Sulfur amino acid metabolism in doxorubicin-resistant breast cancer cells

Ryu, Chang Seon; Kwak, Hui Chan; Lee, Kye Sook; Kang, Keon Wook; Oh, Soo Jin; Lee, Kiho; Kim, Hwan Mook; Yeul, Jin; Kim, Sang Kyum

doi:10.1016/j.taap.2011.06.004

Cited by 24 publications

(14 citation statements)

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“…The significant elevation in Tau concentration was observed in the urine of bladder cancer patients (24). Currently, it is thought that the anti-cancer effect of Tau is mainly through four molecular mechanisms: First, Tau has an efficacy-enhancing and toxicity-reducing effect on chemotherapy drugs (25)(26)(27)(28). Second, Tau inhibits cancer growth by improving the antioxidant capacity in vivo (29).…”

Section: Discussionmentioning

confidence: 99%

Taurine induces the apoptosis of breast cancer cells by regulating apoptosis-related proteins of mitochondria

Zhang

Lü

Wang

et al. 2014

International Journal of Molecular Medicine

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Abstract. Taurine (Tau), the most abundant free amino acid in humans has numerous potential health benefits through its antioxidant and anti-inflammatory properties. However, limited studies have assessed its effect on tumors and the antitumor mechanism remains unknown. The present study investigated the cellular and molecular changes induced by Tau, leading to the induction of apoptosis in human breast cancer cell lines MCF-7 and MDA-MB-231. MCF-7 is p53 proficient (p53 +/+ ) and MDA-MB-231 is a p53 null mutant (p53 -/-). Cell proliferation and viability were assessed by MTT. Flow cytometry and hoechst33342 fluorescent staining were employed to detect apoptosis. Spectrophotometry was used to detect caspase-3 activity. Reverse transcription-polymerase chain reaction and western blot analysis were used to detect the levels of mRNA and proteins of p53-upregulated modulator of apoptosis (PUMA), Bax and Bcl-2. Finally, the affect of Tau on the growth of MDA-MB-231-cell-nude mice xenografts was examined. In the study, Tau inhibited growth and induced apoptosis of the two cell lines in a concentration-and time-dependent manner. Notably, the inhibitory effect of Tau on p53 -/-cancer cells was clearly significant compared to the p53 +/+ cancer cells. Further studies showed that Tau promoted apoptosis in human breast cancer cells and inhibited the growth of tumor in nude mice by inducing the expression of PUMA, which further up-and downregulated the expression of Bax and Bcl-2 protein, giving rise to increased activation of caspase-3. Collectively, these results indicate that Tau is a potent candidate for the chemotherapy of breast cancer through increasing the PUMA expression independent of p53 status. IntroductionIn recent years, cancer has become the leading cause of mortality, and it is detrimental to health and quality of life. Environmental chemical carcinogens have been estimated to contribute significantly to the causation of a sizable fraction, perhaps a majority, of human cancers, when exposures are correlated to 'life-style' factors, such as diet (1). Therefore, the anticancer substances in the diet have become of current interest in research for cancer prevention.Tau, chemically identified as 2-aminoethanesulfonic acid, is a sulfur-containing amino acid of a simple chemical structure. Tau accounts for ~0.1% of total human body weight and exists in a free-state in all the organs. However, the ability of endogenous Tau synthesis is limited. A large number of studies and clinical applications demonstrated that Tau has extensive physiological effects, and has been identified to be the endogenous anti-injury material. Recently, Tau has been used to in the therapy of diseases, including liver and gallbladder disease (2), cardiovascular disease (3), diabetes (4,5) and cataract (6,7). However, studies on its effect on tumors remains limited and the mechanism of its antitumor ability is ambiguous. Tau has been reported to protect cells from oxidant-induced injury by scavenging strong oxidant and cytotoxic agents (8). ...

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Section: Discussionmentioning

confidence: 99%

Taurine induces the apoptosis of breast cancer cells by regulating apoptosis-related proteins of mitochondria

Zhang

Lü

Wang

et al. 2014

International Journal of Molecular Medicine

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“…The drug resistance literature in the field of cancer biology has also begun to appreciate metabolic methods of drug resistance. Changes in central carbon metabolism [39], including the Warburg effect [40], and in amino acids involved in oxidative stress responses [41,42] have been demonstrated to confer drug resistance in tumor cells. Combining proteomic and metabolomic approaches will be essential to understanding the metabolomic basis of malaria drug resistance.…”

Section: Discussionmentioning

confidence: 99%

A genomic and evolutionary approach reveals non-genetic drug resistance in malaria

et al. 2014

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Background: Drug resistance remains a major public health challenge for malaria treatment and eradication. Individual loci associated with drug resistance to many antimalarials have been identified, but their epistasis with other resistance mechanisms has not yet been elucidated. Results: We previously described two mutations in the cytoplasmic prolyl-tRNA synthetase (cPRS) gene that confer resistance to halofuginone. We describe here the evolutionary trajectory of halofuginone resistance of two independent drug resistance selections in Plasmodium falciparum. Using this novel methodology, we discover an unexpected non-genetic drug resistance mechanism that P. falciparum utilizes before genetic modification of the cPRS. P. falciparum first upregulates its proline amino acid homeostasis in response to halofuginone pressure. We show that this non-genetic adaptation to halofuginone is not likely mediated by differential RNA expression and precedes mutation or amplification of the cPRS gene. By tracking the evolution of the two drug resistance selections with whole genome sequencing, we further demonstrate that the cPRS locus accounts for the majority of genetic adaptation to halofuginone in P. falciparum. We further validate that copy-number variations at the cPRS locus also contribute to halofuginone resistance. Conclusions: We provide a three-step model for multi-locus evolution of halofuginone drug resistance in P. falciparum. Informed by genomic approaches, our results provide the first comprehensive view of the evolutionary trajectory malaria parasites take to achieve drug resistance. Our understanding of the multiple genetic and non-genetic mechanisms of drug resistance informs how we will design and pair future anti-malarials for clinical use.

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“…Although resistance-related genes and proteins were examined, and previous studies on MCF-7Adr and MCF-7S cells suggested that elevated glycolysis, lactate and ATP production, and sulfur-containing amino acids were involved in MCF-7Adr chemoresistance (Broxterman et al 1989; Lyon et al 1988; Ryu et al 2011), little is known about the metabolic patterns and shifts between the sensitive and resistant breast cancer cells (Budczies et al 2012; Denkert et al 2012), especially after exposure to chemotherapeutic drugs such as adriamycin. Tumor cells are characterized by reprogrammed metabolic pathways including enhanced anaerobic glycolysis and reduced tricarboxylic acid cycle activity, i.e., the Warburg effect, alternative utilization of glutamine as an energy supply, and they display a role for glycine in rapid cancer cell proliferation (DeBerardinis et al 2008; Jain et al 2012; Tomita and Kami 2012).…”

Section: Introductionmentioning

confidence: 99%

Metabolomic approach to evaluating adriamycin pharmacodynamics and resistance in breast cancer cells

Cao

Zha

et al. 2013

Metabolomics

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Continuous exposure of breast cancer cells to adriamycin induces high expression of P-gp and multiple drug resistance. However, the biochemical process and the underlying mechanisms for the gradually induced resistance are not clear. To explore the underlying mechanism and evaluate the anti-tumor effect and resistance of adriamycin, the drug-sensitive MCF-7S and the drug-resistant MCF-7Adr breast cancer cells were used and treated with adriamycin, and the intracellular metabolites were profiled using gas chromatography mass spectrometry. Principal components analysis of the data revealed that the two cell lines showed distinctly different metabolic responses to adriamycin. Adriamycin exposure significantly altered metabolic pattern of MCF-7S cells, which gradually became similar to the pattern of MCF-7Adr, indicating that metabolic shifts were involved in adriamycin resistance. Many intracellular metabolites involved in various metabolic pathways were significantly modulated by adriamycin treatment in the drug-sensitive MCF-7S cells, but were much less affected in the drug-resistant MCF-7Adr cells. Adriamycin treatment markedly depressed the biosynthesis of proteins, purines, pyrimidines and glutathione, and glycolysis, while it enhanced glycerol metabolism of MCF-7S cells. The elevated glycerol metabolism and down-regulated glutathione biosynthesis suggested an increased reactive oxygen species (ROS) generation and a weakened ability to balance ROS, respectively. Further studies revealed that adriamycin increased ROS and up-regulated P-gp in MCF-7S cells, which could be reversed by N-acetylcysteine treatment. It is suggested that adriamycin resistance is involved in slowed metabolism and aggravated oxidative stress. Assessment of cellular metabolomics and metabolic markers may be used to evaluate anti-tumor effects and to screen for candidate anti-tumor agents.Electronic supplementary materialThe online version of this article (doi:10.1007/s11306-013-0517-x) contains supplementary material, which is available to authorized users.

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Sulfur amino acid metabolism in doxorubicin-resistant breast cancer cells

Cited by 24 publications

References 38 publications

Taurine induces the apoptosis of breast cancer cells by regulating apoptosis-related proteins of mitochondria

Taurine induces the apoptosis of breast cancer cells by regulating apoptosis-related proteins of mitochondria

A genomic and evolutionary approach reveals non-genetic drug resistance in malaria

Metabolomic approach to evaluating adriamycin pharmacodynamics and resistance in breast cancer cells

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