Modulation of epirubicin cytotoxicity by tamoxifen in human breast cancer cell lines

Azab, Samar S.; El‐Demerdash, Ebtehal; Abdel-Naim, Ashraf B.; Youssef, Ekram; El-Sharkawy, Nahla; Osman, Amira

doi:10.1016/j.bcp.2005.03.036

Cited by 9 publications

(7 citation statements)

References 18 publications

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“…These results are in accordance with studies reporting that several MDR cells were not found to over express p-gp, although they show a typical MDR profile [33,34]. Importantly, we [35] and others [36,37] have shown that MDR1 may not solely account for development or regulation of MDR phenotype, but actually additional contributing factors are involved and still to be declared.…”

Section: Discussionsupporting

confidence: 95%

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2-Methoxyestradiol and multidrug resistance: can 2-methoxyestradiol chemosensitize resistant breast cancer cells?

Azab

Salama

Abdel-Naim

et al. 2008

Breast Cancer Res Treat

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2-Methoxyestradiol (2ME), a natural derivative of estradiol, is currently evaluated in clinical trials for breast cancer. The current study aims to evaluate the modulatory effects of 2ME on regulation of multidrug resistance (MDR) in doxorubicin (Dox) resistant breast cancer cells (MCF-7/Dox) and its underlying mechanisms. The chemosensitizing effect of 2ME on Dox cytotoxicity is tested by MTT assay. RT(2) Profiler PCR Array was used to identify differentially expressed genes in Dox and/or 2ME treatment groups, based on significance of results 4 genes were selected: MDR1, Bcl2, P53 and Cyclin D1. The expression of these genes was confirmed using western blotting. Lastly, functions of these genes were examined by studying p-glycoprotein (p-gp) function, caspase 3 activity and flowcytometric cell cycle assays respectively. 2ME significantly increased sensitivity of the resistant MCF-7/Dox cells to the cytotoxic effect of Dox by 2.9-folds. The array and western blotting showed that Bcl2 and Cyclin D1 expression were down regulated; P53 expression was not affected while MDR1 was over expressed by combination of 2ME with Dox. 2ME increased p-gp function by 24+/-7.05%, compared to control. Addition of 2ME to Dox increased caspase activity by 27-folds. Combination of 2ME to Dox arrested the cell cycle in G(1) and S phases, compared to Dox. In conclusion, 2ME chemosensitizes resistant breast cancer cells to Dox cytotoxicity by down regulating expression of Bcl2 and Cyclin D1, augmenting caspase 3 activity as well as inducing cell cycle block in G(1) and S phases.

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Section: Discussionsupporting

confidence: 95%

“…These results confirmed our earlier results of MDR1 expression. These results can be explained on the following basis: MDR can be acquired after exposure to cytotoxic agents and p-gp antagonists such as verapamil, cyclosporine A and tamoxifen [35,46,47].…”

Section: Discussionmentioning

confidence: 99%

2-Methoxyestradiol and multidrug resistance: can 2-methoxyestradiol chemosensitize resistant breast cancer cells?

Azab

Salama

Abdel-Naim

et al. 2008

Breast Cancer Res Treat

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“…However, the effect of caspase‐3 in controlling both apoptosis and autophagy requires further study. Interestingly, our results also show that EPI induced G 2 /M arrest in both cell lines and these data were similar to previous work with EPI and MCF‐7 cells . Reports also suggest that EPI may not necessarily trigger autophagy in other breast cancer cells, so how cells respond to EPI treatment is more complex than “either autophagy or apoptosis”, and requires further study.…”

Section: Discussionsupporting

confidence: 90%

Inhibiting autophagy increases epirubicin's cytotoxicity in breast cancer cells

Guo

Wang

et al. 2016

Cancer Science

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Chemotherapy, radiotherapy, and endocrinotherapy are documented to induce autophagy among breast cancer cells, but the role of autophagy in this disease has been attributed as cytoprotective as well as tumor‐suppressing. Thus we studied MDA‐MB‐231 and SK‐BR‐3 breast cancer cell lines treated with epirubicin (EPI) to assess autophagy and apoptosis. We found out that EPI induced apoptosis and autophagy in both cell lines. The lysosomal inhibitor bafilomycin A1 inhibited cellular autophagy and enhanced EPI‐triggered apoptosis, perhaps due to inhibition of autolysosome formation, which then inhibited autophagic effects of engulfing and clearing damaged mitochondria. This inhibition increased mitochondrial cytochrome C release which augmented epirubicin‐induced caspase‐dependent apoptosis and cytotoxicity. In addition, the lysosomal neutralizing agent ammonia chloride (AC), and Atg7 knockdown by siRNA, could inhibit epirubicin‐triggered autophagy, enhance cytotoxicity, and increase caspase‐9‐ and caspase‐3‐dependent apoptosis. Thus, autophagy plays a prosurvival role in EPI‐treated MDA‐MB‐231 and SK‐BR‐3 cells, and autophagy inhibition can potentially reverse this effect and increase the cytotoxicity of EPI.

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“…Cytotoxicity was determined using SulphoRhodamine-B (SRB) method as previously described by Azab et al [11]. Cells were seeded in microtiter plates at a concentration of 5 9 10 4 -10 5 cells/well.…”

Section: Assay Of Cytotoxic Activitymentioning

confidence: 99%

Altered Expression of Proliferation-Inducing and Proliferation-Inhibiting Genes Might Contribute to Acquired Doxorubicin Resistance in Breast Cancer Cells

Saleh

El‐Awady

Alim

et al. 2009

Cell Biochem Biophys

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This study was designed to investigate the molecular changes that may develop during exposure of breast cancer cells to anticancer agents and that may lead to acquired resistance. We used two breast cancer cell lines, a parental (MCF7/WT) and a doxorubicin-resistant (MCF7/DOX) one. Cell survival, cell cycle distribution and RT-PCR expression level of genes involved in DNA damage response, MDR1, GST and TOPOIIalpha were measured. MCF7/DOX cells were five-fold more resistant to doxorubicin (DOX) than the MCF7/WT cells. DOX treatment causes arrest of MCF7/DOX cells in G1 and G2 phases of cell cycle whereas MCF7/WT cells were arrested in S-phase. The molecular changes in both cell lines due to DOX treatment could be classified into: (1) the basal level of p53, p21, BRCA1, GST and TOPOIIalpha mRNA was higher in MCF7/DOX than MCF7/WT. During DOX treatment, the expression level of these genes decreased in both cell lines but the rate of down-regulation was faster in MCF7/WT than MCF7/DOX cells. (2) The expression level of MDR1 was the same in both cell lines but 48 and 72 h of drug treatment, MDR1 disappeared in MCF7/WT but still expressed in MCF7/DOX. (3) There was no change in the expression level of BAX, FAS and BRCA2 in both cell lines. Conclusively, after validation in clinical samples, overexpression of genes like BRCA1, p53, p21, GST, MDR1 and TOPOIIalpha could be used as a prognostic biomarker for detection of acquired resistance in breast cancer and as therapeutic targets for the improvement of breast cancer treatment strategies.

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Modulation of epirubicin cytotoxicity by tamoxifen in human breast cancer cell lines

Cited by 9 publications

References 18 publications

2-Methoxyestradiol and multidrug resistance: can 2-methoxyestradiol chemosensitize resistant breast cancer cells?

2-Methoxyestradiol and multidrug resistance: can 2-methoxyestradiol chemosensitize resistant breast cancer cells?

Inhibiting autophagy increases epirubicin's cytotoxicity in breast cancer cells

Altered Expression of Proliferation-Inducing and Proliferation-Inhibiting Genes Might Contribute to Acquired Doxorubicin Resistance in Breast Cancer Cells

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