Treatment of Pancreatic Cancer Cells with Dicumarol Induces Cytotoxicity and Oxidative Stress

Lewis, Anne Marie; Ough, Matthew; Li, Ling; Hinkhouse, Marilyn M.; Ritchie, Justine M.; Spitz, Douglas R.; Cullen, Joseph J.

doi:10.1158/1078-0432.ccr-03-0667

Cited by 65 publications

(69 citation statements)

References 35 publications

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“…Dicoumarol has been reported to have various functions through inhibition of NQO1, including accumulation Dicoumarol-mediated enhancement of CDDP cytotxicity J Watanabe et al of intracellular reactive oxygen species (ROS) (Lewis et al, 2004) or abrogation of p53 protein (Asher et al, 2001;Anwar et al, 2003). Ubiquitous expression of NQO1 was confirmed in the examined cell lines, and these cells also presented the almost similar sensitivity to dicoumarol.…”

Section: Discussionmentioning

confidence: 68%

“…As for its role in cancer, NQO1 is thought to protect cancer cells because it acts as a detoxification enzyme that removes free radicals and makes cells resistant to anticancer agents that induce oxidative injury (Danson et al, 2004). 3-3 0 -Methylene-bis [4-hydroxycoumarin] (dicoumarol) was characterized as an enzymatic inhibitor of NQO1 and was shown to inhibit proliferation of pancreatic cancer cells through an accumulation of oxidative stress (Madari et al, 2003;Lewis et al, 2004). In addition, dicoumarol induced p53 degradation through NQO1 inhibition and modulated p53-mediated apoptosis in g-irradiated normal thymocyte (Asher et al, 2001;Anwar et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

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Dicoumarol potentiates cisplatin-induced apoptosis mediated by c-Jun N-terminal kinase in p53 wild-type urogenital cancer cell lines

et al. 2006

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3-3 0 -Methylene-bis [4-hydroxycoumarin] (dicoumarol), an inhibitor of NADPH:quinone oxidoreductase 1, has been reported to possess potential antineoplastic effects and the ability to abrogate p53 protein. In the present study, we investigated the cytotoxic effects of dicoumarol in combination with cisplatin (CDDP), using four bladder (RT112, 253J, J82 and UMUC3) and two prostate (LNCap and PC3) cancer cell lines. Single treatment with 100 lM dicoumarol suppressed cell proliferation but did not induce apoptosis at 24 h in all cell lines examined. On the other hand, pretreatment with dicoumarol enhanced cytotoxicity of CDDP in three cell lines with wild type of p53 (RT112, 253J and LNCap), but not in three other cell lines with mutant p53 or in RT112 stable transfectants with a dominant-negative mutant of p53. In RT112 and LNCap, CDDP induced p53 and p21 expression, while pretreatment of dicoumarol suppressed induction of p53/p21 and resulted in sequential activation of c-Jun N-terminal kinase (JNK) in a time-dependent manner. Furthermore, inhibition of JNK, using SP600125, completely suppressed activity of caspases and poly-(ADPribose) polymerase cleavage, leading to suppression of enhancement of CDDP-mediated apoptosis by dicoumarol. These results suggested that dicoumarol could enhance cytotoxicity of CDDP in urogenital cancer cells with wild-type p53 through the p53/p21/JNK pathways.

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Section: Discussionmentioning

confidence: 68%

Section: Introductionmentioning

confidence: 99%

Dicoumarol potentiates cisplatin-induced apoptosis mediated by c-Jun N-terminal kinase in p53 wild-type urogenital cancer cell lines

et al. 2006

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“…Vaquero et al [51] reported that ROS produced by Nox4 are prosurvival and antiapoptotic for human pancreatic adenocarcinoma cell lines, MIA PaCa-2 and PANC-1. In the MIA PaCa-2 cell line, Lewis et al [52] showed that inhibition of NQO1 by dicoumarol suppresses the malignant phenotype of pancreatic cancer cells and induces cell apoptosis. Finally, our study described 4 quinones derivatives especially AA-861 and tBuBHQ capable of enhancing Nox4 ROS production.…”

Section: Discussionmentioning

confidence: 99%

Quinone compounds regulate the level of ROS production by the NADPH oxidase Nox4

Nguyen

Lardy

Rousset

et al. 2013

Biochemical Pharmacology

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NADPH oxidase Nox4 is expressed in a wide range of tissues and plays a role in cellular signaling by providing reactive oxygen species (ROS) as intracellular messengers. Nox4 oxidase activity is thought to be constitutive and regulated at the transcriptional level; however, we challenge this point of view and suggest that specific quinone derivatives could modulate this activity. In fact, we demonstrated a significant stimulation of Nox4 activity by 4 quinone derivatives (AA-861, tBuBHQ, tBuBQ, and duroquinone) observed in 3 different cellular models, HEK293E, T-REx™, and chondrocyte cell lines. Our results indicate that the effect is specific toward Nox4 versus Nox2. Furthermore, we showed that NAD(P)H:quinone oxidoreductase (NQO1) may participate in this stimulation. Interestingly, Nox4 activity is also stimulated by reducing agents that possibly act by reducing the disulfide bridge (Cys226, Cys270) located in the extracellular E-loop of Nox4. Such model of Nox4 activity regulation could provide new insight into the understanding of the molecular mechanism of the electron transfer through the enzyme, i.e., its potential redox regulation, and could also define new therapeutic targets in diseases in which quinones and Nox4 are implicated

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“…Lewis et al reported that cell viability decreases to 60% when incubated with 100M dicoumarol for 48 hours. 39 These results suggest that NQO1 contributes minimally to the reduction of vitamin K to KH 2 in the vitamin K cycle. Therefore, another, still-unidentified dicoumarol/warfarininsensitive enzyme must be the major antidotal enzyme that reduces vitamin K in HEK293 cells.…”

mentioning

confidence: 82%

Functional study of the vitamin K cycle in mammalian cells

Tie

Jin

Straight

et al. 2011

Blood

152

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We describe a cell-based assay for studying vitamin K-cycle enzymes. A reporter protein consisting of the gla domain of factor IX (amino acids 1-46) and residues 47-420 of protein C was stably expressed in HEK293 and AV12 cells. Both cell lines secrete carboxylated reporter when fed vitamin K or vitamin K epoxide (KO). However, neither cell line carboxylated the reporter when fed KO in the presence of warfarin. In the presence of warfarin, vitamin K rescued carboxylation in HEK293 cells but not in AV12 cells. Dicoumarol, an NAD(P)H-dependent quinone oxidoreductase 1 (NQO1) inhibitor, behaved similarly to warfarin in both cell lines. Warfarin-resistant vitamin K epoxide reductase (VKOR-Y139F) supported carboxylation in HEK293 cells when fed KO in the presence of warfarin, but it did not in AV12 cells. These results suggest the following: (1) our cell system is a good model for studying the vitamin K cycle, (2) the warfarin-resistant enzyme reducing vitamin K to hydroquinone (KH 2 ) is probably not NQO1, (3) there appears to be a warfarin-sensitive enzyme other than VKOR that reduces vitamin K to KH 2 , and (4) the primary function of VKOR is the reduction of KO to vitamin K. (Blood. 2011;117(10):2967-2974) IntroductionVitamin K hydroquinone (KH 2 ) is a cofactor for ␥-glutamyl carboxylase (GGCX), which catalyzes the posttranslational carboxylation of specific glutamic acid residues to ␥-carboxyglutamic acid (gla) in a variety of vitamin K-dependent proteins. 1 ␥-Glutamyl carboxylation is essential for the biologic functions of vitamin K-dependent proteins involved in blood coagulation, bone metabolism, signal transduction, and cell proliferation. Concomitant with ␥-glutamyl carboxylation, KH 2 is oxidized to vitamin K 2,3-epoxide (KO). KO must then be converted back to vitamin K (the quinone form) and then to KH 2 by separate 2 electron reductions to support the carboxylation reaction. The cyclic production of KO and the conversion back to KH 2 constitutes the vitamin K cycle (Figure 1). The only enzymes unequivocally identified as part of the cycle are GGCX and vitamin K epoxide reductase (VKOR). 2 Sherman et al first proposed that the reduction of KO to vitamin K is carried out by a sulfhydryl-dependent epoxide reductase that is sensitive to warfarin inhibition. 3 This enzyme is probably VKOR, the only enzyme thus far shown to reduce KO to vitamin K. On the other hand, some reports suggest that the reduction of vitamin K to KH 2 can be accomplished by at least 2 microsomal enzymes called vitamin K reductases. 4 However, other studies 5,6 suggest that one enzyme serves as both the epoxide reductase and the vitamin K reductase, catalyzing both the reduction of KO to vitamin K and that of vitamin K to KH 2 .Wallin proposed that there are 2 enzymes that reduce vitamin K in support of vitamin K-dependent carboxylation. 7 One enzyme is inhibited by anticoagulant drugs such as warfarin, 8 while the other is an NADH-dependent reductase that is resistant to inhibition by warfarin. 4,[9][10][11] Consistent with the latte...

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Treatment of Pancreatic Cancer Cells with Dicumarol Induces Cytotoxicity and Oxidative Stress

Abstract: Conclusions: Inhibition of NQO 1 with dicumarol induces cell killing and oxidative stress in pancreatic cancer cells and speculate that dicumarol may prove to be useful in pancreatic cancer therapeutics.

Cited by 65 publications

References 35 publications

Dicoumarol potentiates cisplatin-induced apoptosis mediated by c-Jun N-terminal kinase in p53 wild-type urogenital cancer cell lines

Dicoumarol potentiates cisplatin-induced apoptosis mediated by c-Jun N-terminal kinase in p53 wild-type urogenital cancer cell lines

Quinone compounds regulate the level of ROS production by the NADPH oxidase Nox4

Functional study of the vitamin K cycle in mammalian cells

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