The Dual Histone Deacetylase-Proteasome Inhibitor RTS-V5 Acts Synergistically With Ritonavir to Induce Endoplasmic...

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.