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Updated: Oct 11, 2025
Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
Published on: May 9, 2025
The Dual Histone Deacetylase-Proteasome Inhibitor RTS-V5 Acts Synergistically With Ritonavir to Induce Endoplasmic
Kazuki Okubo1, Nina REßING2, Wolfgang A Schulz3
1Department of Urology, National Defense Medical College, Tokorozawa, Japan.
Background/Aim:
Simultaneous inhibition of histone deacetylase and proteasomes induces endoplasmic reticulum (ER) stress efficiently. RTS-V5 is the first dual histone deacetylase-proteasome inhibitor, and we anticipated that combining it with the cytochrome P450 family 3 subfamily A member 4 inhibitor ritonavir would enhance its activity in bladder cancer cells.
Materials And Methods:
Using bladder cancer cells (human T-24, J-82, murine MBT-2), we evaluated the ability and mechanism by which the combination of RTS-V5 and ritonavir induced ER stress and killed cancer cells.
Results:
The combination of RTS-V5 and ritonavir triggered robust apoptosis and inhibited bladder cancer growth effectively in vitro and in vivo. It caused ubiquitinated protein accumulation and induced ER stress synergistically. The combination inhibited the mammalian target of rapamycin pathway by increasing the expression of AMP-activated protein kinase. We also found that the combination caused histone and tubulin hyperacetylation.
Conclusion:
Ritonavir enhances the ability of RTS-V5 to cause ER stress in bladder cancer cells.
Insights
Combining RTS-V5, a dual histone deacetylase-proteasome inhibitor, with ritonavir effectively kills bladder cancer cells. This combination enhances endoplasmic reticulum (ER) stress, leading to apoptosis and inhibited tumor growth.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Simultaneous inhibition of histone deacetylase and proteasomes effectively induces endoplasmic reticulum (ER) stress.
- RTS-V5 is a novel dual inhibitor targeting both histone deacetylase and proteasomes.
- Ritonavir, a cytochrome P450 3A4 inhibitor, was investigated for its potential to enhance RTS-V5 activity.
Purpose of the Study:
- To evaluate the synergistic effect of combining RTS-V5 and ritonavir in bladder cancer cells.
- To elucidate the mechanism by which this combination induces ER stress and cell death.
- To assess the in vitro and in vivo efficacy of the combination therapy.
Main Methods:
- Utilized human (T-24, J-82) and murine (MBT-2) bladder cancer cell lines.
- Assessed apoptosis, cell growth inhibition, ubiquitinated protein accumulation, and ER stress markers.
- Investigated effects on the mammalian target of rapamycin (mTOR) pathway and AMP-activated protein kinase (AMPK) expression.
- Examined histone and tubulin acetylation levels.
Main Results:
- The combination of RTS-V5 and ritonavir demonstrated robust apoptosis induction and significant inhibition of bladder cancer cell growth in vitro and in vivo.
- Synergistic induction of ER stress and accumulation of ubiquitinated proteins were observed.
- The combination therapy inhibited the mTOR pathway by upregulating AMPK.
- Histone and tubulin hyperacetylation was a notable outcome of the combined treatment.
Conclusions:
- Ritonavir significantly enhances the endoplasmic reticulum (ER) stress-inducing capability of RTS-V5 in bladder cancer cells.
- The combination therapy represents a promising strategy for bladder cancer treatment by targeting multiple cellular pathways.
- Further investigation into this synergistic approach is warranted for clinical translation.
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