scholarly journals Epigenetic Priming with Decitabine Augments the Therapeutic Effect of Cisplatin on Triple-Negative Breast Cancer Cells through Induction of Proapoptotic Factor NOXA

Cancers ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 248
Author(s):  
Wataru Nakajima ◽  
Kai Miyazaki ◽  
Masahiro Sakaguchi ◽  
Yumi Asano ◽  
Mariko Ishibashi ◽  
...  
Keyword(s):  
Cell Lines ◽  
Triple Negative ◽  
Kinase Inhibitor ◽  
Underlying Mechanism ◽  
Breast Cancers ◽  
Hematopoietic Malignancy ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Tnbc Cell ◽  
Aberrant Dna Methylation ◽  
Induced Apoptosis

Epigenetic alterations caused by aberrant DNA methylation have a crucial role in cancer development, and the DNA-demethylating agent decitabine, is used to treat hematopoietic malignancy. Triple-negative breast cancers (TNBCs) have shown sensitivity to decitabine; however, the underlying mechanism of its anticancer effect and its effectiveness in treating TNBCs are not fully understood. We analyzed the effects of decitabine on nine TNBC cell lines and examined genes associated with its cytotoxic effects. According to the effect of decitabine, we classified the cell lines into cell death (D)-type, growth inhibition (G)-type, and resistant (R)-type. In D-type cells, decitabine induced the expression of apoptotic regulators and, among them, NOXA was functionally involved in decitabine-induced apoptosis. In G-type cells, induction of the cyclin-dependent kinase inhibitor, p21, and cell cycle arrest were observed. Furthermore, decitabine enhanced the cytotoxic effect of cisplatin mediated by NOXA in D-type and G-type cells. In contrast, the sensitivity to cisplatin was high in R-type cells, and no enhancing effect by decitabine was observed. These results indicate that decitabine enhances the proapoptotic effect of cisplatin on TNBC cell lines that are less sensitive to cisplatin, indicating the potential for combination therapy in TNBC.

Rapamycin sensitizes multiple myeloma cells to apoptosis induced by dexamethasone

Blood ◽  
2004 ◽  
Vol 103 (8) ◽  
pp. 3138-3147 ◽  
Author(s):  
Thomas Strömberg ◽  
Anna Dimberg ◽  
Anna Hammarberg ◽  
Kristina Carlson ◽  
Anders Österborg ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Lines ◽  
Intracellular Signaling ◽  
Kinase Inhibitor ◽  
Mammalian Target Of Rapamycin ◽  
G1 Arrest ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Induced Apoptosis ◽  
Molecular Mode

Abstract Circumvention of chemoresistance in the B-cell neoplasm multiple myeloma (MM) might be achieved by targeting certain intracellular signaling pathways crucial for survival of the malignant clone. The use of the macrolide rapamycin, selectively inhibiting the phosphoprotein mammalian target of rapamycin (mTOR) downstream of, for example, insulin-like growth factor-I receptor (IGF-IR), possibly represents such a molecular mode of therapy. By using a panel of MM cell lines we showed that rapamycin induced G0/G1 arrest, an effect being associated with an increase of the cyclin-dependent kinase inhibitor p27 and a decrease of cyclins D2 and D3. Interestingly, in primary, mainly noncycling MM cells, rapamycin, at clinically achievable concentrations, induced apoptosis. More important, rapamycin sensitized both MM cell lines and primary MM cells to dexamethasone-induced apoptosis. This effect was associated with a decreased expression of cyclin D2 and survivin. The phosphorylation of the serine/threonine kinase p70S6K at Thr389 and Thr421/Ser424 was down-regulated by rapamycin and/or dexamethasone. Strikingly, the combinatorial treatment with rapamycin and dexamethasone suppressed the antiapoptotic effects of exogenously added IGF-I and interleukin 6 (IL-6) as well as their stimulation of p70S6K phosphorylation. The induction of apoptosis by rapamycin and dexamethasone despite the presence of survival factors was also demonstrated in primary MM cells, thus suggesting this drug combination to be active also in vivo. (Blood. 2004;103:3138-3147)

Targeting mutant p53 with PK11007: A new approach for the treatment of patients with triple-negative breast cancer?

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14099-e14099 ◽  
Author(s):  
Naoise C Synnott ◽  
Matthias R Bauer ◽  
Stephen F. Madden ◽  
Alyson M. Murray ◽  
Rut Klinger ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Cell Lines ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
P53 Protein ◽  
Mutant P53 ◽  
Inhibition Of Proliferation ◽  
Tnbc Cell ◽  
Induced Apoptosis

e14099 Background:The identification of a targeted therapy for patients with triple-negative breast cancer (TNBC) is one of the most urgent needs in breast cancer therapeutics. Since the p53 gene is mutated in approximately 80% of TNBC patients, it is a potential therapeutic target for this form of breast cancer. PK11007 is a 2-sulfonypyrimidine that stabilizes and reactivates mutant p53 (Bauer et al, PNAS 2016). The compound recently was reported to preferentially decrease viability in p53-compromised cancer cells. The aim of this investigation was to evaluate PK11007 as a potential new treatment for TNBC. Methods: Cell viability was determined using the MTT assay. Apoptosis was detected using Annexin V Apoptosis Detection Kit. Migration was determined by Transwell migration assay. Knockdowns of p53 protein were carried out using predesigned Flexitube sequences (Qiagen). Results: IC50 values for inhibition of proliferation by PK11007 in the panel of 17 breast cell lines ranged from 2.3 to 42.2 μM. There were significantly lower IC50values for TNBC than for non-TNBC cell lines (p = 0.03) and for p53-mutated cell lines compared with p53 WT cells (p = 0.003). Response to PK11007 however, was independent of ER or HER2 status of the cells. In addition, PK11007 induced apoptosis and inhibited migration in p53 mutant cell lines. Using RNAseq and gene ontogeny analysis, we found that PK11007 altered the expression of genes enriched in pathways involved in regulated cell death, regulation of apoptosis, signal transduction, protein refolding and locomotion. To establish if PK11007 acts by targeting mutant p53, we used siRNA to knockdown p53 in 3 p53-mutated TNBC cell lines. Reduction in p53 protein levels resulted in a significant decrease in the growth inhibitory effects of PK11007, in all 3 cell lines investigated, suggesting that PK11007 mediates growth inhibition via p53. The observations that PK11007 inhibited cell growth, induced apoptosis, blocked cell migration and altered genes involved in cell death, are all consistent with the ability of PK11007 to activate mutant p53. Conclusions: Based on our data, we conclude that targeting mutant p53 with PK11007 is a potential approach for treating p53-mutated TNBC.

scholarly journals Dihydroartemisinin-Transferrin Adducts Enhance TRAIL-Induced Apoptosis in Triple-Negative Breast Cancer in a P53-Independent and ROS-Dependent Manner

2022 ◽  
Vol 11 ◽  
Author(s):  
Xinyu Zhou ◽  
Abel Soto-Gamez ◽  
Fleur Nijdam ◽  
Rita Setroikromo ◽  
Wim J. Quax
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Cell Lines ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Breast Cancer Subtype ◽  
Death Receptor ◽  
Dependent Manner ◽  
Tnbc Cell ◽  
Induced Apoptosis

Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype independent of estrogen receptor, progesterone receptor, or human epidermal growth factor receptor 2. It has a poor prognosis and high recurrence. Due to its limited treatment options in the clinic, novel therapies are urgently needed. Single treatment with the death receptor ligand TRAIL was shown to be poorly effective. Recently, we have shown that artemisinin derivatives enhance TRAIL-induced apoptosis in colon cancer cells. Here, we utilized transferrin (TF) to enhance the effectiveness of dihydroartemisinin (DHA) in inducing cell death in TNBC cell lines (MDA-MB-231, MDA-MB-436, MDA-MB-468 and BT549). We found that the combination of DHA-TF and the death receptor 5-specific TRAIL variant DHER leads to an increase in DR5 expression in all four TNBC cell lines, while higher cytotoxicity was observed in MDA-MB-231, and MDA-MB-436. All the data point to the finding that DHA-TF stimulates cell death in TNBC cells, while the combination of DHA-TF with TRAIL variants will trigger more cell death in TRAIL-sensitive cells. Overall, DHA-TF in combination with TRAIL variants represents a potential novel combination therapy for triple-negative breast cancer.

Molecular Mechanism by Which Rituximab Sensitizes B-NHL Cells to TRAIL Apoptosis: Induction of RKIP and DR5 Expression Via Inhibition of NF-Kb, Snail, and YY1.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1596-1596
Author(s):  
Mario I. Vega ◽  
Melisa Martinez-Paniagua ◽  
Sara Huerta-Yepez ◽  
Yeung Kam ◽  
Stavroula Baritaki ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Cell Lines ◽  
Kinase Inhibitor ◽  
Proteasome Inhibitors ◽  
Underlying Mechanism ◽  
Inhibitor Protein ◽  
Rt Pcr ◽  
Yin Yang 1 ◽  
Induced Apoptosis

Abstract There have been significant advances in the treatment of patients with B-NHL using combination of rituximab and CHOP. However, a subset of patients does not initially respond or develop resistance to further treatments; hence, the need for alternative therapies to overcome resistance. TRAIL and agonist DR4/DR5 monoclonal antibodies have been examined clinically against a variety of tumors in Phase I/II. However, the majority of B-NHL derived from patients and cell lines are resistant to TRAIL-induced apoptosis. Recent findings demonstrated that treatment of TRAIL-resistant-B-NHL with rituximab sensitizes the tumor cells to TRAIL apoptosis. The underlying mechanism of rituximab-induced sensitization to TRAIL, however, is not clear. We have recently reported that treatment of tumor cells with sensitizing agents (example CDDP, proteasome inhibitors) resulted in the reversal of resistance to TRAIL via induction of Raf-1 kinase inhibitor protein (RKIP) and demonstrated the pivotal role of RKIP in the regulation of tumor cell sensitivity to TRAIL. Hence, since rituximab induces the expression of RKIP in B-NHL, we determined the role of RKIP induction by rituximab in the sensitization of B-NHL to TRAIL apoptosis. Various B-NHL cell lines were used as models for study. Treatment of B-NHL cells with rituximab (20 ng/ml) and TRAIL (5–10 ng/ml) resulted in significant potentiation of apoptosis and synergy was achieved. Rituximab induced the expression of RKIP as determined by RT-PCR and western concomitantly with inhibition of NF-kB. The inhibition of NF-kB resulted in upregulation of RKIP expression and was mediated, in large part, by inhibition of the transcription repressor Snail (downstream of NF-kB). Further, RKIP-induced inhibition of NF-kB by rituximab resulted in downstream inhibition of the DR5 transcription repressor Yin Yang 1 (YY1) and concomitantly with the upregulation of DR5 expression. The role of RKIP induction by rituximab in the upregulation of DR5 and sensitization to TRAIL apoptosis was corroborated by the use of cells over expressing RKIP which were sensitive to TRAIL apoptosis in the absence of rituximab. Our findings reveal a novel mechanism of rituximab-induced sensitization of B-NHL to TRAIL apoptosis via inhibition of NF-kB and Snail and upregulation of RKIP and DR-5. The combination of rituximab and TRAIL may be effective in the treatment of B-NHL. Further, our studies suggest that agents other than rituximab that can induce RKIP can reverse resistance to TRAIL in B-NHL that are unresponsive to rituximab treatment.

scholarly journals Optical Redox Imaging Differentiates Triple-Negative Breast Cancer Subtypes

2021 ◽  
pp. 253-258
Author(s):  
Jinxia Jiang ◽  
Min Feng ◽  
Annemarie Jacob ◽  
Lin Z. Li ◽  
He N. Xu
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Treatment Options ◽  
Response Patterns ◽  
Breast Cancers ◽  
Cancer Subtypes ◽  
Mitochondrial Inhibitors ◽  
Tnbc Cell

AbstractTriple-negative breast cancer (TNBC) is a highly diverse group of cancers with limited treatment options, responsible for about 15% of all breast cancers. TNBC cells differ from each other in many ways such as gene expression, metabolic activity, tumorigenicity, and invasiveness. Recently, many research and clinical efforts have focused on metabolically targeted therapy for TNBC. Metabolic characterization of TNBC cell lines can facilitate the assessment of therapeutic effects and assist in metabolic drug development. Herein, we used optical redox imaging (ORI) techniques to characterize TNBC subtypes metabolically. We found that various TNBC cell lines had differing redox statuses (levels of reduced nicotinamide adenine dinucleotide (NADH), oxidized flavin adenine dinucleotide (FAD), and the redox ratio (FAD/(NADH+FAD)). We then metabolically perturbed the cells with mitochondrial inhibitors and an uncoupler and performed ORI accordingly. As expected, we observed that these TNBC cell lines had similar response patterns to the metabolic perturbations. However, they exhibited differing redox plasticity. These results suggest that subtypes of TNBC cells are different metabolically and that ORI can serve as a sensitive technique for the metabolic profiling of TNBC cells.

Activity of dasatinib with chemotherapy in triple-negative breast cancer cells

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e14605-e14605
Author(s):  
D. Tryfonopoulos ◽  
N. O'Donovan ◽  
B. Corkery ◽  
M. Clynes ◽  
J. Crown
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Kinase Inhibitor ◽  
Combined Treatment ◽  
Breast Cancer Cell Lines ◽  
Breast Cancer Patients ◽  
Tnbc Cell ◽  
Her 2

e14605 Background: Triple-negative breast cancers (TNBC) lack expression of oestrogen, progesterone, and are HER-2 normal. TNBC cell lines have displayed greater sensitivity to growth inhibition by the multi-target kinase inhibitor, dasatinib, than luminal or HER- 2 positive breast cancer cell lines. The aim of this study was to assess the direct anti-tumor effects of dasatinib in combination with chemotherapy in TNBC. Methods: Four TNBC cell lines (MDA-MB-231, HCC-1143, HCC-1937, MDA-MB-468) were treated with dasatinib in combination with docetaxel, cisplatin or 5'-5' DFUR. IC50 values were calculated for each drug alone by determining response in a 5-day proliferation (acid phosphatase) assay. Combination index (CI) values were determined, using CalcuSyn, to assess the interaction between drugs. Results: Three of the cell lines (MDA-MB-231, HCC- 1143, HCC-1937) were sensitive to dasatinib (IC50 < 1 μM) whereas MDA-MB-468 was resistant (IC50 > 1 μM) (Table). In MDA-MB-231 and HCC-1143 cells, combined treatment with dasatinib and 5'-5'-DFUR displayed synergy (CI<1.0), whereas the combination was additive in HCC-1937 cells (CI=0.98). Combined treatment with dasatinib and cisplatin was synergistic in the three dasatinib sensitive cell lines (CI<1.0). Dasatinib in combination with docetaxel displayed moderate synergy in MDA-MB-231 and HCC-1937 cells (CI<1.0), but was antagonistic in HCC-1143 cells (CI>1.0). Conclusions: Our findings show that the combination of dasatinib with either 5'-5'-DFUR or cisplatin is synergistic in TNBC cell lines, and suggest that combinations of dasatinib with chemotherapy may improve response in triple negative breast cancer patients. [Table: see text] No significant financial relationships to disclose.

Met and HGF inhibition in triple-negative breast cancer cell lines.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 1066-1066 ◽  
Author(s):  
Patricia Brid Gaule ◽  
Denis Collins ◽  
Naomi Walsh ◽  
Michael J. Duffy ◽  
John Crown ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Growth Inhibition ◽  
Cell Lines ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Kinase Inhibitor ◽  
Day Treatment ◽  
Combined Treatment ◽  
Breast Cancer Cell Lines ◽  
Tnbc Cell

1066 Background: Basal-like breast cancer (BLBC) is associated with high expression of c-Met. c-Met and its ligand HGF may be rational therapeutic targets for BLBC. We evaluated expression of c-Met and response to c-Met/HGF inhibition alone/in combination with other targeted therapies in triple-negative breast cancer (TNBC) cell lines. Methods: Expression and phosphorylation of c-Met was measured by immunoblotting. qRT-PCR was used to measure HGF mRNA. Cell proliferation was measured by acid phosphatase assay after 5 day treatment with a c-Met inhibitor (CpdA), HGF monoclonal antibody, rilotumamab, a panHER inhibitor (neratinib) and a SRC kinase inhibitor, (saracatinib). Invasion through 0.4 μm Matrigel coated membranes was measured for two cell lines. Results: c-Met and p-Met were detected in 7 and 4 of the 7 TNBC cell lines tested, respectively. HGF mRNA was not detectable in any of the TN cell lines. CpdA inhibited growth in 4 TN cell lines with IC50values ranging from 2.1-7.6 μM. Rilotumumab did not inhibit growth, however combined treatment with CpdA and rilotumumab resulted in significantly increased growth inhibition in 3 of 5 cell lines (Table). CpdA in combination with neratinib significantly improved growth inhibition in MDA-MB-468 cells, and in combination with saracatinib significantly improved growth inhibition in 3 of 5 cell lines (Table). CpdA also inhibited invasion of CAL-85-1 cells by 21.4% (± 10.4%) but not HDQ-P1cells. Conclusions: c-Met may represent a viable molecular target in TNBC. Dual targeting of Met and HGF and/or with EGFR or SRC may increase the efficacy of c-Met inhibition in TNBC. [Table: see text]

FoxM1 as a potential therapeutic target for triple-negative breast cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e22063-e22063 ◽  
Author(s):  
Cha Kyong Yom ◽  
Kyung-Min Lee ◽  
Wonshik Han ◽  
Sung-Won Kim ◽  
Hyeong-Gon Moon ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cyclin D1 ◽  
Cell Lines ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cyclin B ◽  
Tnbc Cell ◽  
Forkhead Box M1 ◽  
Elevated Expression ◽  
Induced Apoptosis

e22063 Background: Elevated expression or activity of the transcription factor forkhead box M1 (FoxM1) is associated with development and progression of breast cancer. In this study, we show that whether inhibition of FoxM1 in triple negative breast cancer (TNBC) cell lines causes the changes of cancer progress and response to the treatment. Methods: We inhibited FoxM1 using thiostrepton (FoxM1 inhibitor) and identified the activity of VEGF, cyclin B, cyclin D1, p27, CD44 and cleaved capase-3 in MDA-MB-231 cells. Invasion assay was evaluated in BT-20 cells and combination with cisplatin and inhibition of FoxM1 were treated in triple negative breast cancer (TNBC) cell lines including MDA-MB-231, MDA-MB-157, and BT-20. Results: When FoxM1 was inhibited using thiostrepton in MDA-MB-231 cells, expressions of VEFG, cyclin B, cyclin D1, p27, and CD44 were decreased. On the other hand, cleaved caspase-3 expression was increased. Intersetingly, response to inhibition of FoxM1 depended on the expression of p53 in each cell lines. Invasiveness of BT-20 cells is markedly reduced by inhibitioh of FoxM1. Co-treatment with thiotrepton and cisplatin synergistically induced apoptosis of breast cancer cells in MDA-MB-231, MDA-MB-157, and BT-20. Conclusions: Inhibition of FoxM1 increases apoptosis and decreases invasiveness and VEGF exprsssion of TNBC cells. And when inhibition of FoxM1 combines with cisplatin treament, synergistic effect was shown. Therefore, FoxM1 is valuable as a potential target for not only anticancer activity but also overcoming cisplatin resistance in TNBC.

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