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Stat3 Inhibitors TTI-101 and SH5-07 Suppress Bladder Cancer Cell Survival in 3D Tumor Models
Surya P Singh1,2, Gopal Pathuri1,2, Adam S Asch2
1Center for Cancer Prevention and Drug Development, Stephenson Cancer Center, Hem-Onc Section, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
Cells
|September 14, 2024
Summary
Targeting the STAT3 pathway with TTI-101 and SH5-07 effectively reduced bladder cancer (BCa) cell proliferation and induced cell death. These small-molecule inhibitors also suppressed cancer stem cells (CSCs) in 3D models.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Bladder cancer (BCa) is a lethal malignancy with high recurrence and poor survival rates.
- The signal transducer and activator of transcription 3 (STAT3) pathway is implicated in BCa proliferation, invasion, and chemoresistance.
Purpose of the Study:
- To investigate the efficacy of STAT3 inhibitors TTI-101 and SH5-07 in bladder cancer.
- To elucidate the underlying mechanisms of action in three-dimensional (3D) models.
Main Methods:
- Optimized growth of BCa spheroids and organoids from human, rat, and mouse cell lines.
- Assessed cell viability, mitochondrial function (ATP, ROS, calcium), and pharmacodynamic markers via Western blot.
- Evaluated STAT3 signaling, proliferation, apoptosis, and cancer stem cell markers (CD44, CD133).
Main Results:
- STAT3 inhibition by TTI-101 and SH5-07 significantly reduced BCa spheroid and organoid proliferation.
- Inhibitors decreased pSTAT3, Cyclin D1, and PCNA expression, while inducing ROS production and cell death.
- STAT3 inhibition triggered apoptosis via caspase 3/7 activation and PARP cleavage, and suppressed CSC markers.
Conclusions:
- TTI-101 and SH5-07 demonstrate significant anti-cancer effects in 3D BCa models.
- These inhibitors target STAT3 signaling and cancer stem cells, offering a potential therapeutic strategy for bladder cancer.
