Novel Aza-podophyllotoxin derivative induces oxidative phosphorylation and cell death via AMPK activation in triple-negative breast cancer

Dhanir Tailor, Catherine C. Going, Angel Resendez, Vineet Kumar, Dhanya K. Nambiar, Yang Li, Arpit Dheeraj, Edward Lewis LaGory, Ali Ghoochani, Alisha M. Birk, Tanya Stoyanova, Jiangbin Ye, Amato J. Giaccia, Quynh Thu Le, Rana P. Singh, George W. Sledge, Sharon J. Pitteri, Sanjay V. Malhotra

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Background: To circumvent Warburg effect, several clinical trials for different cancers are utilising a combinatorial approach using metabolic reprogramming and chemotherapeutic agents including metformin. The majority of these metabolic interventions work via indirectly activating AMP-activated protein kinase (AMPK) to alter cellular metabolism in favour of oxidative phosphorylation over aerobic glycolysis. The effect of these drugs is dependent on glycaemic and insulin conditions. Therefore, development of small molecules, which can activate AMPK, irrespective of the energy state, may be a better approach for triple-negative breast cancer (TNBC) treatment. Methods: Therapeutic effect of SU212 on TNBC cells was examined using in vitro and in vivo models. Results: We developed and characterised the efficacy of novel AMPK activator (SU212) that selectively induces oxidative phosphorylation and decreases glycolysis in TNBC cells, while not affecting these pathways in normal cells. SU212 accomplished this metabolic reprogramming by activating AMPK independent of energy stress and irrespective of the glycaemic/insulin state. This leads to mitotic phase arrest and apoptosis in TNBC cells. In vivo, SU212 inhibits tumour growth, cancer progression and metastasis. Conclusions: SU212 directly activates AMPK in TNBC cells, but does not hamper glucose metabolism in normal cells. Our study provides compelling preclinical data for further development of SU212 for the treatment of TNBC.

Original languageEnglish (US)
Pages (from-to)604-615
Number of pages12
JournalBritish Journal of Cancer
Volume124
Issue number3
DOIs
StatePublished - Feb 2 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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