Targeting the NRF2 pathway with linagliptin to inhibit human hepatocellular carcinoma growth

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality.
• Dipeptidyl peptidase 4 (DPP4) inhibitors are established treatments for type 2 diabetes.
• Exploring novel therapeutic strategies for HCC is critical.

Purpose of the Study:

• To investigate the anti-cancer effects of linagliptin on hepatocellular carcinoma (HCC) cell lines.
• To elucidate the underlying mechanisms, including reactive oxygen species (ROS) production, NRF2 pathway activation, and autophagy.
• To evaluate the efficacy of linagliptin in combination with NRF2 inhibitors in HCC models.

Main Methods:

• In vitro studies using HCC cell lines (e.g., Hep3B) exposed to linagliptin.
• Assessment of cell proliferation, apoptosis, ROS levels, NRF2 pathway activation, and autophagy.
• In vivo studies using a xenograft mouse model of HCC.
• Combination therapy experiments with linagliptin and brusatol (NRF2 inhibitor).

Main Results:

• Linagliptin significantly inhibited HCC cell proliferation and induced apoptosis, while sparing normal liver cells.
• Linagliptin treatment increased ROS production and activated the NRF2 pathway and autophagy in HCC cells.
• Combination therapy with linagliptin and brusatol demonstrated synergistic anti-tumor effects in vitro and in vivo.
• Linagliptin alone reduced tumor growth in the xenograft model.

Conclusions:

• Linagliptin exhibits significant therapeutic potential as an anti-cancer agent for HCC.
• Linagliptin's anti-tumor activity involves ROS induction, NRF2 pathway activation, and autophagy modulation.
• Combining linagliptin with NRF2 inhibitors like brusatol enhances its efficacy against HCC, warranting further clinical investigation.