Nitazoxanide and related thiazolides induce cell death in cancer cells by targeting the 20S proteasome with novel binding modes

Nitazoxanide and related thiazolides are a novel class of anti-infectious agents against protozoan parasites, bacteria and viruses. In recent years, it is demonstrated that thiazolides can also induce cell cycle arrest and apoptotic cell death in cancer cells. Due to their fast proliferating nature, cancer cells highly depend on the proteasome system to remove aberrant proteins. Many of these aberrant proteins are regulators of cell cycle progression and apoptosis, such as the cyclins, BCL2 family members and nuclear factor of kappa B (NF-kappa B). Here, we demonstrate at both molecular and cellular levels that the 20S proteasome is a direct target of NTZ and related thiazolides. By concurrently inhibiting the multiple catalytic subunits of 20S proteasome, NTZ promotes cell cycle arrest and triggers cell death in colon cancer cells, either directly or as a sensitizer to other anti-tumor agents, especially doxorubicin. We further show that the binding mode of NTZ in the beta 5 subunit of the 20S proteasome is different from that of bortezomib and other existing proteasome inhibitors. These findings provide new insights in the design of novel small molecular proteasome inhibitors as anti-tumor agents suitable for solid tumor treatment in an oral dosing form.

Automated summary

Nitazoxanide and related thiazolides are effective against protozoan parasites, bacteria, and viruses, and have also shown potential in inducing cell cycle arrest and apoptosis in cancer cells. This study reveals that the 20S proteasome is a direct target of these compounds, leading to cell cycle arrest and cell death in colon cancer cells. The binding mode of these compounds in the 20S proteasome is different from existing proteasome inhibitors, providing insights for the design of novel anti-tumor agents.