Stable Isotope Tracing Metabolomics to Investigate the Metabolic Activity of Bioactive Compounds for Cancer Prevention and Treatment

Abstract

A major hallmark of cancer is the metabolic reprogramming of cancer cells to fuel tumor growth and proliferation. Various plant-derived bioactive compounds efficiently target the metabolic vulnerabilities of cancer cells and exhibit potential as emerging therapeutic agents. Due to their safety and common use as dietary components, they are also ideal for cancer prevention. However, to render their use as efficient as possible, the mechanism of action of these phytochemicals needs to be well characterized. Stable isotope tracing is an essential technology to study the molecular mechanisms by which nutraceuticals modulate and target cancer metabolism. The use of positionally labeled tracers as exogenous nutrients and the monitoring of their downstream metabolites labeling patterns enable the analysis of the specific metabolic pathway activity, via the relative production and consumption of the labeled metabolites. Although stable isotope tracing metabolomics is a powerful tool to investigate the molecular activity of bioactive compounds as well as to design synergistic nutraceutical combinations, this methodology is still underutilized. This review aims to investigate the research efforts and potentials surrounding the use of stable isotope tracing metabolomics to examine the metabolic alterations mediated by bioactive compounds in cancer.

In VitroAnticancer Activity of the Light Stable Zinc Isotope (64Zn) Compounds

“…According to the available data, stable isotopes have already been used for effective and highly sensitive diagnostics of various types of malignant neoplasms. A study carried out by Tea et al showed that an isotope signature of 13 C and 15 N characteristic of the breast cancer tissue differed significantly from that of normal breast tissue (3).…”

“…It is known that zinc significantly affects the lipid metabolism, glycolysis and redox reactions in malignant cells (14). It is also known that changes in the isotopic composition of zinc may have a considerable effect on its metabolic activity in the cell (15). These facts suggest that compounds enriched in light stable isotopes of zinc may have significant anticancer potential.…”

Mitochondria: It is all about energy

“…The Warburg effect results from an interplay of different mechanisms and driving processes. HIF1 overexpression, oncogene activation (cMyc, K-ras- mTORC1, and Akt), activation of signaling pathways (PI3K/Akt/mTORC1, Ras/Raf/MEK/ERK), an increase in glucose (GLUT) and lactate (MCT4) transporters, and the activation of glycolytic enzymes (HK2, PFK1, ENO1, PKM2, and LDHA) ( Wallace, 2005 ; Choudhury et al, 2020 ; Han et al, 2021 ; Mariani et al, 2021 ; Pluimakers et al, 2021 ; Shen et al, 2021 ; Vaupel and Multhoff, 2021 ; Zhu et al, 2022c ) are all part of the metabolic change observed in cancer cells. Furthermore, the functions of tumor suppressors (mutant p53, mutant PTEN, and microRNAs 29, 143, and 144), Sirtuins 3 and 6, and the AMPK signaling pathway ( Kumar et al, 2016 ; Alhebshi et al, 2021 ; Jazvinšćak Jembrek et al, 2021 ; Zhang et al, 2022a ) are inhibited to prevent cell death and reduce metabolic stress of tumor cells.…”

Predicting and Quantifying Antagonistic Effects of Natural Compounds Given with Chemotherapeutic Agents: Applications for High-Throughput Screening

“…The use of primary, patient-derived tissues or implementation of co-culturing methods for screening experiments can also help to reduce disparities between in vitro and in vivo results [ 108 ]. It is important that in vitro drug combinations that exhibit synergy or antagonism be used not as absolute proof of drug interaction effects but to identify drug combinations that warrant further mechanistic investigation, which may include metabolomics, proteomics, genomics, and in vivo experiments for validation [ 60 , 109 ].…”