Hyperglycemia decreases anti-cancer efficiency of Adriamycin via AMPK pathway

Area of Science:

• Oncology
• Metabolic Disorders
• Molecular Biology

Background:

• Diabetic liver cancer patients exhibit reduced sensitivity to intra-arterial chemotherapy.
• The molecular mechanisms underlying this diminished chemotherapeutic response remain largely unknown.

Purpose of the Study:

• To investigate the impact of hyperglycemia on Adriamycin (ADR) chemotherapeutic sensitivity in liver cancer.
• To elucidate the role of the AMPK pathway in mediating this effect.

Main Methods:

• In vitro studies using HepG2 and Bel-7402 cells treated with ADR under varying glucose conditions.
• In vivo studies using diabetic mouse models (db/db and STZ-induced) with hepatoma xenografts.
• Analysis included cell proliferation assays, apoptosis assays, FACs, Western blotting, and assessment of AMPK activation and DNA damage markers (H2AX).

Main Results:

• Hyperglycemia significantly increased the IC50 of ADR in liver cancer cells, indicating reduced drug sensitivity.
• High glucose concentrations protected cells from ADR-induced apoptosis and DNA damage.
• ADR's tumor growth inhibitory effect was diminished in diabetic mice, but restored by insulin therapy.
• Hyperglycemia suppressed ADR-induced AMPK activation and H2AX expression, which was reversed by AMPK activators (AICAR) and exacerbated by AMPK inhibitors (Compound C) or silencing.

Conclusions:

• Hyperglycemia impairs Adriamycin chemotherapeutic sensitivity in liver cancer by down-regulating the AMPK pathway.
• This inhibition leads to reduced ADR-induced DNA damage, contributing to treatment resistance in diabetic patients.