ArticleMolecular and cellular biochemistry2016
Elucidation of a novel phenformin derivative on glucose-deprived stress responses in HT-29 cells.
Article in Molecular and cellular biochemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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7 citing papers in PubMed, 9 citations in OpenAlex.
- Characterization of Novel Decenoic Acid Derivatives Exhibiting Cytotoxic Activity Against T98G Glioma Cells Under a Serum- and Glucose-deprived Condition.Cell biochemistry and biophysics · 2026Article
- Investigation of MANF regulation of glioma stemness via STAT3/TGF-β/SMAD4/p38 pathway based on pan-cancer analysis.Translational oncology · 2025Article
- Progress in antitumor mechanisms and applications of phenformin (Review).Oncology reports · 2024Review
- Development of antitumor biguanides targeting energy metabolism and stress responses in the tumor microenvironment.Scientific reports · 2021Article
- The Exploration of Natural Compounds for Anti-Diabetes from Distinctive Species GarciniaBiomolecules · 2019Review
- Expression analysis and functional characterization of the mouse cysteine-rich with EGF-like domains 2.Scientific reports · 2018Article
- Application of a novel HiBiT peptide tag for monitoring ATF4 protein expression in Neuro2a cells.Biochemistry and biophysics reports · 2017Article
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7 authors at 3 institutions in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
Recently, we developed a variety of phenformin derivatives as selective antitumor agents. Based on previous findings, this study evaluated a promising compound, 2-(2-chlorophenyl)ethylbiguanide (2-Cl-Phen), on the basis of stress responses in the human colon cancer cell line HT-29 under a serum- and glucose-deprived condition. 2-Cl-Phen triggered morphological changes such as shrinkage and plasma membrane disintegration, as well as a decrease in mitochondrial activity and an increase in LDH leakage. To understand intracellular issues relating to 2-Cl-Phen, this study focused on the expression levels of ER stress-inducible genes and several oncogenic genes. Serum and glucose deprivation significantly induced a variety of ER stress-inducible genes, but a 12-h treatment of 2-Cl-Phen down-regulated expression of several ER stress-related genes, with the exception of GADD153. Interestingly, the expression levels of ATF6α, GRP78, MANF, and CRELD2 mRNA were almost completely decreased by 2-Cl-Phen. This study also observed that a 24-h treatment of 2-Cl-Phen attenuated the expression levels of GRP78, GADD153, and c-Myc protein. The decrease in c-Myc protein occurred before the fluctuation of GRP78 protein, while the expression of c-Myc mRNA showed little change with cotreatment of serum and glucose deprivation with 2-Cl-Phen. To further understand the 2-Cl-Phen-induced down-regulation of ATF6-related genes, this study investigated the stability of ATF6α and GRP78 proteins using NanoLuc-tagged constructs. The expression levels of NanoLuc-tagged ATF6α and GRP78 were significantly down-regulated by 2-Cl-Phen in the presence or absence of the translation inhibitor cycloheximide. Taken together, our novel phenformin derivative 2-Cl-Phen has the unique characteristic of diminishing tumor adaptive responses, especially the expression of ATF6-related genes, as well as that of c-Myc protein, in a transcriptional and posttranscriptional manner under a serum- and glucose-deprived condition. Further characterization of cytotoxic mechanisms related to phenformin derivatives may give new insights into developing additional promising anticancer agents.
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