Identification of a synergistic combination of dimethylaminoparthenolide and shikonin alters metabolism and inhibits proliferation of pediatric precursor‐B cell acute lymphoblastic leukemia

Abstract

Exploiting metabolic vulnerabilities of cancer cells with nontoxic, plant derived compounds constitutes a novel strategy for both chemoprevention and treatment. A high‐throughput screening approach was used to evaluate a library of natural products to determine the most synergistic combination in precursor‐B cell acute lymphoblast leukemia. Dimethylaminoparthenolide and shikonin effectively inhibited proliferation resulting in cell death in primary and immortalized leukemia cells, while having negligible effects on normal cells. Dimethylaminoparthenolide and shikonin have been shown separately to inhibit cell survival and proliferative signaling and activate tumor suppressors and proapoptotic pathways. Untargeted metabolomics and metabolic flux analysis with stable isotopically labeled glucose and glutamine exhibited a global shift in metabolism following treatment. Pathway analysis indicated significant differences in amino acid, antioxidant, tricarboxylic acid cycle, and nucleotide metabolism. Together, dimethylaminoparthenolide and shikonin reduced the shunting of glycolytic intermediates into the pentose phosphate pathway for biosynthetic purposes. Similarly, the incorporation of glutamine and glutamine‐derived metabolites into purine and pyrimidine synthesis was inhibited by the combination of dimethylaminoparthenolide and shikonin, effectively impeding biosynthetic pathways critical for leukemia cell survival. This approach demonstrates that a synergistic pair of compounds with malignant cell specificity can effectively target metabolic pathways crucial to leukemia cell proliferation and induce apoptosis.

The Study on the Pathogenesis of Pediatric Lymphoma Based on the Combination of Pseudotargeted and Targeted Metabolomics

“…Taurine is a potent antioxidant. The significance of taurine and hypotaurine metabolism suggests oxidative stress following treatment [28]. The level of 1-methylnicotinamide is higher in pediatric lymphoma patients than in the treatment group.…”

The Combined Treatment With the FLT3-Inhibitor AC220 and the Complex I Inhibitor IACS-010759 Synergistically Depletes Wt- and FLT3-Mutated Acute Myeloid Leukemia Cells

“…AML cell lines (U937 and OCI-AML3; 10 7 cells/sample, 3 replicates per group) were incubated with unlabeled or labeled RPMI 1640 medium. Cells were treated with 5 nM of IACS-010759 and/or 500 nM AC220, with a final concentration of 0.1% DMSO in hypoxia for 24 h. After treatment, samples were extracted as previously reported ( 33 ). In short, metabolites were extracted by 1:1 methanol:water with 10 mM ammonium bicarbonate and equal parts of chloroform.…”

“…The polar fractions were spiked with a mixture of deuterated internal standards (IS) before analysis. Both polar and apolar fractions were analyzed as previously described ( 33 ) on a Q Exactive Hybrid Quadrupole-Orbitrap Mass Spectrometer equipped with an electrospray source, connected with a Vanquish UHPLC system (Thermo Scientific). Calibration of the mass spectrometer for both ionization modes corresponding to the highest m/z range was achieved with routine commercial calibration solutions provided by the manufacturer.…”

Integrated proteomics and metabolomics reveals the comprehensive characterization of antitumor mechanism underlying Shikonin on colon cancer patient-derived xenograft model

“…Shikonin induced apoptosis of paclitaxel-resistant non-small cell lung cancer (NSCLC) cell lines and xenograft tumors through suppressing NEAT1 and Akt signaling 5 . Recently, Shikonin was reported to impede biosynthetic pathways critical for leukemia cell survival by the combination of dimethylaminoparthenolide 6 . Considering the excellent antitumor activity of Shikonin, it is imperative to discover its molecular pharmacological mechanisms.…”