The kinesin Eg5 inhibitor K858 induces apoptosis but also survivin-related chemoresistance in breast cancer cells

Summary Inhibitors of kinesin spindle protein Eg5 are characterized by pronounced antitumor activity. Our group has recently synthesized and screened a library of 1,3,4-thiadiazoline analogues with the pharmacophoric structure of K858, an Eg5 inhibitor. We herein report the effects of K858 on four different breast cancer cell lines: MCF7 (luminal A), BT474 (luminal B), SKBR3 (HER2 like) and MDA-MB231 (basal like). We demonstrated that K858 displayed anti-proliferative activity on every analyzed breast cancer cell line by inducing apoptosis. However, at the same time, we showed that K858 up-regulated survivin, an anti-apoptotic molecule. We then performed a negative regulation of survivin expression, with the utilization of wortmannin, an AKT inhibitor, and obtained a significant increase of K858-dependent apoptosis. These data demonstrate that K858 is a potent inhibitor of replication and induces apoptosis in breast tumor cells, independently from the tumor phenotype. This anti-proliferative response of tumor cells to K858 can be limited by the contemporaneous over-expression of survivin; consequently, the reduction of survivin levels, obtained with AKT inhibitors, can sensitize tumor cells to K858-induced apoptosis.
Source: Investigational New Drugs - Category: Drugs & Pharmacology Source Type: research

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Condition:   Metastatic Breast Cancer Interventions:   Drug: Trastuzumab deruxtecan;   Drug: Durvalumab;   Drug: Paclitaxel;   Drug: Capivasertib;   Drug: Anastrozole;   Drug: Fulvestrant;   Drug: Capecitabine Sponsors:   AstraZeneca;   Daiichi Sankyo Company, Limited Not yet recruiting
Source: ClinicalTrials.gov - Category: Research Source Type: clinical trials
Contributors : Denise Wolf ; Christina Yau ; Julia Wulfkuhle ; Emanuel F Petricoin III ; Laura van ‘t VeerSeries Type : Protein profiling by protein arrayOrganism : Homo sapiensThe AKT inhibitor MK2206 (M) was one of the experimental agents evaluated in I-SPY 2, a neoadjuvant platform trial for high risk, early stage breast cancer, and graduated in the HER2+, HR-, and HR-HER2+ signatures. Based on the hypotheses that since MK2206 is an enzymatic inhibitor of AKT, response to MK2206 may be predicted by the relative pre-treatment levels of phosphorylation of AKT kinase substrates, in pre-defined analyses we assessed 26...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Protein profiling by protein array Homo sapiens Source Type: research
Contributors : Denise Wolf ; Christina Yau ; Julia Wulfkuhle ; Emanuel F Petricoin III ; Laura van ‘t VeerSeries Type : Expression profiling by arrayOrganism : Homo sapiensThe AKT inhibitor MK2206 (M) was one of the experimental agents evaluated in I-SPY 2, a neoadjuvant platform trial for high risk, early stage breast cancer, and graduated in the HER2+, HR-, and HR-HER2+ signatures. Based on the hypotheses that since MK2206 is an enzymatic inhibitor of AKT, response to MK2206 may be predicted by the relative pre-treatment levels of AKT kinase substrates, in pre-defined analyses we assessed 10 genes in the HER-AKT-m...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by array Homo sapiens Source Type: research
Publication date: Available online 19 September 2020Source: Biochimica et Biophysica Acta (BBA) - Gene Regulatory MechanismsAuthor(s): Yini Yang, Lavanya Choppavarapu, Kun Fang, Alireza S. Naeini, Bakhtiyor Nosirov, Jingwei Li, Ke Yang, Zhijing He, Yufan Zhou, Rachel Schiff, Rong Li, Yanfen Hu, Junbai Wang, Victor X. Jin
Source: Biochimica et Biophysica Acta (BBA) Gene Regulatory Mechanisms - Category: Genetics & Stem Cells Source Type: research
Condition:   Metastatic Breast Cancer Interventions:   Drug: Trastuzumab deruxtecan;   Drug: Durvalumab;   Drug: Paclitaxel;   Drug: Capivasertib;   Drug: Anastrozole;   Drug: Fulvestrant;   Drug: Capecitabine Sponsors:   AstraZeneca;   Daiichi Sankyo Company, Limited Not yet recruiting
Source: ClinicalTrials.gov - Category: Research Source Type: clinical trials
Tumor human epidermal growth factor receptor 2 (HER2) status is defined by either protein expression using immunohistochemistry (IHC) or gene amplification using fluorescence in situ hybridization (FISH). Approximately 20% of HER2-positive breast cancer is HER2 IHC 2+/FISH-positive. Unlike trastuzumab, it has not been studied whether the response to trastuzumab emtansine (T-DM1) differs according to HER2-positive status. We retrospectively identified and reviewed medical records of all patients with HER2-positive advanced breast cancer (ABC) who received T-DM1 in our hospital from October 2013 to December 2016. We compared...
Source: Anti-Cancer Drugs - Category: Cancer & Oncology Tags: Case Reports Source Type: research
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Source: Medicine - Category: Internal Medicine Tags: Research Article: Observational Study Source Type: research
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Source: Medicine - Category: Internal Medicine Tags: Research Article: Observational Study Source Type: research
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Source: Oncotarget - Category: Cancer & Oncology Tags: Oncotarget Source Type: research
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Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
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