scholarly journals Hypoxia‐Induced Acidification Causes Mitoxantrone Resistance Not Mediated by Drug Transporters in Human Breast Cancer Cells

2005 ◽  
Vol 27 (1) ◽  
pp. 43-49
Author(s):  
A. E. Greijer ◽  
M. C. de Jong ◽  
G. L. Scheffer ◽  
A. Shvarts ◽  
P. J. van Diest ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Drug Transporters ◽  
Human Breast ◽  
Protein Levels ◽  
Resistance To Doxorubicin ◽  
Resistance To Chemotherapy ◽  
Mcf 7

Hypoxia has clinically been associated with resistance to chemotherapy. The aim of this study was to investigate whether hypoxia induces resistance to doxorubicin and mitoxantrone, two common drugs in cancer treatment, in MCF‐7 breast cancer cells, and SW1573 non‐small lung cancer cells. In addition, the role of drug transporters P‐gp, BCRP and MRP1 was analysed. Hypoxia induced resistance in MCF‐7 cells to mitoxantrone shifted the IC50 value from 0.09 μM (±0.01) to 0.54 μM (±0.06) under hypoxia, whereas survival of MCF‐7 and SW1573 cells in the presence of doxorubicin was not altered. Accumulation of mitoxantrone and daunorubicin, a doxorubicin fluorescent homologue, appeared to be 5.3 and 3.2 times lower in MCF‐7 cells, respectively. Cytotoxicity assays showed no increased functionality of the drug transporters P‐gp, BCRP and MRP1 under hypoxia. In addition, protein levels of these drug transporters were not changed. Medium of the MCF‐7 cells became more acidic under hypoxia thereby causing a decreased uptake of mitoxantrone. Hypoxia induces mitoxantrone resistance in MCF‐7 cells not mediated by the three major MDR transporters. Hypoxia‐induced acidification may cause this resistance by decreased cellular uptake together with a lowered cytotoxicity due to pH‐dependent topoisomerase type II activity.

scholarly journals Iron metabolism disturbances in the MCF-7 human breast cancer cells with acquired resistance to doxorubicin and cisplatin

2013 ◽  
Vol 43 (5) ◽  
pp. 1481-1486 ◽  
Author(s):  
VASYL F. CHEKHUN ◽  
NATALIA Yu. LUKYANOVA ◽  
ANATOLIY P. BURLAKA ◽  
NATALIA A. BEZDENEZHNYKH ◽  
SVITLANA I. SHPYLEVA ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Iron Metabolism ◽  
Human Breast Cancer ◽  
Breast Cancer Cells ◽  
Acquired Resistance ◽  
Human Breast Cancer Cells ◽  
Human Breast ◽  
Resistance To Doxorubicin ◽  
Mcf 7

scholarly journals miR-193b Modulates Resistance to Doxorubicin in Human Breast Cancer Cells by Downregulating MCL-1

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Jingpei Long ◽  
Zhiwei Ji ◽  
Kai Jiang ◽  
Zhaoyang Wang ◽  
Guanmin Meng
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Myeloid Cell ◽  
Untranslated Regions ◽  
Human Breast Cancer Cells ◽  
Cell Leukemia ◽  
Human Breast ◽  
Resistance To Doxorubicin ◽  
Mcf 7

MicroRNAs (miRNAs) family, which is involved in cancer development, proliferation, apoptosis, and drug resistance, is a group of noncoding RNAs that modulate the expression of oncogenes and antioncogenes. Doxorubicin is an active cytotoxic agent for breast cancer treatment, but the acquisition of doxorubicin resistance is a common and critical limitation to cancer therapy. The aim of this study was to investigate whether miR-193b mediated the resistance of breast cancer cells to doxorubicin by targeting myeloid cell leukemia-1 (MCL-1). In this study, we found that miR-193b levels were significantly lower in doxorubicin-resistant MCF-7 (MCF-7/DOXR) cells than in the parental MCF-7 cells. We observed that exogenous miR-193b significantly suppressed the ability of MCF-7/DOXR cells to resist doxorubicin. It demonstrated that miR-193b directly targeted MCL-1 3′-UTR (3′-Untranslated Regions). Further studies indicated that miR-193b sensitized MCF-7/DOXR cells to doxorubicin through a mechanism involving the downregulation of MCL-1. Together, our findings provide evidence that the modulation of miR-193b may represent a novel therapeutic target for the treatment of breast cancer.

scholarly journals Enhanced formation of non-phenolic androgen metabolites with intrinsic oestrogen-like gene transactivation potency in human breast cancer cells: a distinctive metabolic pattern

2006 ◽  
Vol 190 (3) ◽  
pp. 805-818 ◽  
Author(s):  
Gregorio Pérez-Palacios ◽  
René Santillán ◽  
Rocío García-Becerra ◽  
Elizabeth Borja-Cacho ◽  
Fernando Larrea ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Reporter Gene ◽  
Human Breast Cancer ◽  
Breast Cancer Cells ◽  
Yeast Cells ◽  
Human Breast ◽  
Metabolic Pattern ◽  
Mcf 7

Breast cancer is a sex steroid hormone-dependent malignant neoplasia. The role of oestradiol in this malignancy has been well documented; however, the involvement of androgens has remained controversial. To determine the role of non-phenolic androgen metabolites in human breast cancer, we studied the metabolism of [14C] testosterone and [14C] androstenedione in oestrogen-dependent MCF-7 cells and non-oestrogen-dependent MDA-MB 231 cells, at different substrate concentrations (1–10 μM) and time periods (30 min–48 h). Cultured non-oestrogen-dependent HeLa and yeast cells served as controls. Metabolites were identified and quantified by reverse isotope dilution. A distinctive pattern of androgen metabolism was identified in MCF-7 cells, being the 5α-androstane-3α,17β-diol (3α,5α-diol) and its 3β epimer (3β,5α-diol), the major conversion products of testosterone (48.3%), with 5α-dihydrotestosterone as intermediary. The formation of 3α,5α-diol and 3β,5α-diol (diols) was substrate concentration- and time-dependent, and abolished by finasteride. In contrast, very little of any diol formation was observed in MDA-MB 231, HeLa and yeast cell incubations. Additional enzyme gene expression studies revealed an overexpression of 5α-steroid reductase type-1 in MCF-7 cells, as compared with MDA-MB 231 cells. The oestrogen-like activities of diols were assessed in HeLa cells co-transfected with expression vectors for α or β subtypes of the human oestrogen receptor (hER) genes and for an oestrogen-responsive reporter gene. The results show that 3β, 5α-diol and to a lesser extent 3α,5α-diol bind with high relative affinity to hERα and hERβ. Both diols induced hER-mediated reporter gene transactivation in a dose–response manner, similar to that induced by oestradiol, though with lower potency, an effect that was abolished by ICI-182 780. Furthermore, 3β,5α-diol and to lesser extent 3α,5α-diol induced MCF-7 cell proliferation. The overall results demonstrated that MCF-7 cells exhibit enhanced expression and activity of androgen-metabolising enzymes, leading to rapid and large diol formation, and provide evidence that these androgen metabolites exert a potent oestrogen-agonistic effect, at genomic level, in oestrogen-dependent breast cancer cells. The data suggest that diols may act as in situ intracrine factors in breast cancer and that its formation can be pharmacologically inhibited.

scholarly journals Matrix degradation and cell proliferation are coupled to promote invasion and escape from an engineered human breast microtumor

2021 ◽  
Vol 13 (1) ◽  
pp. 17-29
Author(s):  
Emann M Rabie ◽  
Sherry X Zhang ◽  
Andreas P Kourouklis ◽  
A Nihan Kilinc ◽  
Allison K Simi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Type I ◽  
Matrix Degradation ◽  
Human Breast ◽  
Rate Of Invasion

Abstract Metastasis, the leading cause of mortality in cancer patients, depends upon the ability of cancer cells to invade into the extracellular matrix that surrounds the primary tumor and to escape into the vasculature. To investigate the features of the microenvironment that regulate invasion and escape, we generated solid microtumors of MDA-MB-231 human breast carcinoma cells within gels of type I collagen. The microtumors were formed at defined distances adjacent to an empty cavity, which served as an artificial vessel into which the constituent tumor cells could escape. To define the relative contributions of matrix degradation and cell proliferation on invasion and escape, we used pharmacological approaches to block the activity of matrix metalloproteinases (MMPs) or to arrest the cell cycle. We found that blocking MMP activity prevents both invasion and escape of the breast cancer cells. Surprisingly, blocking proliferation increases the rate of invasion but has no effect on that of escape. We found that arresting the cell cycle increases the expression of MMPs, consistent with the increased rate of invasion. To gain additional insight into the role of cell proliferation in the invasion process, we generated microtumors from cells that express the fluorescent ubiquitination-based cell cycle indicator. We found that the cells that initiate invasions are preferentially quiescent, whereas cell proliferation is associated with the extension of invasions. These data suggest that matrix degradation and cell proliferation are coupled during the invasion and escape of human breast cancer cells and highlight the critical role of matrix proteolysis in governing tumor phenotype.

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