Investigating the metabolic impact of Metformin and Berberine in combination with Venetoclax for Acute Myeloid Leukaemia treatment

Abstract

Acute myeloid leukaemia (AML) stands as a significant challenge in haematological malignancies, particularly due to poor outcomes in older patients and resistance to therapy. BCL-2, an anti-apoptotic protein, is overexpressed in AML. The BCL-2 antagonist Venetoclax inhibits OXPHOS and induces apoptosis in AML cells, which is potentiated when combined with Metformin an anti-hyperglycaemic agent used to treat type 2 diabetes, which also has anti-cancer properties. This study explored the effects of Venetoclax combined with Metformin or Berberine, an herbal supplement with a similar mechanism of action to metformin, on AML cell death and metabolic changes. The combination of Metformin and Venetoclax (Met+Ven) showed a synergistic cell death response in the HL60 cell line, unlike Berberine and Venetoclax (BBR+Ven). The combination treatments increased lactate production compared to their monotherapy, however Met+Ven increased lactate retention and reduced expression of the lactate efflux protein MCT4, whereas BBR+Ven increased MCT4 expression. Both combinations increased mitochondrial membrane permeability, correlating with increased cell death. Proteomic analysis of Met+Ven treated cells revealed decreased expression of core mitochondrial respiratory chain complex 1 protein (NDUFV1) and alterations in complex 4 proteins (increased COX5A, decreased NDUFA4). Additionally, endoplasmic reticulum proteins related to protein folding and ubiquitylation were upregulated, suggesting endoplasmic reticulum stress. These findings suggest that the Met+Ven combination could induce both ER and mitochondrial stress, leading to increased calcium flux and necroptosis, and could have clinical applications to patients who are ineligible for induction chemotherapy.

Date of Award	2025
Original language	English
Supervisor	Kris Jeremy (Director of Studies (First Supervisor)), Vikram Sharma (Other Supervisor), Andrew Foey (Other Supervisor) & Shagun Khera (Other Supervisor)