Background: Despite cisplatin’s effectiveness against ovarian cancer, these cancer cells
have shown the ability to resist chemotherapy – a resistance that represents a major obstacle to current
Objective: The objective of the study was to determine whether or not cellular resistance could be
linked to changes in metabolites.
Methods: Liquid Chromatography-mass Spectrometry (LC-MS) hydrophilic interaction chromatography
was used to analyze the intracellular metabolomic profile of ovarian cancer cell line A2780 and the
cisplatin resistant cell line A2780CR, before and following treatment with cisplatin at inhibitory concentration
(IC50). Phenotype MicroArray™ (PM) experiments were also applied in order to test carbon
substrate utilization or sensitivity in both cell lines after exposure to cisplatin. Data extraction was carried
out with MZmine 2.10 with metabolite searching against an in-house database. The data were analyzed
using univariate and multivariate Principal Component Analysis (PCA) and Orthogonal Projections
to Latent Structures Discriminant Analysis (OPLS-DA) methods.
Results: There was clear discrimination between the controls and the cisplatin treated samples on the
basis of PCA and OPLS-DA. The cisplatin-sensitive cells were as expected more sensitive to cisplatin
than the resistant cells with IC50 values of 4.9 and 10.8 µg/mL, respectively. The results demonstrated
that the intracellular metabolomic changes induced by cisplatin in the cisplatin-sensitive cells led to
reduced levels of acetylcarnitine, phosphocreatine, arginine, proline and Glutathione Disulfide (GSSG)
as well as to increased levels of tryptophan and methionine. While PM experiments showed lowered
glucose metabolism in the sensitive cells following treatment which was reflected in decreased levels
Conclusion: Overall the metabolic changes induced in A2780CR cells by cisplatin were much fewer
than those induced in A2780 cells. The sensitive cells had a much quicker onset of apoptosis than the
resistant cells as judged by measurement of caspase 3. Increased resistance to oxidative stress in the
resistant cells was consistent with higher levels of proline, due to less induction of proline dehydrogenase,
and elevated levels of glutathione (GSH) and GSSG following cisplatin treatment.