Franczak Marika, Toenshoff Isabel, Jansen Gerrit, Smolenski Ryszard T, Giovannetti Elisa, Peters Godefridus J
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.
Curr Med Chem. 2023;30(11):1209-1231. doi: 10.2174/0929867329666220401110418.
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.
线粒体是活细胞中的主要能量工厂。为了快速增殖和转移，肿瘤细胞增加了它们的能量需求。因此，线粒体成为对它们来说最重要的细胞器之一。的确，许多研究表明癌症化疗耐药性与线粒体功能改变之间存在相互作用。在这篇综述中，我们聚焦于癌症细胞与正常细胞在能量代谢方面的差异，以便更好地理解它们的耐药性以及如何开发针对能量代谢和核苷酸合成的药物。癌症细胞与正常细胞的差异之一是烟酰胺腺嘌呤二核苷酸（NAD+）水平较高，它是三羧酸循环（TCA）的一种辅助因子，可增强它们的增殖能力，并帮助癌细胞在缺氧条件下存活。一个重要的变化是一种称为瓦伯格效应的代谢转换。这种效应基于能量获取方式从依赖氧气的转变为氧化磷酸化（OXPHOS），使它们适应肿瘤环境。另一种机制是一碳（1C）代谢酶的高表达。同样，这使癌细胞能够通过产生用于合成核苷酸和氨基酸的前体来增加增殖。我们综述了临床上正在使用和研发的针对NAD+、OXPHOS和1C代谢的药物。将新型药物与传统抗肿瘤药物联合使用可能会成为一种有前景的抗癌治疗新方法。
