TLR4 Blockade Using Docosahexaenoic Acid Restores Vulnerability of Drug-Tolerant Tumor Cells and Prevents Breast...

Area of Science:

• Oncology
• Immunology
• Pharmacology

Background:

• Nonmutational drug tolerance allows a subpopulation of cancer cells to survive chemotherapy, potentially leading to resistance and relapse.
• Signaling pathways, including inflammatory responses, contribute to the phenotypic switch enabling drug tolerance.
• Toll-like receptor 4 (TLR4) activation is implicated in promoting drug tolerance in cancer cells.

Purpose of the Study:

• To investigate the potential of docosahexaenoic acid (DHA) to restore doxorubicin (DOX) efficacy in drug-tolerant breast cancer cells.
• To evaluate the combined effects of DHA and DOX on primary tumor growth, metastasis, and recurrence in preclinical models.
• To assess the safety and efficacy of co-encapsulated DHA and DOX in a nanoemulsion formulation.

Main Methods:

• Utilized the 4T1 breast tumor cell line, known for developing drug tolerance.
• Administered DHA in combination with DOX to lipopolysaccharide-treated 4T1 cells and in orthotopic and metastasis models.
• Investigated tumor growth, lung metastasis, tumor recurrence post-surgery, and systemic toxicity in mouse models.
• Co-encapsulated DHA and DOX in a nanoemulsion for enhanced delivery and reduced toxicity.

Main Results:

• DHA restored the cytotoxic effect of DOX in 4T1 cells, preventing the switch to a drug-tolerant phenotype.
• The DHA + DOX combination significantly reduced primary tumor growth and lung metastasis.
• DHA + DOX delayed and inhibited tumor recurrence after surgical removal of primary tumors.
• Co-encapsulated DHA + DOX in nanoemulsions prolonged survival in a postsurgical relapse model with reduced systemic toxicity.

Conclusions:

• DHA acts as a TLR4-interacting lipid that sensitizes breast cancer cells to doxorubicin, overcoming drug tolerance.
• The synergistic combination of DHA and DOX demonstrates significant antitumor, antimetastasis, and antirecurrence effects.
• Targeting TLR4 activation with DHA offers a promising strategy to enhance chemotherapy efficacy and prevent tumor relapse.