Tacrolimus inhibits oral carcinogenesis through cell cycle control

Area of Science:

• Immunology
• Oncology
• Pharmacology

Background:

• Tacrolimus (TAC, FK506) is a calcineurin inhibitor used for organ transplants and immune diseases.
• Guidelines recommend TAC for oral potentially malignant disorders (OPMDs) like oral lichen planus (OLP).
• The oncogenic risk of TAC remains controversial.

Purpose of the Study:

• To investigate the effect of tacrolimus on oral carcinogenesis.
• To determine if tacrolimus impacts cell proliferation and the cell cycle in oral squamous cell carcinoma (OSCC) progression.

Main Methods:

• Utilized a 4-Nitroquinoline N-oxide (4NQO)-induced oral carcinogenesis model in rats.
• Assessed cancer formation rates, Ki67 and proliferation cell nuclear antigen (PCNA) expression.
• Analyzed liver, kidney, lung function, and tumor immune microenvironment.
• Investigated cell cycle progression and protein expression (cyclinD1, cyclinE1, c-Myc) in vitro and in vivo.

Main Results:

• Tacrolimus treatment significantly reduced oral cancer formation (52.94% vs. 90%) and decreased Ki67/PCNA-positive cells.
• No adverse effects were observed on rat organ functions or the tumor immune microenvironment.
• Tacrolimus induced G1/S phase arrest and downregulated cyclinD1, cyclinE1, and c-Myc expression, inhibiting cell proliferation.

Conclusions:

• Tacrolimus effectively blocks oral carcinogenesis by inhibiting epithelial cell proliferation, independent of immunosuppression.
• The drug is a safe therapeutic strategy for OPMDs, retarding oral cell carcinogenesis.
• Tacrolimus-induced G1/S phase arrest via cyclin/c-Myc inhibition supports its safety in OPMD treatment.