Ritonavir and ixazomib kill bladder cancer cells by causing ubiquitinated protein accumulation

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Advanced bladder cancer lacks curative treatments.
• Targeting protein degradation pathways is a novel therapeutic strategy.
• Ritonavir, an HIV protease inhibitor, can induce unfolded protein accumulation.

Purpose of the Study:

• To investigate the synergistic effect of ixazomib and ritonavir on bladder cancer cells.
• To determine if this combination induces ubiquitinated protein accumulation and endoplasmic reticulum stress.
• To explore the underlying mechanisms of the combination's anti-cancer activity.

Main Methods:

• Combination treatment of bladder cancer cells with ixazomib and ritonavir.
• Assessment of apoptosis, cell growth inhibition, and cell cycle progression.
• Analysis of protein expression, ubiquitinated protein levels, and endoplasmic reticulum stress markers.
• Evaluation of histone acetylation and histone deacetylase expression.

Main Results:

• The combination of ixazomib and ritonavir synergistically induced apoptosis and inhibited bladder cancer cell growth.
• The treatment led to ubiquitinated protein accumulation and endoplasmic reticulum stress.
• Combination therapy decreased cyclin D1 and cyclin-dependent kinase 4 expression and increased the sub-G1 fraction.
• The anti-cancer effect was dependent on the accumulation of ubiquitinated proteins and involved histone acetylation.

Conclusions:

• Ixazomib and ritonavir combination therapy is a promising strategy for advanced bladder cancer.
• The mechanism involves inducing ubiquitinated protein accumulation and endoplasmic reticulum stress.
• This approach provides a theoretical basis for developing new therapies targeting protein degradation pathways in bladder cancer.