Pharmacometabolomics Identifies 3-Hydroxyadipic Acid, d-Galactose, Lysophosphatidylcholine (P-16:0), and Tetradecenoyl-l-Carnitine as Potential Predictive Indicators of Gemcitabine Efficacy in Pancreatic Cancer Patients

Abstract

Gemcitabine (GEM)-based chemotherapy is the standard regimen for the treatment of pancreatic cancer (PC). However, chemoresistance is a major challenge in PC treatment. Reliable biomarkers are urgently needed to predict the response to GEM-based therapies. GEM-sensitive (GEM-S) and GEM-resistant (GEM-R) pancreatic carcinoma xenograft models were established, and GEM monotherapy and GEM plus nanoparticle albumin-bound paclitaxel (nab-PTX) doublet therapy were administered to GEM-S/R tumor-bearing mice. Metabolomic mass spectrometry (MS) analysis of serum, liver, and tumor samples was performed using an ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometer. The results showed that both GEM monotherapy and combination therapy significantly inhibited the tumor growth in GEMS subgroup. However, in the GEM-R subgroup, tumor growth was not significantly inhibited by GEM monotherapy, but was significantly suppressed by GEM combination therapy. Metabolic profiling analysis by hierarchical cluster analysis and partial least squares discriminant analysis showed that the differences in metabolites were most significant in serum of three types of samples in the GEM-S/R subgroups, regardless of the administration of GEM monotherapy or combination therapy. The differential metabolite analysis of serum samples revealed 38 and 26 differential metabolites between the GEM-R and GEMS subgroups treated with GEM monotherapy or combination therapy, and four common discriminating metabolites were investigated: 3-hydroxyadipic acid, D-galactose, lysophosphatidylcholine (LysoPC) (P-16:0), and tetradecenoyl-L-carnitine. The relative amounts of the four metabolites changed significantly and consistently after GEM monotherapy or combination therapy. The levels of these four metabolites Wu et al.

Lysophosphatidylcholine: Potential Target for the Treatment of Chronic Pain

“…At present, the accurate detection of LPC relies on metabolomics or lipidomics technology, which provides assays for exploiting the role of LPC in chronic pain. Apart from chronic pain, LPC or LPC species in body fluids such as blood, urine, cerebrospinal fluid, and tissues are uniquely or collectively related to cancer [ 150 , 151 , 152 ], diabetes [ 153 , 154 , 155 , 156 ], coronary atherosclerosis [ 157 ], Alzheimer’s disease [ 158 , 159 ], rheumatoid arthritis [ 83 ], COVID-19 [ 160 ], liver and kidney damage [ 161 , 162 ], etc. Whether LPC is necessary for other chronic pain conditions, such as cancer pain, has not been confirmed.…”

Review on analytical technologies and applications in metabolomics

“…Such information subsequently facilitates the discovery of biomarkers that are associated with pathologic conditions and play vital roles in mapping the effectiveness of drug therapies through various metabolomics approaches [141]. The identification of metabolic pathways affected by a specific drug treatment through metabolomics, as well as a subsequent analysis of genetic variations within these metabolic pathway components could help to achieve personalized medicine [138,142,143]. Profiling of drug-induced changes in metabolites or creating metabolite signatures of different disease subtypes, such as invasive or non-invasive tumors, through high-resolution targeted metabolomics tools serves an important biomarker discovery and diagnostic tool development [143][144][145].…”

Application of Mass Spectrometry in Pancreatic Cancer Translational Research

“…Wu et al adopted UPLC/Q-TOFMS for mapping the metabolic profiles following GEM monotherapy or combination therapy. They found that both monotherapy and combination therapy contribute to significant metabolic changes, and the relative levels of 3-hydroxyadipic acid, d-galactose, LysoPC (P-16:0), and tetradecenoyl-l-carnitine could be regarded as biomarkers to predict the efficacy of chemotherapy (58).…”