Inhibition Mechanism of the Intracellular Transporter Ca2+-Pump from Sarco-Endoplasmic Reticulum by the Antitumor Agent Dimethyl-Celecoxib

Coca, Ramón; Soler, Fernando; Cortés‐Castell, Ernesto; Gil-Guillén, Vicente Francisco; Fernández-Belda, Francisco

doi:10.1371/journal.pone.0102083

Cited by 6 publications

(9 citation statements)

References 44 publications

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“…The ability of DMC as well as celecoxib to induce ER stress has been associated mainly with its ability to inhibit SERCA, thus leading to an important leakage of calcium from the ER (Johnson et al, 2002;Pyrko et al, 2007;Coca et al, 2014). We also found that upon DMC treatment, the amount of calcium in the ER is strongly decreased, thus suggesting a common mechanism in our model.…”

Section: Dmc Induces Apoptosis and Cell Cycle Alterations In Leukemiasupporting

confidence: 56%

2,5-Dimethyl-Celecoxib Inhibits Cell Cycle Progression and Induces Apoptosis in Human Leukemia Cells

Sobolewski

Rhim

Legrand

et al. 2015

J Pharmacol Exp Ther

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Cyclooxygenase-2 (COX-2) is an essential regulator of cancer promotion and progression. Extensive efforts to target this enzyme have been developed to reduce growth of cancer cells for chemopreventive and therapeutic reasons. In this context, cyclooxygenase-2 inhibitors present interesting antitumor effects. However, inhibition of COX-2 by anti-COX-2 compounds such as celecoxib was recently associated with detrimental cardiovascular side effects limiting their clinical use. As many anticancer effects of celecoxib are COX-2 independent, analogs such as 2,5-dimethyl-celecoxib (DMC), which lacks COX-2-inhibitory activity, represent a promising alternative strategy. In this study, we investigated the effect of this molecule on growth of hematologic cancer cell lines (U937, Jurkat, Hel, Raji, and K562). We found that this molecule is able to reduce the growth and induces apoptosis more efficiently than celecoxib in all the leukemic cell lines tested. Cell death was associated with downregulation of Mcl-1 protein expression. We also found that DMC induces endoplasmic reticulum stress, which is associated with a decreased of GRP78 protein expression and an alteration of cell cycle progression at the G1/S transition in U937 cells. Accordingly, typical downregulation of c-Myc and cyclin D1 and an upregulation of p27 were observed. Interestingly, for shorter time points, an alteration of mitotic progression, associated with the downregulation of survivin protein expression was observed. Altogether, our data provide new evidence about the mode of action of this compound on hematologic malignancies.

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Section: Dmc Induces Apoptosis and Cell Cycle Alterations In Leukemiasupporting

confidence: 56%

2,5-Dimethyl-Celecoxib Inhibits Cell Cycle Progression and Induces Apoptosis in Human Leukemia Cells

Sobolewski

Rhim

Legrand

et al. 2015

J Pharmacol Exp Ther

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“…The model used was previously applied to several inorganic compounds, including vanadate. In fact, several studies were described about the interaction of organic and inorganic compounds and their effects on P-type ATPases [23,[36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51]. Therefore, several experiments with several vanadium compounds [45,47,48] at the same experimental conditions for comparison were performed, and the potencies of inhibition are compared in Table 2.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, the antipsychotic drug thioridazine and other phenothiazine derivatives also inhibit the PMCA activity [38]. In the case of SERCA, thapsigargin (IC 50 = 0.001-0.029 µM), cyclopiazonic acid (IC 50 = 0.1-0.2 µM), macrocyclic lactones (IC 50 = 66-72 µM), curcuminoids (IC 50 = 7-17 µM), and celecoxib (IC 50 = 35 µM) are examples of well-known inhibitors [39][40][41][42][43]. These drugs are used in several disease treatments and are also employed as anaesthetics, tumour inhibitors, antibiotics, and insulin mimetic agents [39][40][41][42][43], providing an inhibitory effect not so different from the gold compounds described in the present study (Table 3).…”

Section: Discussionmentioning

confidence: 99%

“…In the case of SERCA, thapsigargin (IC 50 = 0.001-0.029 µM), cyclopiazonic acid (IC 50 = 0.1-0.2 µM), macrocyclic lactones (IC 50 = 66-72 µM), curcuminoids (IC 50 = 7-17 µM), and celecoxib (IC 50 = 35 µM) are examples of well-known inhibitors [39][40][41][42][43]. These drugs are used in several disease treatments and are also employed as anaesthetics, tumour inhibitors, antibiotics, and insulin mimetic agents [39][40][41][42][43], providing an inhibitory effect not so different from the gold compounds described in the present study (Table 3). Herein, we aimed to compare the inhibitory capacity of the gold complexes 1-4 with oxometalates, metal complexes, and polyoxometalates (POTs and POVs), as well as known organic drugs.…”

Section: Discussionmentioning

confidence: 99%

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Gold Compounds Inhibit the Ca2+-ATPase Activity of Brain PMCA and Human Neuroblastoma SH-SY5Y Cells and Decrease Cell Viability

Berrocal

Cordoba-Granados

Carabineiro

et al. 2021

Metals

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Plasma membrane calcium ATPases (PMCA) are key proteins in the maintenance of calcium (Ca2+) homeostasis. Dysregulation of PMCA function is associated with several human pathologies, including neurodegenerative diseases, and, therefore, these proteins are potential drug targets to counteract those diseases. Gold compounds, namely of Au(I), are well-known for their therapeutic use in rheumatoid arthritis and other diseases for centuries. Herein, we report the ability of dichloro(2-pyridinecarboxylate)gold(III) (1), chlorotrimethylphosphinegold(I) (2), 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidenegold(I) chloride (3), and chlorotriphenylphosphinegold(I) (4) compounds to interfere with the Ca2+-ATPase activity of pig brain purified PMCA and with membranes from SH-SY5Y neuroblastoma cell cultures. The Au(III) compound (1) inhibits PMCA activity with the IC50 value of 4.9 µM, while Au(I) compounds (2, 3, and 4) inhibit the protein activity with IC50 values of 2.8, 21, and 0.9 µM, respectively. Regarding the native substrate MgATP, gold compounds 1 and 4 showed a non-competitive type of inhibition, whereas compounds 2 and 3 showed a mixed type of inhibition. All gold complexes showed cytotoxic effects on human neuroblastoma SH-SY5Y cells, although compounds 1 and 3 were more cytotoxic than compounds 2 and 4. In summary, this work shows that both Au (I and III) compounds are high-affinity inhibitors of the Ca2+-ATPase activity in purified PMCA fractions and in membranes from SH-SY5Y human neuroblastoma cells. Additionally, they exert strong cytotoxic effects.

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“…2,5‐dimethyl‐celecoxib (DMC) is an analogue of celecoxib, but lacks COX‐2‐inhibitory activity. Studies have demonstrated that aggravated endoplasmic reticulum stress (ER stress), anti‐angiogenisis, induction of apoptosis and inhibition of cell cycle progression are independently involved in the antitumor activity of DMC . Notably, DMC caused cell death is found to be associated with down‐regulation of Mcl‐1 protein expression in leukaemic cells , which inspires us that DMC can potentially synergize with ABT‐737 through the regulation of Mcl‐1 level.…”

Section: Introductionmentioning

confidence: 99%

Dimethyl celecoxib sensitizes gastric cancer cells to ABT‐737 via AIF nuclear translocation

Zhang

Yan

et al. 2016

J Cellular Molecular Medi

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Gastric cancer is the fourth most common cancer in the world. The clinical applications of both chemotherapy and targeted drugs are limited because of the complexity of gastric cancer. In this study, sulforhodamine B, colony formation assay, 4',6‐diamidino‐2‐phenylindole (DAPI) stain, flow cytometry were used to determine the in vitro cytotoxicity, apoptosis and mitochondrial membrane potential of gastric cancer AGS and HGC‐27 cells before and after treatment. Real‐time PCR and Western blot were used to analyse the mRNA transcription and protein expression respectively. Confocal microscopy was used to determine the localization of target protein within the cells. Treatment with the combination of ABT‐737 and 2,5‐dimethyl‐celecoxib (DMC) showed strong synergistic effect in both AGS and HGC‐27 cells. Moreover, DMC would not influence the intracellular prostaglandin E2 (PGE2) level, thus lacking the toxicity profile of celecoxib. Interestingly, given the significant synergistic effect, combination treatment did not affect the protein expression of BH‐3 proteins including Puma, Noxa and Bim. In combination treatment, cell apoptosis was found independent of caspase‐3 activation. The translocation of apoptosis‐inducing factor (AIF) from mitochondrion to nuclear was responsible for the induced apoptosis in the combination treatment. Taken together, this study provided a novel combination treatment regimen for gastric cancer. Furthermore, the existence of caspase‐independent apoptotic pathway induced by treatment of ABT‐737 was not yet seen until combined with DMC, which shed light on an alternative mechanism involved in Bcl‐2 inhibitor‐induced apoptosis.

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Inhibition Mechanism of the Intracellular Transporter Ca2+-Pump from Sarco-Endoplasmic Reticulum by the Antitumor Agent Dimethyl-Celecoxib

Cited by 6 publications

References 44 publications

2,5-Dimethyl-Celecoxib Inhibits Cell Cycle Progression and Induces Apoptosis in Human Leukemia Cells

2,5-Dimethyl-Celecoxib Inhibits Cell Cycle Progression and Induces Apoptosis in Human Leukemia Cells

Gold Compounds Inhibit the Ca2+-ATPase Activity of Brain PMCA and Human Neuroblastoma SH-SY5Y Cells and Decrease Cell Viability

Dimethyl celecoxib sensitizes gastric cancer cells to ABT‐737 via AIF nuclear translocation

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