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Image Search Results
Journal: Cancer research
Article Title: Undermining glutaminolysis bolsters chemotherapy while NRF2 promotes chemoresistance in KRAS-driven pancreatic cancers
doi: 10.1158/0008-5472.CAN-19-1363
Figure Lengend Snippet: A, Survival of PANC-1 cells pre-treated with CM or -Q for 72 hours followed by 36-hour gemcitabine (2μM) treatment as indicated. Values were normalized to cell survival in CM-treated condition as control, which were given a value of 100%. B, PANC-1 cells were plated and shifted to CM or media lacking Q. Cells were additionally treated with a combination of (5mM) DMKG and (1X) NEAA mixture for 72 hours following glutamine withdrawal where indicated. Gemcitabine (2μM, 36 hours) was added for respective samples, and the percent of non-viable cells was calculated using the trypan blue dye exclusion assay. C, SU.86.86 cells were plated and treated with no glutamine media as in A. Cells were treated with 0.2μM gemcitabine for the last 24 hours as indicated, and the percent of non-viable cells was calculated. D, One day after plating, HPNE-hTERT cells were shifted to CM or medium lacking Q for 48 hours then treated with or without (2μM) gemcitabine for an additional 24 hours in the presence of pretreatment as indicated. The percent of non-viable cells was determined. E, PANC-1 cells were plated in CM overnight, after which cells were treated with 10μM CB-839 or 10μM BPTES for 72 hours where indicated. An additional treatment of 2μM capecitabine, 2μM gemcitabine, or 10μM 5-FU was given for 36 hours as indicated. The percent of non-viable cells was determined. F, PANC-1 cells were treated with RSL3 (10ηM) and/or gemcitabine (2μM) for 24 hours. The percent of non-viable cells was determined as in B. A-F, Error bars represent the SEM for four independent experiments. G, Experimental design for H-P. H-O, Mice bearing tumors of KPC (H-I), MIA PaCa-2 (J-K), SU.86.86 (L-M) and PANC-1 cells (N-O) were administered drug schedules as indicated in the schematic representation G. Tumor volumes (H, J, L, N) and body weights of mice (I, K, M, O) were shown with error bars representing SEM for each group. Threshold for p-value was <0.05. P, Survival of PANC-1 tumor-bearing mice represented as a Kaplan-Meier plot. H-P, Statistical differences between treatment groups were determined with a critical p value of <0.05. Synergistic effect of CB-839+Gemcitabine is evident by comparing tumor volumes (H,J,L,N) with single compound treated groups with statistical significance whereas insignificant body weight changes has been documented (I,K,M,O) for either of four treatment groups in all cases.
Article Snippet:
Techniques: Exclusion Assay
Journal: Cancer research
Article Title: Undermining glutaminolysis bolsters chemotherapy while NRF2 promotes chemoresistance in KRAS-driven pancreatic cancers
doi: 10.1158/0008-5472.CAN-19-1363
Figure Lengend Snippet: Model illustrates reprogrammed metabolic pathways in RAS-driven PDAC cells linked to KRAS mutation and NRF2 activation, which drive glutaminolysis. Mutant KRAS-mediated NRF2 activation leads to chemoresistance by regulating antioxidant genes. Modulation of nucleotide synthesis by NRF2 also supports PDAC cell growth. Anaplerotic glutamine utilization is a key feature of KRAS-driven PDAC cells. KRAS-regulated glutamine metabolic rewiring influenced the TCA cycle, which is critical for nucleotide and DNA synthesis to support cell growth and survival (12,29). CB-839 inhibits GLS, whereas gemcitabine blocks DNA synthesis. This model potentiates CB-839 treatment along with gemcitabine as a therapeutic strategy to combat chemoresistance in KRAS-driven pancreatic cancers.
Article Snippet:
Techniques: Mutagenesis, Activation Assay, DNA Synthesis