L-asparaginase (LA) catalyzes the degradation of asparagine, an essential amino acid for leukemic cells, into ammonia and aspartate. Owing to its ability to inhibit protein biosynthesis in lymphoblasts, LA is used to treat acute lymphoblastic leukemia (ALL). Different isozymes of this enzyme have been isolated from a wide range of organisms, including plants and terrestrial and marine microorganisms. Pieces of information about the three-dimensional structure of L-asparaginase from Escherichia coli and Erwinia sp. have identified residues that are essential for catalytic activity. This review catalogues the major sources of L-asparaginase, the methods of its production through the solid state (SSF) and submerged (SmF) fermentation, purification, and characterization as well as its biological roles. In the same breath, this article explores both the past and present applications of this important enzyme and discusses its future prospects.
Low molecular weight heparin (LMWH), the guideline based drug for prophylaxis and treatment of cancer-associated thrombosis, was recently shown to sensitize cisplatin resistant A2780cis human ovarian cancer cells for cisplatin cytotoxicity upon 24 h pretreatment with 50 μg × mL−1 of the LMWH tinzaparin in vitro, equivalent to a therapeutic dosage. Thereby, LMWH induced sensitization by transcriptional reprogramming of A2780cis cells via not yet elucidated mechanisms that depend on cellular proteoglycans. Here we aim to illuminate the underlying molecular mechanisms of LMWH in sensitizing A2780cis cells for cisplatin. Using TCF/LEF luciferase promotor assay (Top/Flash) we show that resistant A2780cis cells possess a threefold higher Wnt signaling activity compared to A2780 cells. Furthermore, Wnt pathway blockade by FH535 leads to higher cisplatin sensitivity of A2780cis cells. Glypican-3 (GPC3) is upregulated in A2780cis cells in response to LMWH treatment, probably as counter-regulation to sustain the high Wnt activity against LMWH. Hence, LMWH reduces the cisplatin-induced rise in Wnt activity and TCF-4 expression in A2780cis cells, but keeps sensitive A2780 cells unaffected. Consequently, Wnt signaling pathway appears as primary target of LMWH in sensitizing A2780cis cells for cisplatin toxicity. Considering the outstanding role of LMWH in clinical oncology, this finding appears as promising therapeutic option to hamper chemoresistance.
In conclusion, NAC could be used as a therapeutic agent in the treatment of wound healing, acute bronchiolitis and congenital heart defects (CHDs). The focus of future research should be the following; (1) to examine NAC clinically to be considered in the treatment of wound healing; (2) to investigate whether NAC could be used alone or with insulin to prevent CHDs in infants with pregestational diabetes; (3) to evaluate the application of NAC as a potential agent for PAH treatment.
Heparan sulfate (HS) mediates the activity of various growth factors including TGF‐β. Heparanase is an endo‐glucuronidase that specifically cleaves and modifies HS structure. In this study, we examined the effect of heparanase expression on TGF‐β1‐dependent signaling activities. We found that overexpression of heparanase in human tumor cells (i.e., Fadu pharyngeal carcinoma, MCF7 breast carcinoma) attenuated TGF‐β1‐stimulated Smad phosphorylation and led to a slower cell proliferation. TGF‐β1‐stimulated Akt and Erk phosphorylation was also affected in the heparanase overexpression cells. This effect involved the enzymatic activity of heparanase, as overexpression of mutant inactive heparanase did not affect TGF‐β1 signaling activity. Analysis of HS isolated from Fadu cells revealed an increase in sulfation of the HS that had a rapid turnover in cells overexpressing heparanase. It appears that the structural alterations of HS affect the ability of TGF‐β1 to signal via its receptors and elicit a growth response. Given that heparanase expression promotes tumor growth in most cancers, this finding highlights a crosstalk between heparanase, HS, and TGF‐β1 function in tumorigenesis.
Ovarian
cancer (OC) is the most lethal among female reproductive
system malignancies. Depending upon the stage at presentation, the
five year survival ratio varies from ∼92 to ∼30%. The
role of biomarkers in early cancer diagnosis, including OC, is well
understood. In our previous study, through an initial screening, we
have analyzed eleven proteins that exhibited differential expression
in OC using two-dimensional gel electrophoresis (2D-GE) and matrix-assisted
laser desorption/ionization-time of flight mass spectrometric (MALDI-TOF
MS) analysis. In continuation of our previous study, the present work
describes analysis of twenty more proteins that showed aberrant expression
in OC. Among these, six showed consistent significant deregulation
in the OC false discovery rate [FDR ≤ 0.05]. Upon MS analysis,
they were identified as vimentin, tubulin beta 2C chain, tubulin alpha
1C chain, actin cytoplasmic 2, apolipoprotein A-I, and collagen alpha
2(VI) chain [peptide mass fingerprint (PMF) score ≥ 79]. One
of the differentially regulated proteins, tubulin beta 2C chain, was
found to be significantly (fold change, 2.5) enhanced in OC. Verification
by western blot and enzyme-linked immunosorbent assay (ELISA) demonstrated
that the tubulin beta 2C chain may serve as a valuable marker for
OC (ANOVA
p
< 0.0001). The assessment of the likely
association of TBB2C with OC in a larger population will not only
help in developing clinically useful biomarkers in the future but
also improve our understanding of the progression of OC disease.
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