Augmented antitumor effects of combination therapy of cisplatin with ethaselen as a novel thioredoxin reductase inhibitor on human A549 cell in vivo

Tan, Qiang; Li, Jing; Yin, Hong; Wang, Lihui; Tang, Wan-chen; Zhao, Fang; Liu, Xinmin; Zeng, Hu

doi:10.1007/s10637-009-9235-7

Cited by 41 publications

(33 citation statements)

References 41 publications

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“…Our lab has previously reported the significant growth inhibition, apoptosis induction and cell cycle retarding effect of BBSKE against A549, MCF-7, PANC-1, and RKO cells in vitro (Shi et al, 2003;Zhao et al, 2006). BBSKE treatment in combination with cisplatin, fluorouracil or radiation therapy showed synergistic effect and attenuated toxicity in LoVo, BGC-823, and A549 cells (Li et al, 2008;Tan et al, 2010;Fu et al, 2011;Wang et al, 2011).…”

Section: Introductionmentioning

confidence: 87%

Synergistic Effect of Ethaselen and Selenite Treatment against A549 Human Non-small Cell Lung Cancer Cells

Xu¹,

Ma²

2014

Asian Pacific Journal of Cancer Prevention

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Background: In this study, we aimed to evaluate the growth inhibitory effect of the combination of ethaselen (BBSKE) and low fixed dose of selenite against A549 human non-small cell lung cancer cells in vitro. Materials and Methods: Growth inhibitory effects against A549 cells were determined by SRB assay. Combination index (CI) values were calculated based on Chou-Talalay median-effect analyses. Dose reduction index (DRI) values were applied to calculate dose reduction of selenite. Contents of free thiols and GSH were determined by DTNB assay and intracellular ROS levels by DCFH-DA fluorescence labeling. Results: Compared with BBSKE or selenite single treatment, the combined application of ethaselen and a low fixed dose of selenite shortened the onset time of sodium selenite, reduced IC 50 values, and increased the maximum inhibition rates, suggesting a possible molecular mechanism of the synergism. Obvious synergistic effects were observed after different times of combination treatment, especially after 24 h. Compared with selenite single treatment, dosage of selenite could be remarkably reduced in combination therapy to gain the same inhibitory effect on cell proliferation. Compared with BBSKE single treatment, the content of free thiols and GSH were significantly reduced and ROS levels greatly elevated in the combination group. For the combination treatment, cell viability increased as greater concentrations of GSH were added. Conclusions: All these results indicate that the combination treatment of BBSKE and selenite showed synergism to inhibit A549 cell proliferation in vitro, and also reduced the selenite dosage to mitigate its toxicity which is very meaningful for combination chemotherapy of lung cancer. The synergism was probably caused by the accelerated exhaustion of intracellular reductive substances, such as free thiols and GSH, which ultimately leads to enhanced oxidative stress and apoptosis.

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Section: Introductionmentioning

confidence: 87%

Synergistic Effect of Ethaselen and Selenite Treatment against A549 Human Non-small Cell Lung Cancer Cells

Xu¹,

Ma²

2014

Asian Pacific Journal of Cancer Prevention

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“…Moreover, a synergistic effect has been observed in the study of the combination of Ethaselen and cisplatin (CDDP) in vivo. Studies have shown that the antitumor efficacy of cisplatin on the stomach cancer cell line BGC-823, the human lung cancer cell line PG-BE1, the subcutaneous transplanted lung cancer cell line A459 in the nude mice, and the human colon adenocarcinoma cell line LoVo would be further enhanced through synergetic combination with Ethaselen (Tan et al, 2010). These previous studies have indicated that there is a close link of the antitumor mechanism between Ethaselen and CDDP, suggesting that Ethaselen may be a potential and efficient method for reversing cisplatin resistance.…”

Section: Introductionmentioning

confidence: 99%

Ethaselen: a novel organoselenium anticancer agent targeting thioredoxin reductase 1 reverses cisplatin resistance in drug-resistant K562 cells by inducing apoptosis

Yang²,

Wu³

et al. 2017

J. Zhejiang Univ. Sci. B

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It has been reported that Ethaselen shows inhibitory effects on thioredoxin reductase (TrxR) activity and human tumor cell growth. In order to find an efficient way to reverse cisplatin resistance, we investigated the reversal effects of Ethaselen on cisplatin resistance in K562/cisplatin (CDDP) cells that were established by pulse-inducing human erythrocyte leukemic cell line K562, which are fivefold more resistant to cisplatin compared to K562 cells. The morphology and growth showed that the adhesion of K562/CDDP further decreased while the cell volume increased. The proliferation of K562/CDDP is strengthened. The antitumor activities in vitro were assessed by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and combination index (CI), showing the significant synergic effects of cisplatin and Ethaselen. Focusing on apoptosis, a series of comparisons was made between K562 and K562/CDDP. Cisplatin induced higher reactive oxygen species (ROS) generation in K562 and subsequently induced the formation of mitochondrial permeability transition pores (PTPs). In addition, cisplatin increased the ratio of Bax to Bcl-2 in K562, which can influence the mitochondrial membrane permeability. PTP formation and mitochondrial membrane permeabilization eventually resulted in the release of cytochrome c and activation of the Caspase pathway. However, these effects were not clearly seen in K562/CDDP, which may be the reason for the acquired CDDP resistance. However, Ethaselen can induce a high level of ROS in K562/CDDP by TrxR activity inhibition and increased ratio of Bax to Bcl-2 in K562/CDDP by nuclear factor κB (NF-κB) suppression, which subsequently induces the release of cytochrome c in K562/CDDP. This response is partly responsible for the reversal of the cisplatin resistance in K562/CDDP cells.

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“…In light of above reports, using ebselen as a lead compound, ethaselen [1,2-(bis-1,2-benzisoselenazol-3(2H)-one)ethane, Fig. 1], as a typical thioredoxin reductase (TrxR) inhibitor, has been synthesized and found to exhibit broad spectrum of antitumor effects with slight toxicity (He et al, 2012;Tan et al, 2010;Xing et al, 2008;Zhao et al, 2006). Currently, a Phase I clinical trail of ethaselen for antitumor activity is being carried out in China (He et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and in vitro antiproliferative activity of novel benzisoselenazolone derivatives

et al. 2014

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A series of novel benzisoselenazolone derivatives bearing 1,3,4-thiadiazole moiety were designed, synthesized and evaluated for their in vitro antiproliferative activities against human cancer cell lines SMMC-7721, MCF-7, A549, and normal cell lines L929 by CCK-8 assay.The bioassay results demonstrated that most of the tested compounds showed potent antitumor activities, and some compounds exhibited better effects than positive control ebselen and ethaselen against various cancer cell lines. Among these compounds, compound 7l showed significant antiproliferative activity against SMMC-7721 cells, with IC 50 values of 2.18 lM. Compound 7j exhibited the best inhibitory effect against MCF-7 cells, with IC 50 values of 2.89 lM. Compounds 7e and 7i displayed highly effective antitumor activities against A549 cells, with IC 50 values of 2.33 and 2.33 lM, respectively. Furthermore, most of the tested compounds showed weak cytotoxic effect against the normal cell lines L929. The pharmacological results suggest that the substituents of benzoylmethylthio-moiety at position-2 on 1,3,4-thiadiazole are vital for modulating antiproliferative activities against various tumor cell lines.

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Augmented antitumor effects of combination therapy of cisplatin with ethaselen as a novel thioredoxin reductase inhibitor on human A549 cell in vivo

Cited by 41 publications

References 41 publications

Synergistic Effect of Ethaselen and Selenite Treatment against A549 Human Non-small Cell Lung Cancer Cells

Synergistic Effect of Ethaselen and Selenite Treatment against A549 Human Non-small Cell Lung Cancer Cells

Ethaselen: a novel organoselenium anticancer agent targeting thioredoxin reductase 1 reverses cisplatin resistance in drug-resistant K562 cells by inducing apoptosis

Synthesis and in vitro antiproliferative activity of novel benzisoselenazolone derivatives

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