Synergistic effect of antimetabolic and chemotherapy drugs in triple-negative breast cancer.

The triple-negative breast cancer (TNBC) subtype comprises approximately 15% of all breast cancers and is associated with poor long-term outcomes. Classical chemotherapy remains the standard of treatment, with toxicity and resistance being major limitations. TNBC is a high metabolic group, and antimetabolic drugs are effective in inhibiting TNBC cell growth. We analyzed the combined effect of chemotherapy and antimetabolic drug combinations in MDA-MB-231, MDA-MB-468 and HCC1143 human TNBC cell lines. Cells were treated with each drug or with drug combinations at a range of concentrations to establish the half-maximal inhibitory concentrations (IC50). The dose-effects of each drug or drug combination were calculated, and the synergistic or antagonistic effects of drug combinations were defined. Chemotherapy and antimetabolic drugs exhibited growth inhibitory effects on TNBC cell lines. Antimetabolic drugs targeting the glycolysis pathway had a synergistic effect with chemotherapy drugs, and antiglycolysis drug combinations also had a synergistic effect. The use of these drug combinations could lead to new therapeutic strategies that reduce chemotherapy drug doses, decreasing their toxic effect, or that maintain the doses but enhance their efficacy by their synergistic effect with other drugs.

Ultrahigh-Resolution NMR with Water Signal Suppression for a Deeper Understanding of the Action of Antimetabolic Drugs on Diffuse Large B-Cell Lymphoma.

Ultrahigh-resolution NMR has recently attracted considerable attention in the field of complex samples analysis. Indeed, the implementation of broadband homonuclear decoupling techniques has allowed us to greatly simplify crowded 1H spectra, yielding singlets for almost every proton site from the analyzed molecules. Pure shift methods have notably shown to be particularly suitable for deciphering mixtures of metabolites in biological samples. Here, we have successfully implemented a new pure shift pulse sequence based on the PSYCHE method, which incorporates a block for solvent suppression that is suitable for metabolomics analysis. The resulting experiment allows us to record ultrahigh-resolution 1D NOESY 1H spectra of biofluids with suppression of the water signal, which is a crucial step for highlighting metabolite mixtures in an aqueous phase. We have successfully recorded pure shift spectra on extracellular media of diffuse large B-cell lymphoma (DLBCL) cells. Despite a lower sensitivity, the resolution of pure shift data was found to be better than that of the standard approach, which provides a more detailed vision of the exo-metabolome. The statistical analyses carried out on the resulting metabolic profiles allow us to successfully highlight several metabolic pathways affected by these drugs. Notably, we show that Kidrolase plays a major role in the metabolic pathways of this DLBCL cell line.

Metabolic Inhibitors as Antiparasitic Drugs: Pharmacological, Biochemical and Molecular Perspectives.

BACKGROUND: Human diseases caused by the infectious parasites have been one of the major problems throughout the evolutionary journey. Protozoan and metazoan parasitic infections result in a large number of deaths, disabilities and socio-economic loss worldwide to date. Despite the best efforts for developing suitable antiparasitics, these infections take a massive toll on human health. The prevalence of emerging resistance to the existing drugs, lack of efficacy and toxic side effects are as added complications. Being enlisted under 'neglected' category, serious diseases like leishmaniasis, filariasis, trypanosomiasis etc. have failed to draw attention of the governments as well as the pharmaceutical companies. Thus, target specific as well as cost-convenient therapy needs to be employed for the treatment of these diseases and selective targeting of metabolic pathways appears to be the most promising mean. METHODS: In this context, quality works have been explored for screening either anti-metabolic drugs or selective targets in different groups of parasites. Moreover, complete genome sequencing and metabolomic profiling have provided the initiatives to search for new lethal targets in parasites. RESULTS: New metabolic targets are being reported from different organelles and other sub-cellular compartments of parasites such as mitochondrion, kinetoplast, apicoplast, glycosome, hydrogenosome, acidocalcisome, plasma membrane, cytoskeleton, etc. Herein, unique findings achieved in identifying new antimetabolic drugs or targets and studying their molecular mode of actions have been reviewed by incorporating existing and upcoming approaches. CONCLUSION: Considering the alarming scenario of diseases caused by parasites globally, this paper provides a comprehensive review to the scientific community on the development of novel interventions based on metabolic targets to combat the challenges posed by parasites.