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      The Effect of Selective Estrogen Receptor Modulators (SERMs) on the Tamoxifen Resistant Breast Cancer Cells

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          Abstract

          Selective estrogen receptor modulators (SERMs) are synthetic molecules which bind to estrogen receptors (ER) and can modulate its transcriptional capabilities in different ways in diverse estrogen target tissues. Tamoxifen, the prototypical SERM, is extensively used for targeted therapy of ER positive breast cancers. Unfortunately, the use of tamoxifen is associated with acquired resistance and some undesirable side effects. This study investigated the availability of the conventional SERMs on the TAM-resistance breast cancer cells. SERMs showed more effectiveness in MCF-7 cells than tamoxifen resistant cells, except toremifene and ospemifene. Especially, toremifene was more efficacious in tamoxifen resistant cells than MCF-7. Ospemifene had similar cytotoxic activity on the two types of breast cancers. The other SERMs used in this experiment didn’t inhibit efficiently the proliferation of tamoxifen resistant cells. These results support the possibility to usage of toremifene on tamoxifen resistant cancer. The effectiveness by toremifene on tamoxifen resistant cells might be different pathways from the apoptosis and the autophagy. Further study should be needed to elucidate the underlying mechanism of effect of toremifene on tamoxifen resistant cancer.

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          Superoxide is the major reactive oxygen species regulating autophagy.

          Y. Chen, M B Azad, S B Gibson (2009)
          Autophagy is involved in human diseases and is regulated by reactive oxygen species (ROS) including superoxide (O(2)(*-)) and hydrogen peroxide (H(2)O(2)). However, the relative functions of O(2)(*-) and H(2)O(2) in regulating autophagy are unknown. In this study, autophagy was induced by starvation, mitochondrial electron transport inhibitors, and exogenous H(2)O(2). We found that O(2)(*-) was selectively induced by starvation of glucose, L-glutamine, pyruvate, and serum (GP) whereas starvation of amino acids and serum (AA) induced O(2)(*-) and H(2)O(2). Both types of starvation induced autophagy and autophagy was inhibited by overexpression of SOD2 (manganese superoxide dismutase, Mn-SOD), which reduced O(2)(*-) levels but increased H(2)O(2) levels. Starvation-induced autophagy was also inhibited by the addition of catalase, which reduced both O(2)(*-) and H(2)O(2) levels. Starvation of GP or AA also induced cell death that was increased following treatment with autophagy inhibitors 3-methyladenine, and wortamannin. Mitochondrial electron transport chain (mETC) inhibitors in combination with the SOD inhibitor 2-methoxyestradiol (2-ME) increased O(2)(*-) levels, lowered H(2)O(2) levels, and increased autophagy. In contrast to starvation, cell death induced by mETC inhibitors was increased by 2-ME. Finally, adding exogenous H(2)O(2) induced autophagy and increased intracellular O(2)(*-) but failed to increase intracellular H(2)O(2). Taken together, these findings indicate that O(2)(*-) is the major ROS-regulating autophagy.
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            Targeting the prodeath and prosurvival functions of autophagy as novel therapeutic strategies in cancer.

            Ibrahim Tekedereli, Bulent Ozpolat, Gabriel Lopez-Berestein … (2010)
            Autophagy is an evolutionarily conserved lysosomal pathway for degrading cytoplasmic proteins, macromolecules, and organelles. While autophagy has become one of the most attractive topics in cancer research, the current autophagy literature is often viewed as confusing, because of its association with apparently contradictory roles, such as survival and cell death. Autophagy can serve as a tumor suppressor, as a partial reduction in autophagic capacity or defective autophagy (e.g., heterozygous knockdown BECN1 (+/-) in mice) provides an oncogenic stimulus, causing malignant transformation and spontaneous tumors. In addition, autophagy seems to function as a protective cell survival mechanism against environmental and cellular stress (e.g., nutrient deprivation, hypoxia and therapeutic stress) and causes resistance to antineoplastic therapies. Recent studies have demonstrated that the inhibition of autophagy in cancer cells may be therapeutically beneficial in some circumstances, as it can sensitize cancer cells to different therapies, including DNA-damaging agents, antihormone therapies (e.g., tamoxifen), and radiation therapy. This supports the hypothesis that inhibiting autophagy can negatively influence cancer cell survival and increase cell death when combined with anticancer agents, providing a therapeutic advantage against cancer. On the other hand, the induction of autophagy by the inhibition of anti-autophagic proteins, such as Bcl-2, PKCdelta, and tissue transglutaminase 2 (TG2), may lead to autophagic cell death in some apoptosis-resistant cancers (i.e., breast and pancreatic cancers), indicating that the induction of autophagy alone may also be used as a potential therapy. Overall, the data suggest that, depending on the cellular features, either the induction or the inhibition of autophagy can provide therapeutic benefits to patients and that the design and synthesis of the first-generation modulators of autophagy may provide the tools for proof of concept experiments and the impetus for translational studies that may ultimately lead to new therapeutic strategies in cancer.
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              Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine.

              Vered Stearns, Michael D L Johnson, James Rae … (2003)
              Tamoxifen, a selective estrogen receptor modulator (SERM), is converted to 4-hydroxy-tamoxifen and other active metabolites by cytochrome P450 (CYP) enzymes. Selective serotonin reuptake inhibitors (SSRIs), which are often prescribed to alleviate tamoxifen-associated hot flashes, can inhibit CYPs. In a prospective clinical trial, we tested the effects of coadministration of tamoxifen and the SSRI paroxetine, an inhibitor of CYP2D6, on tamoxifen metabolism. Tamoxifen and its metabolites were measured in the plasma of 12 women of known CYP2D6 genotype with breast cancer who were taking adjuvant tamoxifen before and after 4 weeks of coadministered paroxetine. We assessed the inhibitory activity of pure tamoxifen metabolites in an estradiol-stimulated MCF7 cell proliferation assay. To determine which CYP isoforms were involved in the metabolism of tamoxifen to specific metabolites, we used CYP isoform-specific inhibitors. All statistical tests were two-sided. We separated, purified, and identified the metabolite 4-hydroxy-N-desmethyl-tamoxifen, which we named endoxifen. Plasma concentrations of endoxifen statistically significantly decreased from a mean of 12.4 ng/mL before paroxetine coadministration to 5.5 ng/mL afterward (difference = 6.9 ng/mL, 95% confidence interval [CI] = 2.7 to 11.2 ng/mL) (P =.004). Endoxifen concentrations decreased by 64% (95% CI = 39% to 89%) in women with a wild-type CYP2D6 genotype but by only 24% (95% CI = 23% to 71%) in women with a variant CYP2D6 genotype (P =.03). Endoxifen and 4-hydroxy-tamoxifen inhibited estradiol-stimulated MCF7 cell proliferation with equal potency. In vitro, troleandomycin, an inhibitor of CYP3A4, inhibited the demethylation of tamoxifen to N-desmethyl-tamoxifen by 78% (95% CI = 65% to 91%), and quinidine, an inhibitor of CYP2D6, reduced the subsequent hydroxylation of N-desmethyl-tamoxifen to endoxifen by 79% (95% CI = 50% to 108%). Endoxifen is an active tamoxifen metabolite that is generated via CYP3A4-mediated N-demethylation and CYP2D6-mediated hydroxylation. Coadministration of paroxetine decreased the plasma concentration of endoxifen. Our data suggest that CYP2D6 genotype and drug interactions should be considered in women treated with tamoxifen.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Toxicol Res
                Journal ID (iso-abbrev): Toxicol Res
                Journal ID (publisher-id): ksot
                Title: Toxicological Research
                Publisher: The Korean Society of Toxicology
                ISSN (Print): 1976-8257
                Publication date (Print): June 2011
                Volume: 27
                Issue: 2
                Pages: 85-93
                Affiliations
                Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan 570-749, Korea
                Author notes
                Correspondence to: Sung Yeon Kim, Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan 570-749, Korea E-mail: sungykim@ 123456wku.ac.kr
                Abbreviations: SERM; selective estrogen receptors, TAM; tamoxifen,TOR; toremifene, OSP; ospemifene, IDO; idoxifene, RAL; raloxifene
                Article
                Publisher ID: toxicr-27-85
                DOI: 10.5487/TR.2011.27.2.085
                PMC ID: 3834369
                PubMed ID: 24278556
                SO-VID: cec7dc36-7f6c-4bf1-8ffb-3fa4e1cd2998
                Copyright © Copyright ©2011, The Korean Society of Toxicology
                History
                Date received : 08 May 2011
                Date revision received : 13 May 2011
                Date accepted : 16 May 2011
                Categories
                Subject: Articles

                Keywords: selective estrogen receptor modulators (serms),tamoxifen resistant breast cancer,toremifene,apoptosis,autophagy
                Data availability:
                Keywords: selective estrogen receptor modulators (serms), tamoxifen resistant breast cancer, toremifene, apoptosis, autophagy

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