Abstract 1636
Background
Even though new molecular targeted agents are now being developed, they are still premature in application of clinical use for triple negative breast cancers (TNBCs). Therefore, it is highly demanded to explore the effective antitumor agents against TNBCs. Novel non-camptothecin topoisomerase I inhibitors are discovered and evaluated in this study.
Methods
Human MDA-MB-231 (BCRC-60425), BT-549 (ATCC® HTB-122™) and MCF-7 (BCRC-60436) were used in this study. Top1 assay was determined by gel mobility assay to validate the Top1-mediated DNA cleavages at different concentrations of non-camptothecin compounds. Cell viability analysis (MTT assay), comet assay and flow cytometry analysis were used to evaluate their growth inhibitory activity, DNA damage, and induction of cell arrest. Mechanistic pathways were studied and validated through western blot analysis, flow cytometry and confocal microscopy analysis. Binding interactions between top1 and non-camptothecin compound were analyzed by computational analysis (Discovery Studio).
Results
The IC50 values (growth inhibitory activity) of these non-camptothecin compounds are in the micromolar to nanomolar range (1.8 μM to 190 nM) against MDA-MB-231, BT-549 and MCF-7 cell lines. These compounds significantly inhibited the process in which supercoiled DNA strand transforms into its relaxed state and showed antitumor spectra similar to camptothecin rather than doxorubicin. Comet tails were observed to increase significantly with various doses of compounds in a dose-dependent manner. In addition, their mode of actions were shown to involve G2/M arrest of the cell cycle along with a dose-dependent increase in protein levels of cleaved caspase-3 and cleavage of cPARP. Except apoptosis pathway, non-camptothecin compounds also induce necrosis, and autophagy. Favorable ADMET characteristics of non-camptothecin compounds were observed using ADMET Descriptors.
Conclusions
Our results have provided evidence for therapeutic intervention in the treatment of TNBC using new top1 inhibitors, non-camptothecin compounds.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Wen-Shan Li.
Funding
Ministry of Science and Technology, Taiwan and Academia Sinica, Taiwan.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
5595 - Is there any prognostic significance in pleural involvement and/or effusion (Ple-I/E) in patients with ALK-positive NSCLC?
Presenter: Saadettin Kilickap
Session: Poster Display session 1
Resources:
Abstract
5840 - Crizotinib in patients with advanced or metastatic ROS1-rearranged lung cancer (EUCROSS): A European phase 2 clinical trial – Updated progression-free survival, overall survival and mechanisms of resistance
Presenter: Sebastian Michels
Session: Poster Display session 1
Resources:
Abstract
1905 - NTRK1-3 Genomic Fusions in Non-Small Cell Lung Cancer (NSCLC) Determined by Comprehensive Genomic Profiling
Presenter: Sai-Hong Ou
Session: Poster Display session 1
Resources:
Abstract
3016 - Preferential expression of the affected MET allele in lung carcinomas with heterozygous MET exon 14 skipping mutations: implications for clinical testing
Presenter: Evgeny Imyanitov
Session: Poster Display session 1
Resources:
Abstract
4120 - Brain metastases, treatment patterns and outcomes in ROS1-positive NSCLC patients from US oncology community centers
Presenter: Matthew G Krebs
Session: Poster Display session 1
Resources:
Abstract
3764 - Patients with metastatic non-small cell lung cancer and targetable molecular alterations in Germany. Treatment and first outcome data from the prospective German Registry Platform CRISP (AIO-TRK-0315)
Presenter: Frank Griesinger
Session: Poster Display session 1
Resources:
Abstract
4070 - Crizotinib vs Platinum-based Chemotherapy as First-line Treatment for Advanced Non-small Cell Lung Cancer with Different ROS1 Fusion Variants
Presenter: Haiyan Xu
Session: Poster Display session 1
Resources:
Abstract
5528 - Genomic and clinical characterization of Non-small cell lung cancer (NSCLC) patients harboring mutations in FGFR2 and FGFR3
Presenter: Matthias Scheffler
Session: Poster Display session 1
Resources:
Abstract
3779 - The expression of HER2-gene polymorphisms -1985G>T and P1170A C>G and their association with the risk of development of lung adenocarcinoma
Presenter: Ivan Aleric
Session: Poster Display session 1
Resources:
Abstract
3020 - Circulating tumor DNA (ctDNA) analysis depicts mechanisms of resistance and tumor response to BRAF inhibitors in BRAF-mutant non-small cell lung cancer (NSCLC)
Presenter: Sandra Ortiz - Cuaran
Session: Poster Display session 1
Resources:
Abstract