ArticleMolecular cancer2016
ERK mediated upregulation of death receptor 5 overcomes the lack of p53 functionality in the diaminothiazole DAT1 induced apoptosis in colon cancer models: efficiency of DAT1 in Ras-Raf mutated cells.
Article in Molecular cancer, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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8 citing papers in PubMed, 16 citations in OpenAlex.
- Unveiling the Therapeutic Potential of Compounds Carrying Mono- and Bis-Thiazole Nuclei with Distinct Heterocyclic Analogues for Addressing Cancer Challenges.Current cancer drug targets · 2026Review
- Antiproliferative and Pro-Apoptotic Effects ofMetabolites · 2025Article
- A Positive Feedback DNA-PK/MYT1L-CXCR1-ERK1/2 Proliferative Signaling Loop in Glioblastoma.International journal of molecular sciences · 2025Article
- PLEKHA4 knockdown induces apoptosis in melanoma cells through the MAPK and β‑catenin signaling pathways.Molecular medicine reports · 2025Article
- Thiazole, Isatin and Phthalimide Derivatives TestedCurrent medicinal chemistry · 2024Review
- Enhancement of Apo2L/TRAIL signaling pathway receptors by the activation of Klotho gene with CRISPR/Cas9 in Caco-2 colon cancer cells.Medical oncology (Northwood, London, England) · 2021Article
- N-myc downstream-regulated gene 1 promotes apoptosis in colorectal cancer via up-regulating death receptor 4.Oncotarget · 2017Article
- α-Fodrin-CENP-E interaction is critical for pancreatic cancer progression and drug response.Cell cycle (Georgetown, Tex.)Article
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4 authors at 2 institutions in 1 country.
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Abstract
backgroundp53 is a tumour suppressor protein that plays a key role in many steps of apoptosis, and malfunctioning of this transcription factor leads to tumorigenesis. Prognosis of many tumours also depends upon the p53 status. Most of the clinically used anticancer compounds activate p53 dependent pathway of apoptosis and hence require p53 for their mechanism of action. Further, Ras/Raf/MEK/ERK axis is an important signaling pathway activated in many cancers. Dependence of diaminothiazoles, compounds that have gained importance recently due to their anticancer and anti angiogenic activities, were tested in cancer models with varying p53 or Ras/Raf mutational status.
methodsIn this study we have used p53 mutated and knock out colon cancer cells and xenograft tumours to study the role of p53 in apoptosis mediated by diaminothiazoles. Colon cancer cell lines with varying mutational status for Ras or Raf were also used. We have also examined the toxicity and in vivo efficacy of a lead diaminothiazole 4-Amino-5-benzoyl-2-(4-methoxy phenylamino)thiazole (DAT1) in colon cancer xenografts.
resultsWe have found that DAT1 is active in both in vitro and in vivo models with nonfunctional p53. Earlier studies have shown that extrinsic pathway plays major role in DAT1 mediated apoptosis. In this study, we have found that DAT1 is causing p53 independent upregulation of the death receptor 5 by activating the Ras/Raf/MEK/ERK signaling pathway both in wild type and p53 suppressed colon cancer cells. These findings are also confirmed by the in vivo results. Further, DAT1 is more efficient to induce apoptosis in colon cancer cells with mutated Ras or Raf.
conclusionsMinimal toxicity in both acute and subacute studies along with the in vitro and in vivo efficacy of DAT1 in cancers with both wild type and nonfunctional p53 place it as a highly beneficial candidate for cancer chemotherapy. Besides, efficiency in cancer cells with mutations in the Ras oncoprotein or its downstream kinase Raf raise interest in diaminothiazole class of compounds for further follow-up.
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