Title:The Influence of Mitochondrial Energy and 1C Metabolism on the
Efficacy of Anticancer Drugs: Exploring Potential Mechanisms of
Resistance
Volume: 30
Issue: 11
Author(s): Marika Franczak, Isabel Toenshoff, Gerrit Jansen, Ryszard T. Smolenski, Elisa Giovannetti and Godefridus J. Peters*
Affiliation:
- Department of Biochemistry, Medical University of Gdansk, Gdansk, Poland
- Department of Medical Oncology,
Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUMC), Vrije Universiteit
Amsterdam, The Netherlands
Keywords:
Cancer, mitochondria, NAD+, oxidative phosphorylation (OXPHOS), 1C metabolism, resistance.
Abstract: Mitochondria are the main energy factory in living cells. To rapidly proliferate
and metastasize, neoplastic cells increase their energy requirements. Thus, mitochondria
become one of the most important organelles for them. Indeed, much research shows the
interplay between cancer chemoresistance and altered mitochondrial function. In this review,
we focus on the differences in energy metabolism between cancer and normal cells
to better understand their resistance and how to develop drugs targeting energy metabolism
and nucleotide synthesis. One of the differences between cancer and normal cells is
the higher nicotinamide adenine dinucleotide (NAD+) level, a cofactor for the tricarboxylic
acid cycle (TCA), which enhances their proliferation and helps cancer cells survive
under hypoxic conditions. An important change is a metabolic switch called the Warburg
effect. This effect is based on the change of energy harvesting from oxygen-dependent
transformation to oxidative phosphorylation (OXPHOS), adapting them to the tumor environment.
Another mechanism is the high expression of one-carbon (1C) metabolism enzymes.
Again, this allows cancer cells to increase proliferation by producing precursors
for the synthesis of nucleotides and amino acids. We reviewed drugs in clinical practice
and development targeting NAD+, OXPHOS, and 1C metabolism. Combining novel drugs
with conventional antineoplastic agents may prove to be a promising new way of anticancer
treatment.
