Hemiprotonic ph-ph⁺ with two targets inhibits metastatic breast cancer and concurrent candidiasis

Area of Science:

• Oncology
• Infectious Diseases
• Pharmacology

Background:

• Concurrent infections significantly increase mortality in breast cancer patients.
• Current treatments lack efficacy in managing both breast cancer and infections simultaneously.
• Metastatic breast cancer with concurrent infections presents a critical unmet medical need.

Purpose of the Study:

• To investigate a novel one-drug, dual-target strategy for treating concurrent breast cancer and fungal infections.
• To explore the efficacy of the small chemical ph-ph+ as a combined anticancer and antifungal agent.
• To elucidate the molecular mechanisms underlying the action of ph-ph+.

Main Methods:

• Utilized ph-ph+ in preclinical models to assess its effects on breast cancer cell proliferation, metastasis, and Candida albicans.
• Investigated the activation of the protease CLpP in both cancer cells and C. albicans.
• Analyzed the role of the PLAGL2 signaling pathway in mediating ph-ph+'s anticancer effects.
• Evaluated the in vivo efficacy of ph-ph+ in experimental animals with metastatic breast cancer and infection.

Main Results:

• Ph-ph+ demonstrated significant inhibition of breast cancer cell proliferation and metastasis.
• Ph-ph+ exhibited potent antifungal activity against C. albicans.
• The drug's mechanism involves activating CLpP in both cancer and fungal cells and engaging the PLAGL2 pathway in cancer cells.
• In vivo studies showed that ph-ph+ suppressed tumor growth, metastasis, and eliminated C. albicans.

Conclusions:

• Ph-ph+ represents a promising therapeutic candidate for treating metastatic breast cancer with concurrent fungal infections.
• The dual-targeting strategy of ph-ph+ offers a novel approach to enhance survival rates in complex patient cases.
• Targeting both CLpP and PLAGL2 provides a feasible strategy for managing refractory breast cancer and associated infections.