Targeted BRD4 degradation by multivalent dendrimer-based PROTAC and its combined effects with chemotherapy on colon...

Chemoresistance, often driven by aberrant transcriptional and epigenetic mechanisms, remains a significant barrier to effective colon cancer therapy. This study introduces a dendrimer-based proteolysis-targeting chimera (PROTAC) system, JTP, generated by conjugation of polyamidoamine (PAMAM-G4) dendrimer with 4-hydroxythalidomide (an E3 ligase recruiter) and JQ1 carboxylic acid (a BRD4 inhibitor). The multivalent dendrimer scaffold increases local surface ligand density, promotes endocytic uptake and endosomal escape, and facilitates cytosolic engagement of BRD4 for proteasome-mediated degradation. In vitro, JTP effectively increased the chemosensitivity of CT26 colon cancer cells to chemotherapy, particularly to irinotecan, leading to enhanced DNA damage, cell cycle arrest in the S and G2/M phases, and apoptosis, as well as a synergistic reduction in oncoprotein expression. In vivo studies in orthotopic colon cancer-bearing mice demonstrated a prominent antitumor effect of JTP in combination with irinotecan, yielding marked inhibition of tumors and metastases and promoting long-term survival, with toxicity within a well-tolerated range. The in vivo studies also demonstrated the robust effects of JTP on reducing the expression of TFEB, c-Myc, β-catenin, Bcl-2, VEGFR2, IL-1β, TNF-α, HIF-1α, and vimentin by BRD4 elimination in tumor tissues. These findings demonstrate that combining JTP with epigenetic modulation offers an effective strategy to promote chemotherapeutic effects in colon cancer.