Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

LMB-100 (RG7787) is a recombinant immunotoxin, which kills mesothelin-expressing cancer cells and now being evaluated in phase 1 trials. To enhance the anti-tumor activity of LMB-100, we have searched for agents, already approved for cancer therapy, that can be combined with LMB-100 to increase its efficacy. Panbinostat is a pan-histone deacetylase inhibitor that is used to treat multiple myeloma. We incubated different types of cancer cells with panbinostat and LMB-100 and found that they interacted synergistically to cause cell death. We found that panbinostat and the combination increased levels of mRNAs encoding TNF/TNFR family members, as well as BNIP3L and CASP-9, and markedly decreased mRNA levels for c-FLIP and BID. Western blots confirmed a fall in levels of cFLIP protein and a rise in BNIP3L and caspase-9. The combination also increased levels of cleaved BID (t-BID), cleaved-capsase-3 and -8 and PARP. To assess the importance of the fall in cFLIP levels, we treated cells with the cFLIP inhibitor, Rocaglamide, and found it also enhanced killing of tumor cells by LMB-100. LMB-100, which activates the intrinsic pathway of apoptosis, and panbinostat, which activates the extrinsic pathway, work in a synergistic manner to kill cancer cell lines.
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PMID:Panbinostat decreases cFLIP and enhances killing of cancer cells by immunotoxin LMB-100 by stimulating the extrinsic apoptotic pathway. 2915 82

Autophagy has an important role in the pathogenesis of plasma cell development and multiple myeloma (MM); however, the prognostic role of autophagy-related genes (ARGs) in MM remains undefined. In the present study, the expression profiles of 234 ARGs were obtained from a Gene Expression Omnibus dataset (accession GSE24080), which contains 559 samples of patients with MM analyzed with 54,675 probes. Univariate Cox regression analysis identified 55 ARGs that were significantly associated with event-free survival of MM. Furthermore, a risk score with 16 survival-associated ARGs was developed using multivariate Cox regression analysis, including ATIC, BNIP3L, CALCOCO2, DNAJB1, DNAJB9, EIF4EBP1, EVA1A, FKBP1B, FOXO1, FOXO3, GABARAP, HIF1A, NCKAP1, PRKAR1A and SUPT20H, was constructed. Using this prognostic signature, patients with MM could be separated into high- and low-risk groups with distinct clinical outcomes. The area under the curve values for the receiver operating characteristic curves were 0.740, 0.741 and 0.712 for 3, 5 and 10 years prognosis predictions, respectively. Notably, the prognostic role of this risk score could be validated with another four independent cohorts (accessions: GSE57317, GSE4581, GSE4452 and GSE4204). In conclusion, ARGs may serve vital roles in the progression of MM, and the ARGs-based prognostic model may provide novel ideas for clinical applications in MM.
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PMID:A predicted risk score based on the expression of 16 autophagy-related genes for multiple myeloma survival. 3161 41

Mitophagy, the elimination of damaged mitochondria through autophagy, promotes neuronal survival in cerebral ischemia. Previous studies found deficient mitophagy in ischemic neurons, but the mechanisms are still largely unknown. We determined that BNIP3L/NIX, a mitophagy receptor, was degraded by proteasomes, which led to mitophagy deficiency in both ischemic neurons and brains. BNIP3L exists as a monomer and homodimer in mammalian cells, but the effects of homodimer and monomer on mitophagy are unclear. Site-specific mutations in the transmembrane domain of BNIP3L (S195A and G203A) only formed the BNIP3L monomer and failed to induce mitophagy. Moreover, overexpression of wild-type BNIP3L, in contrast to the monomeric BNIP3L, rescued the mitophagy deficiency and protected against cerebral ischemic injury. The macroautophagy/autophagy inhibitor 3-MA and the proteasome inhibitor MG132 were used in cerebral ischemic brains to identify how BNIP3L was reduced. We found that MG132 blocked the loss of BNIP3L and subsequently promoted mitophagy in ischemic brains. In addition, the dimeric form of BNIP3L was more prone to be degraded than its monomeric form. Carfilzomib, a drug for multiple myeloma therapy that inhibits proteasomes, reversed the BNIP3L degradation and restored mitophagy in ischemic brains. This treatment protected against either acute or chronic ischemic brain injury. Remarkably, these effects of carfilzomib were abolished in bnip3l -/- mice. Taken together, the present study linked BNIP3L degradation by proteasomes with mitophagy deficiency in cerebral ischemia. We propose carfilzomib as a novel therapy to rescue ischemic brain injury by preventing BNIP3L degradation.
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PMID:BNIP3L/NIX degradation leads to mitophagy deficiency in ischemic brains. 3272 81