The role of reactive oxygen species in cisplatin-induced apoptosis in human malignant testicular germ cell lines

Schweyer, Stefan; Soruri, Afsaneh; Heintze, A.; Radzun, Heinz-Joachim; Fayyazi, Afshin

doi:10.3892/ijo.25.6.1671

Cited by 21 publications

(11 citation statements)

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“…Overexpression or deletion of antioxidant enzymes can alter the sensitivity of cancer cells to various cytotoxic insults, which substantiates the notion that ROS or their reactive derivatives are critical components of signal transduction pathways involved in cell proliferation and apoptosis (35). Although the mechanism of intracellular induction of oxidative stress by EGCG in malignant cells in vivo needs to be elucidated, high antioxidant capacity of the tumor cells can be hypothesized to lead to high resistance to apoptosis induced by EGCG, chemotherapeutic drugs, or radiation, which are known to exert their antitumor effects by inducing the production of ROS (25,36,37).…”

Section: Discussionsupporting

confidence: 57%

“…2, A, B, and D) sustains high concentration of intracellular iron produced by HO-1 catalytic activity that may result in phosphorylation of PKC␣ and subsequent activation of Nrf2 (48,51). In this scenario, we speculated that EGCG, as an iron chelator (26,33) and not as an ROS generator (36,37), may exert its inhibitory effects on phosphorylation of PKC␣ (Fig. 7D) followed by inhibition of Nrf2 signaling (Fig.…”

Section: Discussionmentioning

confidence: 96%

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Constitutive Overexpression of Nrf2-dependent Heme Oxygenase-1 in A549 Cells Contributes to Resistance to Apoptosis Induced by Epigallocatechin 3-Gallate

Kweon

Adhami

Lee

et al. 2006

Journal of Biological Chemistry

230

158

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Epigallocatechin 3-gallate (EGCG), the major polyphenol found in green tea, exerts antiproliferative and proapoptotic effects in many cancer cells. However, we found that among many cancer cells human lung adenocarcinoma A549 cells are markedly resistant to apoptosis induction by EGCG (even at 100 M for 72 h). Heme oxygenase-1 (HO-1) induced by stress stimuli represents a prime cellular defense mechanism, but it may be associated with enhanced cell proliferation and chemoresistance in some cancer cells. Because we found that A549 cells constitutively overexpress HO-1 and its associated transcription factor Nrf2, we tested an hypothesis that EGCG resistance in these cells may be linked with Nrf2-mediated HO-1 overexpression. HO-1 inhibition with tin-protoporphyrin IX and silencing with RNA interference rendered cells more sensitive to apoptosis induction by EGCG and classical prooxidants. Interestingly, EGCG at high concentration (>200 M) induced apoptosis by suppressing expression of HO-1 protein and mRNA, and this effect correlated with a decrease in both Nrf2-ARE binding and HO-1-ARE-luciferase activity, suggesting Nrf2-driven transcriptional activation of ho-1. Because we observed notably high levels of phosphorylated protein kinase C␣ and its suppression by EGCG and deferoxamine (an iron chelator), a possible mechanism involving phosphorylated protein kinase C␣ and iron in Nrf2-HO-1 activation was further investigated. Collectively, our findings suggest that Nrf2-mediated HO-1 overexpression confers resistance to apoptosis induction by EGCG; therefore, its inactivation may be a target for overcoming the resistance to chemoprevention and chemotherapy.Epigallocatechin 3-gallate (EGCG), 2 the major polyphenol found in green tea, is a widely studied cancer chemopreventive agent with potential anticancer activity. The major mechanism of EGCG-mediated anticancer effects is considered to be related to induction of apoptosis (1, 2). Studies have shown differential sensitivity among different tumor cells or tumor cells versus normal cells to EGCG (1, 2). In particular, in many cancer cells EGCG has been shown to modulate multiple and often different signal transduction pathways. The reason for these observed differences is not clear but may be because of the differential oxidative status imposed by EGCG in various cell types or cell type-specific expression of endogenous antioxidant defense enzymes.Heme oxygenase-1 (HO-1) is known to be highly induced by a variety of stress stimuli and many cancer chemopreventive agents, and it represents a prime cellular defense mechanism against oxidative stress via antioxidant function of its catalytic products like bilirubin and carbon monoxide (CO) with concomitant induction of iron sequestering ferritin (3, 54). On the contrary, its overexpression in human cancers may offer cancer cells a growth advantage and cellular resistance against chemotherapy and photodynamic therapy (4, 5). Because the growth of most tumors depends on HO-1 (6), it is also considered as a target for canc...

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Section: Discussionsupporting

confidence: 57%

Section: Discussionmentioning

confidence: 96%

Constitutive Overexpression of Nrf2-dependent Heme Oxygenase-1 in A549 Cells Contributes to Resistance to Apoptosis Induced by Epigallocatechin 3-Gallate

Kweon

Adhami

Lee

et al. 2006

Journal of Biological Chemistry

230

158

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“…Thus, AE could block cisplatin-induced ERK activation at least in part independently of its DNA-repairing action, probably by interfering with some ERK-activating signals that lie downstream of cisplatin-triggered DNA damage. As these signals have been shown to involve generation of reactive oxygen species [38] and activation of Ras [30], the antioxidant and Ras-antagonizing actions previously ascribed to emodin and/or its derivatives [39,40] seem worthy of consideration as possible mechanisms involved in the AE-mediated block of cisplatin-triggered ERK activation. Both emodin and AE have been generally considered as potential anticancer therapeutics due to their ability to induce apoptotic death and/or growth arrest in various tumor cell lines [5][6][7][8][9][10][11][12][13][14][15][16].…”

Section: Discussionmentioning

confidence: 99%

Aloe emodin decreases the ERK-dependent anticancer activity of cisplatin

Mijatović¹,

Maksimović‐Ivanić²,

Radovic³

et al. 2005

CMLS, Cell. Mol. Life Sci.

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The present study describes the ability of an anthraquinone derivative aloe emodin (AE) to reduce the cytotoxic activity of the platinum(II)-based anticancer agent cisplatin toward murine L929 fibrosarcoma and C6 glioma cell lines. The protective effect of AE was demonstrated by MTT and crystal violet assays for cell viability, and involved supression of cisplatin-induced apoptosis and necrosis, as assessed by lactate dehydrogenase release and flow cytometric analysis of DNA fragmentation or phosphatidylserine exposure. Cell-based ELISA and Western blot analysis revealed that AE abolished cisplatin-triggered activation of extracellular signal-regulated kinase (ERK) in tumor cells, while activation of c-Jun N-terminal kinase was not significantly altered. A selective blockade of ERK activation with PD98059 mimicked the protective effect of AE treatment in both tumor cell lines. Moreover, AE failed to protect tumor cells against the ERK-independent toxicity of the Pt(IV)-based complex tetrachloro(O,O-dibutyl-ethylenediamine-N,N'-di-3-propanoate)platinum(IV). Taken together, these data indicate that herbal anthraquinone AE can downregulate the anticancer activity of cisplatin by blocking the activation of ERK in tumor cells.

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“…These comparative results support the utility of a zebraWsh assay for assessing drug-induced ototoxicity. Gentamicin and cisplatin have been shown to cause hair cell loss via oxidative pathways in mammals (Dehne et al, 2001;Rybak and Kelly, 2003;Lautermann et al, 2004;Schweyer et al, 2004); both gentamicin and cisplatin-induced neuromast hair cell loss in zebraWsh, suggesting that zebraWsh may exhibit similar oxidative mechanisms involved in injury to mechanisms in mammals. A study by Hentschel et al (2004) showed that gentamicin, a commonly used nephrotoxic antibiotic, also induced nephrotoxicity and reduced the glomerular Wltration rate in zebraWsh.…”

Section: Drug-induced Ototoxicity In Zebrawshmentioning

confidence: 95%