Estradiol control of ornithine decarboxylase mRNA, enzyme activity, and polyamine levels in MCF-7 breast cancer cells: therapeutic implications

ABSTRACT The effects of the novel vitamin D analogue, EB1089 alone, or in combination with the retinoid, 9-cis retinoic acid (9-cis RA) on indices of apoptosis in MCF-7 breast cancer cells have been examined. EB1089 was capable of reducing bcl-2 protein, a suppressor of apoptosis, and increasing p53 protein levels in MCF-7 cell cultures following 96h treatment. In the presence of 9-cis RA, EB1089 acted to further enhance the down-regulation and up-regulation of bcl-2 and p53 respectively. Furthermore, EB1089 induces DNA fragmentation in MCF-7 cells, a key feature of apoptosis, alone and in combination with 9-cis RA in situ. The observation that EB1089 and 9-cis RA act in a cooperative manner to enhance induction of apoptosis in these cells may have therapeutic implications.

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TrxR1 to promote adriamycin resistance in MCF-7 breast cancer cells by upregulating both gene expression level and enzyme activity: Reversed by shikonin.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e15070 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e15070-e15070

Author(s):

JinQing Yang ◽

Jinhai Tang

Keyword(s):

Breast Cancer ◽

Drug Resistance ◽

Endoplasmic Reticulum ◽

Enzyme Activity ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Inhibitory Concentration ◽

Ic50 Values ◽

Resistance Protein ◽

Mcf 7

e15070 Background: Adriamycin is one of the effective drugs commonly used in the treatment of advanced breast cancer, but its high incidence of drug resistance and cardiotoxicity limit the application of doxorubicin. Recent evidence shows that increased antioxidant capacity of cancer cells is associated with resistance to chemotherapy. Shikonin, a derivative of Lithospermum erythrorhizon Sieb.et Zucc, displays broad antitumor activity and direct cytotoxicity on various tumor cells. Our previous study shows that shikonin was enabled to directly binding and inhibiting TrxR1, which significantly downregulates intracellular ROS in cancer cells, suggesting that shikonin might be a promising drug candidate. In this study, we identified the relationship between TrxR1 and chemotherapeutic drug resistance in cancer cells and effects of shikonin with and without adriamycin on adriamycin-resistance cells. Methods: The direct DTNB reduction assay was employed to test the enzyme activity of TrxR1. Cultured ADR-resistant MCF-7 cells were assayed for their half maximal inhibitory concentration (IC50) values and apoptosis using an CCK8 assay and Annexin V-FITC/PI-labeled flow cytometry. Drug resistance was evaluated by inhibitory concentration (IC50) values and immunoblotting multidrug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP). TrxR1 knockdown was silenced by siRNA, leading to reducing the IC50 value of ADR-resistant MCF-7 cells. Dysfunctional endoplasmic reticulum was measured by western blot analysis of endoplasmic reticulum (ER) stress signaling pathways and observation of morphology using a transmission electron microscope. Results: We found that the TrxR1 was significantly enhanced in adriamycin-resistant (ADR/MCF7) cells.Furthermore, the decreased TrxR1 function by TrxR1-knockdown or TrxR1 inhibitor piperlongumine increased MCF-7 cells sensitivity to adriamycin. Treatment of ADR/MCF7 cells with shikonin (2.5,5,10,20,40 μM) dose-dependently inhibited TrxR1 enzyme activity and the clearance of dysfunctional endoplasmic reticulum, and induced cell apoptosis. Conclusions: Our results suggest that TrxR1 is critical for adriamycin resistance in breast cancer cells(ADR/MCF7),and shikonin or other inhibitors of TrxR1 would be potential in the treatment of cancer cells with adriamycin resistance.

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Polyamine profiles and growth properties of ornithine decarboxylase overexpressing MCF-7 breast cancer cells in culture

Breast Cancer Research and Treatment ◽

10.1007/bf00666490 ◽

1995 ◽

Vol 34 (1) ◽

pp. 45-53 ◽

Cited By ~ 7

Author(s):

Andrea Manni ◽

Rita Wechter ◽

Rhea Grove ◽

Lisa Wei ◽

Julianne Martel ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Ornithine Decarboxylase ◽

Breast Cancer Cells ◽

Cells In Culture ◽

Growth Properties ◽

Mcf 7

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Hyperglycemic Conditions Proliferate Triple Negative Breast Cancer Cells: Role of Ornithine Decarboxylase

10.21203/rs.3.rs-520490/v1 ◽

2021 ◽

Author(s):

Surabhi Chandra ◽

Caleb C. Capellen ◽

Jose A. Ortega ◽

M. Jane Morwitzer ◽

Hadassha Tofilau ◽

...

Keyword(s):

Breast Cancer ◽

Epithelial Cells ◽

Cancer Cells ◽

Ornithine Decarboxylase ◽

Triple Negative Breast Cancer ◽

Breast Cancer Cells ◽

Triple Negative ◽

Polyamine Synthesis ◽

Mcf 7

Abstract Several cancer subtypes (pancreatic, breast, liver, and colorectal) rapidly advance to higher aggressive stages in diabetes. Though hyperglycemia has been considered as a fuel for growth of cancer cells, pathways leading to this condition are still under investigation. Cellular polyamines can modulate normal and cancer cell growth, and inhibitors of polyamine synthesis have been approved for treating colon cancer, however the role of polyamines in diabetes-mediated cancer advancement is unclear as yet. We hypothesized that polyamine metabolic pathway is involved with increased proliferation of breast cancer cells under high glucose(HG) conditions. Studies were performed with varying concentrations of glucose (5mM-25mM) exposure in invasive, triple negative breast cancer cells, MDA-MB-231; non-invasive, estrogen/progesterone receptor positive breast cancer cells, MCF-7; and non-tumorigenic mammary epithelial cells, MCF-10A. There was a significant increase in proliferation with HG (25mM) at 48-72h in both MDA-MB-231 and MCF-10A cells but no such effect was observed in MCF-7 cells. This was correlated to higher activity of ornithine decarboxylase (ODC), the rate limiting enzyme in polyamine synthesis pathway. Inhibitor of polyamine synthesis (difluoromethylornithine, DFMO, 5mM) was quite effective in suppressing HG-mediated cell proliferation and ODC activity in MDA-MB-231 and MCF-10A cells. Polyamine (putrescine) levels were significantly elevated with HG treatment in MDA-MB-231 cells. HG exposure also increased the metastasis of MDA-MB-231 cells. Our findings are the first to indicate that polyamine inhibition can improve prognosis of breast cancer patients with diabetes, and also prevent proliferation of normal breast epithelial cells, which could potentially become tumorigenic.

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