scholarly journals Targeting radioresistant breast cancer cells by single agent CHK1 inhibitor via enhancing replication stress

Oncotarget ◽  
2016 ◽  
Vol 7 (23) ◽  
pp. 34688-34702 ◽  
Author(s):  
Yao Zhang ◽  
Jinzhi Lai ◽  
Zhanwen Du ◽  
Jinnan Gao ◽  
Shuming Yang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Single Agent ◽  
Replication Stress ◽  
Chk1 Inhibitor

scholarly journals HER2-Targeted Tyrosine Kinase Inhibitors Cause Therapy-Induced-Senescence in Breast Cancer Cells

Cancers ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 197 ◽  
Author(s):  
Martina S.J. McDermott ◽  
Neil Conlon ◽  
Brigid C. Browne ◽  
Adam Szabo ◽  
Naoise C. Synnott ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tyrosine Kinase ◽  
Cancer Cells ◽  
Tyrosine Kinase Inhibitors ◽  
Cell Fate ◽  
Breast Cancer Cells ◽  
Kinase Inhibitors ◽  
Single Agent ◽  
Prolonged Treatment ◽  
Her2 Positive

Prolonged treatment of HER2 positive breast cancer cells with tyrosine kinase inhibitors (TKIs) leads to the emergence of acquired resistance. However, the effects of continuous TKI exposure on cell fate, and the steps leading to the acquisition of a resistant phenotype are poorly understood. To explore this, we exposed five HER2 positive cells lines to HER2 targeted therapies for periods of up to 4 weeks and examined senescence associated β-galactosidase (SA-β-gal) activity together with additional markers of senescence. We found that lapatinib treatment resulted in phenotypic alterations consistent with a senescent phenotype and strong SA-β-gal activity in HER2-positive cell lines. Lapatinib-induced senescence was associated with elevated levels of p15 and p27 but was not dependent on the expression of p16 or p21. Restoring wild type p53 activity either by transfection or by treatment with APR-246, a molecule which reactivates mutant p53, blocked lapatinib-induced senescence and caused increased cell death. In contrast to lapatinib, SA-β-gal activity was not induced by exposing the cells to trastuzumab as a single agent but co-administration of lapatinib and trastuzumab induced senescence, as did treatment of the cells with the irreversible HER2 TKIs neratinib and afatinib. Neratinib- and afatinib-induced senescence was not reversed by removing the drug whereas lapatinib-induced senescence was reversible. In summary, therapy-induced senescence represents a novel mechanism of action of HER2 targeting agents and may be a potential pathway for the emergence of resistance.

scholarly journals Review of: Tamoxifen and TRAIL synergistically induce apoptosis in breast cancer cells

2008 ◽  
Vol 11 (2) ◽  
Author(s):  
Alison J. Butt
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Single Agent ◽  
Xenograft Model ◽  
Estrogen Receptor Α ◽  
Tumor Xenograft ◽  
Breast Cancers ◽  
Induced Apoptosis

Citation of original article:C. Lagadec, E. Adriaenssens, R. A. Toillon, V. Chopin, R. Romon, F. Van Coppenolle, H. Hondermarck, X. Le Bourhis. Oncogene advance online publication, 3 September 2007; doi:10.1038/sj.onc.1210749.Abstract of the original article:Tamoxifen (TAM), is widely used as a single agent in adjuvant treatment of breast cancer. Here, we investigated the effects of TAM in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in estrogen receptor-α (ER-α)-positive and -negative breast cancer cells. We showed that cotreatment with TAM and TRAIL synergistically induced apoptosis regardless of ER-α status. By contrast, cotreatment did not affect the viability of normal breast epithelial cells. Cotreatment with TAM and TRAIL in breast cancer cells decreased the levels of antiapoptotic proteins including FLIPs and Bcl-2, and enhanced the levels of proapoptotic proteins such as FADD, caspase 8, tBid, Bax and caspase 9. Furthermore, cotreatment-induced apoptosis was efficiently reduced by FADD- or Bid-siRNA, indicating the implication of both extrinsic and intrinsic pathways in synergistic apoptosis induction. Importantly, cotreatment totally arrested tumor growth in an ER-α-negative MDA-MB-231 tumor xenograft model. The abrogation of tumor growth correlated with enhanced apoptosis in tumor tissues. Our findings raise the possibility to use TAM in combination with TRAIL for breast cancers, regardless of ER-α status.

Chk1 inhibitor synergizes quinacrine mediated apoptosis in breast cancer cells by compromising the base excision repair cascade

2016 ◽  
Vol 105 ◽  
pp. 23-33 ◽  
Author(s):  
Ranjan Preet ◽  
Sumit Siddharth ◽  
Shakti Ranjan Satapathy ◽  
Sarita Das ◽  
Anmada Nayak ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Base Excision Repair ◽  
Breast Cancer Cells ◽  
Excision Repair ◽  
Chk1 Inhibitor ◽  
Base Excision

scholarly journals Inhibition of the polyamine synthesis enzyme ornithine decarboxylase sensitizes triple-negative breast cancer cells to cytotoxic chemotherapy

2020 ◽  
Vol 295 (19) ◽  
pp. 6263-6277 ◽  
Author(s):  
Renee C. Geck ◽  
Jackson R. Foley ◽  
Tracy Murray Stewart ◽  
John M. Asara ◽  
Robert A. Casero ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Ornithine Decarboxylase ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Single Agent ◽  
Cytotoxic Chemotherapy ◽  
Negative Regulator ◽  
Response To Chemotherapy

Treatment of patients with triple-negative breast cancer (TNBC) is limited by a lack of effective molecular therapies targeting this disease. Recent studies have identified metabolic alterations in cancer cells that can be targeted to improve responses to standard-of-care chemotherapy regimens. Using MDA-MB-468 and SUM-159PT TNBC cells, along with LC-MS/MS and HPLC metabolomics profiling, we found here that exposure of TNBC cells to the cytotoxic chemotherapy drugs cisplatin and doxorubicin alter arginine and polyamine metabolites. This alteration was because of a reduction in the levels and activity of a rate-limiting polyamine biosynthetic enzyme, ornithine decarboxylase (ODC). Using gene silencing and inhibitor treatments, we determined that the reduction in ODC was mediated by its negative regulator antizyme, targeting ODC to the proteasome for degradation. Treatment with the ODC inhibitor difluoromethylornithine (DFMO) sensitized TNBC cells to chemotherapy, but this was not observed in receptor-positive breast cancer cells. Moreover, TNBC cell lines had greater sensitivity to single-agent DFMO, and ODC levels were elevated in TNBC patient samples. The alterations in polyamine metabolism in response to chemotherapy, as well as DFMO-induced preferential sensitization of TNBC cells to chemotherapy, reported here suggest that ODC may be a targetable metabolic vulnerability in TNBC.

scholarly journals The Effect of Canertinib on Sensitivity of Cytotoxic Drugs in Tamoxifen-Resistant Breast Cancer Cells In Vitro

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Hesham A. M. Gomaa ◽  
Asmaa T. Ali ◽  
M. Abdel Gabbar ◽  
M. A. Kandeil
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Kinase Inhibitor ◽  
Apoptotic Cell ◽  
Combined Treatment ◽  
Single Agent ◽  
Tamoxifen Resistance ◽  
Cytotoxic Drugs ◽  
Mcf 7

Aims and Objectives. To investigate and examine the reversal effects of canertinib on the activity of EGFR and tamoxifen resistance in drug-resistant human breast carcinoma cells (MCF-7/TamR). Materials and Methods. The antiproliferative activity of canertinib alone or in combination with a conventional EGFR-targeting chemotherapies cytotoxic drugs differing in the mechanism(s) of action, such as paclitaxel, carboplatin, etoposide, vinorelbine, and daunorubicin as well as resistance mechanisms of EGFR targeting, have been investigated. Results. With an elevated dosage of canertinib, a significant decrease in proliferation and increase in apoptosis was observed. The treatment with higher doses of canertinib resulted in a 2-3-fold increase in apoptosis. In the combined treatment, it had been noticed a significant developed apoptotic cell death rather induced by single agent treatment. A significant downregulation of the antiapoptotic protein bcl-2 was exposed by immunocytochemistry investigation. Sensitivity to paclitaxel was also measured and was found to inversely correlate to bcl-2 status. Conclusion. Proliferation inhibition and apoptosis in MCF-7/TAM-R cells increase with increasing dosage of canertinib. This suggests that canertinib can reverse tamoxifen resistance in breast cancer cells. The antitumor effect of this EGFR-irreversible tyrosine kinase inhibitor provides a rationale for its clinical evaluation in combination with other cytotoxic drugs.

scholarly journals The Chk1 inhibitor AZD7762 sensitises p53 mutant breast cancer cells to radiation in vitro and in vivo

2012 ◽  
Vol 6 (4) ◽  
pp. 897-903 ◽  
Author(s):  
ZHIKUN MA ◽  
GUOLIANG YAO ◽  
BO ZHOU ◽  
YONGGANG FAN ◽  
SHEGAN GAO ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Chk1 Inhibitor
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