ArticleCancer science2013
Novel MEK inhibitor trametinib and other retinoblastoma gene (RB)-reactivating agents enhance efficacy of 5-fluorouracil on human colon cancer cells.
Article in Cancer science, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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32 citing papers in PubMed, 49 citations in OpenAlex.
- Caffeic acid suppresses cyclin D1 expression by directly binding to ribosomal protein S5 in colorectal cancer cells.Scientific reports · 2026Article
- Differential Preclinical Efficacy of Combined CDK4/6 and MEK Inhibition in Low-Grade Serous Ovarian Carcinoma Based onInternational journal of molecular sciences · 2026Article
- Combination of AURKA inhibitor and MEK inhibitor strongly enhances G1 arrest and induces synergistic antitumor effect onBiochemistry and biophysics reports · 2025Article
- The kinase ERK plays a conserved dominant role in the heterogeneity of epithelial-mesenchymal transition in pancreatic cancer cells.Science signaling · 2025Article
- Capacity for Compensatory Cyclin D2 Response Confers Trametinib Resistance in Canine Mucosal Melanoma.Cancers · 2025Article
- Capacity for compensatory cyclin D2 response confers trametinib resistance in canine mucosal melanoma.bioRxiv : the preprint server for biology · 2025Article
- Establishment and characterization of patient-derived xenograft of a rare pediatric anaplastic pleomorphic xanthoastrocytoma (PXA) bearing a CDC42SE2-BRAF fusion.Scientific reports · 2023Article
- Molecular-Targeted Therapy for Tumor-Agnostic Mutations in Acute Myeloid Leukemia.Biomedicines · 2022Review
- A chemoproteoinformatics approach demonstrates that aspirin increases sensitivity to MEK inhibition by directly binding to RPS5.PNAS nexus · 2022Article
- CDK Inhibition Reverses Acquired 5-Fluorouracil Resistance in Hepatocellular Carcinoma Cells.Disease markers · 2022Article
- Article
- Overexpression of sortilin is associated with 5-FU resistance and poor prognosis in colorectal cancer.Journal of cellular and molecular medicine · 2021Article
- An Update on the Potential Roles of E2F Family Members in Colorectal Cancer.Cancer management and research · 2021Review
- MEK blockade overcomes the limited activity of palbociclib in head and neck cancer.Translational oncology · 2020Article
- MEK Inhibitor Augments Antitumor Activity of B7-H3-Redirected Bispecific Antibody.Frontiers in oncology · 2020Article
- MEK inhibitor enhanced the antitumor effect of oxaliplatin and 5‑fluorouracil in MEK1 Q56P‑mutant colorectal cancer cells.Molecular medicine reports · 2019Article
- Aberrant modulation of ribosomal protein S6 phosphorylation confers acquired resistance to MAPK pathway inhibitors in BRAF-mutant melanoma.Acta pharmacologica Sinica · 2019Article
- Therapeutic potential of combined BRAF/MEK blockade in BRAF-wild type preclinical tumor models.Journal of experimental & clinical cancer research : CR · 2018Article
- RAS-MAPK Reactivation Facilitates Acquired Resistance inMolecular cancer therapeutics · 2018Article
- System identification of signaling dependent gene expression with different time-scale data.PLoS computational biology · 2017Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Chemotherapy for colorectal cancer has become more complicated and diversified with the appearance of molecular-targeting agents. 5-Fluorouracil (5-FU) has been a mainstay of chemotherapy for colorectal cancer, but it is still unknown whether the combining of 5-FU with novel molecular-targeting agents is effective. Thymidylate synthase (TS) is a direct target of 5-FU, and the low TS level has been generally supposed to sensitize 5-FU's efficacy. We therefore hypothesized that RB-reactivating agents could enhance the efficacy of 5-FU, because the RB-reactivating agents could suppress the function of transcription factor E2F of TS gene promoter. We used three RB-reactivating agents, trametinib/GSK1120212 (MEK inhibitor), fenofibrate (PPARα agonist), and LY294002 (PI3K inhibitor), with 5-FU against human colon cancer HT-29 and HCT15 cells. Trametinib induced p15 and p27 expression and reduced cyclin D1 levels in HT-29 cells. Fenofibrate also dephosphorlated ERK1/2 and reduced cyclin D1 levels in HT-29 cells. LY294002 induced p27 expression in HCT15 cells. All three agents caused dephosphorylation of RB protein and G1-phase arrest with a reduction of TS expression. As a consequence, the combination of 5-FU with each of the agents resulted in a significant decrease of colony numbers in HT-29 or HCT15 cells. These results suggest "RB-reactivation therapy" using molecular-targeting agents to be a new strategy for 5-FU-based chemotherapy. In particular, we strongly expect trametinib, which was discovered in Japan and was recently submitted to FDA for approval, to be used together with established regimens for colorectal cancer.
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