regulation with implications well beyond control of apoptotic cell death.

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“…Consequently, there is an initial increase in the amount and activity of mitochondria of target cells, but which are subsequently suppressed. These changes were not preceded by loss in membrane potential and the release of cytochrome c. After oral administration, distribution in cerebrospinal fluid is variable and weak; etoposide is mostly distributed in the liver, kidneys, brain, heart and intestines [9].…”

Section: Introductionmentioning

confidence: 97%

“…At low concentrations, this drug inhibits the entry of neoplastic cells in prophase, probably due to its action on topoisomerase II [9]. At high concentrations, the lysis of cells entering mitosis is observed.…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of Tumor Growth in Treatment of Murine Melanoma by Transdermal Infusion of Etoposide by Radiofrequency

A¹,

LG²

2015

J Clin Exp Dermatol Res

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Objective: In order to make such a substance cross the epidermal barrier, was utilized a method of transdermal drug delivery system (TDDS) combined with the chemotherapeutic etoposide in the treatment of dorsal melanoma B16F10 tumor on C57BL/6J mice. Methods:The treatment groups were as follows: etoposide followed by radiofrequency (RF); RF followed by etoposide; etoposide and controls. The animals were treated with delivery interval of 72 hours, for 20 days and were analyzed the tumor growth; weight and hematological profile. The histological analysis and cell cycle by flow cytometry were performed after end of the treatment period. Results:The tumors treated with RF followed by etoposide showed slower growth compared to the tumors treated with etoposide followed by RF, and found that treatment with radiofrequency considerably increased the dorsal tumor growth. In fact, the increase in tumor mass is because the radiofrequency cause an inflammatory response and stimulate collagen production by fibroblasts. Conclusions:The results showed that the treatment groups RF followed by etoposide showed a high rate sub-G1 phase cells, indicating better therapeutic efficacy. Therefore, it is important to clarify that the referred technologies are not as harmless at it has been reported.

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Cytotoxicity and Mitochondrial Apoptosis Induced by Etoposide in Melanoma Cells

Cited by 10 publications

References 32 publications

Interaction of translationally controlled tumor protein with Apaf-1 is involved in the development of chemoresistance in HeLa cells

Interaction of translationally controlled tumor protein with Apaf-1 is involved in the development of chemoresistance in HeLa cells

Cellular Mechanisms Controlling Caspase Activation and Function

Evaluation of Tumor Growth in Treatment of Murine Melanoma by Transdermal Infusion of Etoposide by Radiofrequency

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