Oxidative lipid damage by naringenin selectively sensitizes chronic myeloid leukemia cell lines and patient samples to Bcr-Abl tyrosine kinase inhibitors

Biochem Biophys Res Commun. 2024 Nov 12:733:150653. doi: 10.1016/j.bbrc.2024.150653. Epub 2024 Sep 3.

Abstract

Chronic myeloid leukemia (CML) treatment with Bcr-Abl tyrosine kinase inhibitors (TKIs) has significantly improved patient outcomes, yet challenges such as drug resistance and persistence of leukemic stem cells persist. This study explores the potential of naringenin, a natural flavonoid, to enhance the efficacy of Bcr-Abl TKIs in CML therapy. We showed that naringenin reduces viability of a panel of CML cell lines regardless of varying cellular origin and genetic mutations, and acts synergistically with dasatinib and ponatinib. Importantly, naringenin is effective in targeting blast crisis CML CD34+ cells by decreasing their colony formation, self-renewal and viability. Compared to CML, naringenin is significantly less effective against normal bone marrow (NBM) counterparts. In addition, naringenin significantly enhances the inhibitory effects of dasatinib in CML but not NBM CD34+ cells. Mechanism studies showed that naringenin's inhibitory effects were associated with the induction of oxidative stress and lipid damage, as evidenced by increased reactive oxygen species (ROS) and malondialdehyde (MDA) levels. Notably, naringenin upregulated genes related to mitochondrial biogenesis while downregulating antioxidant defense genes. Pretreatment with α-tocopherol, which inhibits lipid-mediated ROS production, completely abolished the ROS increase and restored cell viability, indicating that lysosomal lipid peroxidation plays a crucial role in naringenin's mechanism of action. In a CML xenograft mouse model, the combination of naringenin and dasatinib resulted in remarkably more tumor growth suppression compared to single drug alone. Importantly, this combination was well-tolerated, with no adverse effects on body weight observed. These findings suggest that naringenin, by inducing oxidative lipid damage, enhances the anti-leukemic effects of Bcr-Abl TKIs, offering a promising therapeutic strategy for CML.

Keywords: Bcr-Abl TKIs; CML; Naringenin; Oxidative lipid damage; Synergy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Dasatinib / pharmacology
  • Dasatinib / therapeutic use
  • Drug Synergism
  • Flavanones* / pharmacology
  • Flavanones* / therapeutic use
  • Fusion Proteins, bcr-abl* / antagonists & inhibitors
  • Fusion Proteins, bcr-abl* / genetics
  • Fusion Proteins, bcr-abl* / metabolism
  • Humans
  • Imidazoles / pharmacology
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive* / drug therapy
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive* / metabolism
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive* / pathology
  • Mice
  • Oxidative Stress* / drug effects
  • Protein Kinase Inhibitors* / pharmacology
  • Protein Kinase Inhibitors* / therapeutic use
  • Pyridazines / pharmacology
  • Reactive Oxygen Species / metabolism
  • Tyrosine Kinase Inhibitors
  • Xenograft Model Antitumor Assays

Substances

  • Flavanones
  • naringenin
  • Fusion Proteins, bcr-abl
  • Protein Kinase Inhibitors
  • Dasatinib
  • ponatinib
  • Reactive Oxygen Species
  • Pyridazines
  • Imidazoles
  • Antineoplastic Agents
  • Tyrosine Kinase Inhibitors