ArticleOncotarget2017
NSC30049 inhibits Chk1 pathway in 5-FU-resistant CRC bulk and stem cell populations.
Article in Oncotarget, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
What it found
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The trial behind it
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Who cites it
10 citing papers in PubMed, 17 citations in OpenAlex.
- CHK1 as a Metabolic and Immunological Regulator: Implications for Cancer Therapy.Oncology research · 2026Review
- Altering phosphorylation in cancer through PP2A modifiers.Cancer cell international · 2024Review
- Colorectal Cancer Stem Cells and Targeted Agents.Pharmaceutics · 2023Review
- Article
- Sensitization of FOLFOX-resistant colorectal cancer cells via the modulation of a novel pathway involving protein phosphatase 2A.iScience · 2022Article
- Emerging agents that target signaling pathways to eradicate colorectal cancer stem cells.Cancer communications (London, England) · 2021Review
- Recent Updates on Mechanisms of Resistance to 5-Fluorouracil and Reversal Strategies in Colon Cancer Treatment.Biology · 2021Review
- Ubiquitination of the DNA-damage checkpoint kinase CHK1 by TRAF4 is required for CHK1 activation.Journal of hematology & oncology · 2020Article
- The splicing component ISY1 regulates APE1 in base excision repair.DNA repair · 2020Article
- ASR352, A potent anticancer agent: Synthesis, preliminary SAR, and biological activities against colorectal cancer bulk, 5-fluorouracil/oxaliplatin resistant and stem cells.European journal of medicinal chemistry · 2019Article
Corrections and comments
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
Abstract
The 5-fluorouracil (5-FU) treatment induces DNA damage and stalling of DNA replication forks. These stalled replication forks then collapse to form one sided double-strand breaks, leading to apoptosis. However, colorectal cancer (CRC) stem cells rapidly repair the stalled/collapsed replication forks and overcome treatment effects. Recent evidence suggests a critical role of checkpoint kinase 1 (Chk1) in preventing the replicative stress. Therefore, Chk1 kinase has been a target for developing mono or combination therapeutic agents. In the present study, we have identified a novel orphan molecule NSC30049 (NSC49L) that is effective alone, and in combination potentiates 5-FU-mediated growth inhibition of CRC heterogeneous bulk and FOLFOX-resistant cell lines in culture with minimal effect on normal colonic epithelial cells. It also inhibits the sphere forming activity of CRC stem cells, and decreases the expression levels of mRNAs of CRC stem cell marker genes. Results showed that NSC49L induces 5-FU-mediated S-phase cell cycle arrest due to increased load of DNA damage and increased γ-H2AX staining as a mechanism of cytotoxicity. The pharmacokinetic analysis showed a higher bioavailability of this compound, however, with a short plasma half-life. The drug is highly tolerated by animals with no pathological aberrations. Furthermore, NSC49L showed very potent activity in a HDTX model of CRC stem cell tumors either alone or in combination with 5-FU. Thus, NSC49L as a single agent or combined with 5-FU can be developed as a therapeutic agent by targeting the Chk1 pathway in 5-FU-resistant CRC heterogeneous bulk and CRC stem cell populations.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.