ArticleBMC cancer2015
Enhancement of hypoxia-activated prodrug TH-302 anti-tumor activity by Chk1 inhibition.
Article in BMC cancer, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers, 1 of them a synthesis that pooled it.
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Who cites it
18 citing papers in PubMed, 1 synthesis or guideline pooled it, 24 citations in OpenAlex.
- Targeting Hypoxia: Hypoxia-Activated Prodrugs in Cancer Therapy.Frontiers in oncology · 2021Pooled it
- ROS homeostasis in cell fate, pathophysiology, and therapeutic interventions.Molecular biomedicine · 2025Review
- In vitro and in silico evaluation of synthesized 4-Anilinoquinazoline derivatives as potential anticancer agents.Journal of computer-aided molecular design · 2025Article
- Enhanced pharmacological activities of AKR1C3-activated prodrug AST-3424 in cancer cells with defective DNA repair.International journal of cancer · 2025Article
- Hypoxia-Responsive Prodrug of ATR Inhibitor, AZD6738, Selectively Eradicates Treatment-Resistant Cancer Cells.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Recent Advances in the Application of Nitro(het)aromatic Compounds for Treating and/or Fluorescent Imaging of Tumor Hypoxia.Molecules (Basel, Switzerland) · 2024Review
- Glioblastoma: Current Status, Emerging Targets, and Recent Advances.Journal of medicinal chemistry · 2022Review
- A novel selective AKR1C3-activated prodrug AST-3424/OBI-3424 exhibits broad anti-tumor activity.American journal of cancer research · 2021Article
- The Interplay Between Tumor Suppressor p53 and Hypoxia Signaling Pathways in Cancer.Frontiers in cell and developmental biology · 2021Review
- Hypoxia-activated prodrugs and (lack of) clinical progress: The need for hypoxia-based biomarker patient selection in phase III clinical trials.Clinical and translational radiation oncology · 2019Article
- The clinical significance of CHEK1 in breast cancer: a high-throughput data analysis and immunohistochemical study.International journal of clinical and experimental pathology · 2019Article
- MEK inhibition leads to BRCA2 downregulation and sensitization to DNA damaging agents in pancreas and ovarian cancer models.Oncotarget · 2018Article
- Radiotherapy Synergizes with the Hypoxia-Activated Prodrug Evofosfamide: In Vitro and In Vivo Studies.Antioxidants & redox signaling · 2018Article
- Molecular Pathways: Hypoxia-Activated Prodrugs in Cancer Therapy.Clinical cancer research : an official journal of the American Association for Cancer Research · 2017Review
- Engineered Breast Cancer Cell Spheroids Reproduce Biologic Properties of Solid Tumors.Advanced healthcare materials · 2016Article
- Birinapant (TL32711) Improves Responses to GEM/AZD7762 Combination Therapy in Triple-negative Breast Cancer Cell Lines.Anticancer research · 2016Article
- Anticancer efficacy of the hypoxia-activated prodrug evofosfamide (TH-302) in osteolytic breast cancer murine models.Cancer medicine · 2016Article
- Targeting the hypoxic fraction of tumours using hypoxia-activated prodrugs.Cancer chemotherapy and pharmacology · 2016Review
Corrections and comments
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundThe hypoxia-activated prodrug TH-302 is reduced at its nitroimidazole group and selectively under hypoxic conditions releases the DNA cross-linker bromo-isophosphoramide mustard (Br-IPM). Here, we have explored the effect of Chk1 inhibition on TH-302-mediated pharmacological activities.
methodsWe employed in vitro cell viability, DNA damage, cellular signaling assays and the in vivo HT29 human tumor xenograft model to study the effect of Chk1inhibition on TH-302 antitumor activities.
resultsTH-302 cytotoxicity is greatly enhanced by Chk1 inhibition in p53-deficient but not in p53-proficient human cancer cell lines. Chk1 inhibitors reduced TH-302-induced cell cycle arrest via blocking TH-302-induced decrease of phosphorylation of histone H3 and increasing Cdc2-Y15 phosphorylation. Employing the single-cell gel electrophoresis (comet) assay, we observed a potentiation of the TH-302 dependent tail moment. TH-302 induced γH2AX and apoptosis were also increased upon the addition of Chk1 inhibitor. Potentiation of TH-302 cytotoxicity by Chk1 inhibitor was only observed in cell lines proficient in, but not deficient in homology-directed DNA repair. We also show that combination treatment led to lowering of Rad51 expression levels as compared to either agent alone. In vivo data demonstrate that Chk1 inhibitor enhances TH-302 anti-tumor activity in p53 mutant HT-29 human tumor xenografts, supporting the hypothesis that these in vitro results can translate to enhanced in vivo efficacy of the combination.
conclusionsTH-302-mediated in vitro and in vivo anti-tumor activities were greatly enhanced by the addition of Chk1 inhibitors. The preclinical data presented in this study support a new approach for the treatment of p53-deficient hypoxic cancers by combining Chk1 inhibitors with the hypoxia-activated prodrug TH-302.
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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.