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Reversing Bladder Cancer Chemo-resistance through Blocking Cell Senescence by a Combination Therapy
Yirui He1, Zaixiang Fang1, Jiapeng Zhang1
1Department of Urology, Department of Radiology, Institution of Radiology and Medical Imaging, Huaxi MR Research Center (HMRRC), Department of Hematology, Frontiers Science Center for Disease-Related Molecular Network, National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
Theranostics
|June 5, 2026
Summary
Histone deacetylase inhibitors (HDACis) combined with chemotherapy can overcome chemoresistance in bladder cancer. This epigenetic therapy targets the HDAC-p21-senescence axis, restoring sensitivity to drugs like paclitaxel.
Area of Science:
- Oncology
- Epigenetics
- Cancer Therapeutics
Background:
- Chemoresistance is a major challenge in advanced bladder cancer treatment.
- Histone deacetylases (HDACs) are implicated in tumor progression and treatment resistance, but their role in acquired chemoresistance is not fully understood.
Purpose of the Study:
- To investigate if epigenetic modulation can restore chemotherapy sensitivity in drug-refractory bladder cancer.
- To explore the role of HDACs in acquired chemoresistance.
Main Methods:
- Analyzed HDAC1-3 expression in bladder cancer tissues and correlated it with clinical outcomes.
- Developed and evaluated a co-delivery strategy combining the pan-HDAC inhibitor belinostat (PXD101) with paclitaxel (PTX) in patient-derived organoids and xenograft models.
- Performed functional assays and genetic experiments to understand underlying mechanisms.
Main Results:
- HDAC1-3 were upregulated in bladder cancer tissues, associated with poor prognosis and chemoresistance signatures.
- Combined PXD101 and PTX treatment suppressed tumor growth in models, showing better tolerability than standard regimens.
- PXD101 reduced CDKN1A/p21 expression, restoring paclitaxel's antimitotic activity, with p21 identified as a key regulator of chemoresistance.
Conclusions:
- An HDAC-p21-senescence axis sustains chemoresistance in bladder cancer.
- Combined epigenetic and antimitotic therapy is a promising strategy to overcome acquired drug resistance in bladder cancer.
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