Dicoumarol relieves serum withdrawal-induced G0/1 blockade in HL-60 cells through a superoxide-dependent mechanism

Bello, Rosario I.; Gómez-Dı́az, Consuelo; López-Lluch, Guillermo; Forthoffer, Nathalie; Córdoba-Pedregosa, M. C.; Navas, Plácido; Villalba, José M.

doi:10.1016/j.bcp.2005.03.012

Cited by 14 publications

(4 citation statements)

References 35 publications

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“…We think that mechanisms between p21 suppression and the activation of SAPK family should be further elucidated in various cell lines, because p53 mutant cell lines such as RT112 p53DN and J82 did not show p38 activation after doxorubicin or doxorubicin/dicoumarol treatment although they had already lost p21 inducibility. Concerning the anticancer effect of dicoumarol, several reports have referred to its effect to induce oxidative stress [14,15], and intracellular reactive oxygen species status is also important to activate SAPK family [16]. We now speculate that p21 attenuation is one of the mechanisms of dicoumarol to activate SAPK family but other additional effects of dicoumarol are also necessary to activate SAPK family.…”

Section: Discussionmentioning

confidence: 70%

Dicoumarol enhances doxorubicin‐induced cytotoxicity in p53 wild‐type urothelial cancer cells through p38 activation

et al. 2010

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OBJECTIVE To investigate the effectiveness of a combined treatment of 3–30‐methylene‐bis[4‐hydroxycoumarin] (dicoumarol) with doxorubicin for the treatment of urothelial cancer, as doxorubicin is a common chemotherapeutic agent but its therapeutic efficacy is limited. MATERIALS AND METHODS The synergistic effect of dicoumarol with chemotherapeutic agents such as cisplatin, doxorubicin and paclitaxel was evaluated in RT112 urothelial cancer cells. Then, dicoumarol‐mediated enhancement of doxorubicin‐induced cytotoxicity was screened in urothelial cancer cell lines with different p53 statuses or RT112 stable transfectants with a dominant‐negative mutant of p53 (p53DN). To clarify the importance of the modification of p53 function by dicoumarol to enhance doxorubicin toxicity, the change in the p53‐p21 pathway and mitogen‐activated protein kinase (MAPK)‐mitochondria pathway by the combined treatment were elucidated by Western blot analysis. Finally, the effect of p21 knockdown in the susceptibility to doxorubicin was examined with RT112 stable transfectants with short hairpin RNA (shRNA) of p21. RESULTS Dicoumarol significantly increased the susceptibility of RT112 cells to cisplatin and doxorubicin, but not to paclitaxel in RT112 cells. Dicoumarol (100 µm) also enhanced the cytotoxicity of doxorubicin in other bladder cancer cell lines with wild‐type p53 (wt‐p53; three times in 253J and 13 times in KK47), but not in those with mutant‐type p53 (TCCsup, J82 and EJ) or in RT112 p53DN. The combined treatment with dicoumarol suppressed p53/p21 induction by doxorubicin and resulted in sequential p38 MAPK activation, myeloid cell leukaemia 1 suppression and caspase cleavage. The synergistic effect of doxorubicin/dicoumarol was suppressed by the p38 MAPK inhibitor SB202190 and, furthermore, p21 knockdown with shRNA transfection made RT112 cells six times more susceptible to doxorubicin with p38 MAPK activation. CONCLUSION These results suggest that concomitant use of dicoumarol could enhance the cytotoxicity of doxorubicin in urothelial cancer cells with wt‐p53 through the p53/p21/p38 MAPK pathways. This combined treatment may provide a new therapeutic option to overcome chemoresistance in bladder cancer.

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Section: Discussionmentioning

confidence: 70%

Dicoumarol enhances doxorubicin‐induced cytotoxicity in p53 wild‐type urothelial cancer cells through p38 activation

et al. 2010

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“…Dicoumarol has been gaining interest in the cancer setting due to its action as an inhibitor of nicotinamide adenine dinucleotide phosphate (NAD(P)):(quinone acceptor) oxidoreductase 1 (NQO1), by competing with NAD(P)H at the pyridine nucleotide binding site [ 91 ]. NQO1 is a cytosolic flavoenzyme that catalyzes the two-electron reduction of several quinone substrates to give their corresponding hydroquinones using both NADH and NADPH as electron donors [ 92 ], therefore avoiding the generation of reactive oxygen species (ROS) by redox cycling and functioning as an effective superoxide scavenger [ 92 ]. The toxicity of dicoumarol against cancer cells seems to be mainly mediated by the mitochondrial production of ROS due to NQO1 inhibition (Table 2 ) [ 93 ].…”

Section: Antitumor Action Of Dicoumarolmentioning

confidence: 99%

Dicoumarol: from chemistry to antitumor benefits

et al. 2022

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Dicoumarol, a coumarin-like compound, is known for its anticoagulant properties associated with the ability to inhibit vitamin K, being prescribed as a drug for several decades. The pharmaceutical value of dicoumarol turned it into a focus of chemists’ attention, aiming its synthesis and of dicoumarol derivatives, bringing to light new methodologies. In recent years, several other bioactive effects have been claimed for dicoumarol and its derivatives, including anti-inflammatory, antimicrobial, antifungal, and anticancer, although the mechanisms of action underlying them are mostly not disclosed and additional research is needed to unravel them. This review presents a state of the art on the chemistry of dicoumarols, and their potential anticancer characteristics, highlighting the mechanisms of action elucidated so far. In parallel, we draw attention to the lack of in vivo studies and clinical trials to assess the safety and efficacy as drugs for later application.

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“…Dicoumarol ligand with sodium adduct exerts cytotoxicity in U2OS human bone osteosarcoma epithelial cells (Rehman et al, 2013). Dicoumarol arrests the cell cycle in G0/1 phase by increasing the cellular superoxide in HL-60 human myeloid leukemia cells (Bello et al, 2005). It induces apoptosis of cancer cells in a concentration-and time-dependent manner, which was mediated by oxidative stress, cytochrome c release followed by activation of caspase-9 and cleavage of caspase-3 (Cullen et al 2003).…”

Section: Anticancer Effectmentioning

confidence: 99%

Biological Evidences of Dicoumarol: A Review

Rashed¹

2021

Pla. Sci.

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Dicoumarol, a natural anticoagulant drug chemically designated as is metabolized from coumarin in the sweet clover (Melilotus alba and Melilotus officinalis) by molds, such as Penicillium nigricans and Penicillium jensi. Coumarin (1,2-benzopyrone), the parent molecule of dicoumarol, is the simplest compound of a large class of naturally occurring phenolic substances made of fused benzene and pyrone rings . In addition, the coumarin anticoagulants, dicoumarol (Dicumarol) and its synthetic derivative warfarin sodium (Coumadin), have been shown to decrease metastases in experimental animals. Warfarin sodium, largely replacing dicoumarol therapeutically as an anticoagulant, has been used for the treatment of a variety of cancers and shown to improve tumor response rates and survival in patients with several types of cancer. However, despite numerous studies, little information has been acquired on the cellular mechanism of action of coumarin compounds in the treatment of malignancies. Possibly for this reason, the coumarin compounds have not received much attention for the treatment of cancer.

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Dicoumarol relieves serum withdrawal-induced G0/1 blockade in HL-60 cells through a superoxide-dependent mechanism

Cited by 14 publications

References 35 publications

Dicoumarol enhances doxorubicin‐induced cytotoxicity in p53 wild‐type urothelial cancer cells through p38 activation

Dicoumarol enhances doxorubicin‐induced cytotoxicity in p53 wild‐type urothelial cancer cells through p38 activation

Dicoumarol: from chemistry to antitumor benefits

Biological Evidences of Dicoumarol: A Review

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