Novel Aza-podophyllotoxin derivative induces oxidative phosphorylation and cell death via AMPK activation in triple-negative breast cancer
| Autor: | Dhanir Tailor, Angel Resendez, Alisha M. Birk, Vineet Kumar, George W. Sledge, Edward L. LaGory, Tanya Stoyanova, Rana P. Singh, Ali Ghoochani, Jiangbin Ye, Amato J. Giaccia, Arpit Dheeraj, Dhanya Nambiar, Catherine C. Going, Sanjay V. Malhotra, Quynh-Thu Le, Yang Li, Sharon J. Pitteri |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Cancer Research
Programmed cell death Cell Survival Apoptosis Triple Negative Breast Neoplasms Oxidative phosphorylation Mice SCID AMP-Activated Protein Kinases Article Oxidative Phosphorylation 03 medical and health sciences Mice Random Allocation 0302 clinical medicine Breast cancer Mice Inbred NOD Cell Line Tumor Warburg Effect Oncologic Animals Humans Glycolysis Lactic Acid Protein kinase A Triple-negative breast cancer 030304 developmental biology Cancer Podophyllotoxin 0303 health sciences Mice Inbred BALB C Cell Death Chemistry Lipogenesis AMPK Warburg effect Antineoplastic Agents Phytogenic Neoplasm Proteins Enzyme Activation Glucose Oncology Anaerobic glycolysis 030220 oncology & carcinogenesis Cancer research Female |
| Zdroj: | British Journal of Cancer |
| ISSN: | 1532-1827 0007-0920 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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