Platinum-containing compound platinum pyrithione is stronger and safer than cisplatin in cancer therapy

Area of Science:

• Biochemistry
• Oncology
• Medicinal Chemistry

Background:

• Platinum-based chemotherapy, while effective, faces limitations due to systemic toxicities and drug resistance stemming from non-selective DNA damage.
• Existing strategies to overcome platinum chemotherapy shortcomings have not fully resolved the inherent issues of DNA targeting.

Purpose of the Study:

• To investigate platinum pyrithione (PtPT) as a novel platinum-based anticancer agent with a different mechanism of action.
• To evaluate the selective cytotoxicity and safety profile of PtPT compared to cisplatin and bortezomib.

Main Methods:

• Assessing cytotoxicity of PtPT against various cancer cells and normal human cells.
• Investigating the molecular mechanism of PtPT, focusing on proteasome function and deubiquitinase activity (USP14, UCHL5).
• Evaluating in vivo efficacy and toxicity of PtPT in a tumor xenograft mouse model.

Main Results:

• PtPT demonstrated greater and more selective cytotoxicity to cancer cells than cisplatin, without causing discernible DNA damage.
• PtPT selectively inhibited proteasome-associated deubiquitinases USP14 and UCHL5, unlike bortezomib which targets 20S proteasome peptidase activity.
• PtPT showed selective toxicity towards leukemia patient cancer cells versus healthy donor cells and inhibited tumor xenograft growth in mice without cisplatin-induced adverse effects.

Conclusions:

• PtPT represents a new class of platinum-based anticancer drugs targeting 26S proteasome-associated deubiquitinases, offering a safer and more potent therapeutic strategy.
• The novel mechanism of action, avoiding DNA damage, circumvents key limitations of traditional platinum chemotherapy.
• PtPT shows significant potential for clinical translation as a next-generation platinum-based anticancer agent.