ABSTRACT
Celecoxib, a nonsteroidal anti-inflammatory drug, has been reported to have antitumor and antimetastatic activities, and it has potential for application in cancer treatments. The expression of matrix metalloproteinase (MMP)-2/9 is strongly correlated with cancer malignancy, and inhibition of these MMPs is believed to be effective in improving the antitumor and antimetastatic effects of drugs. We have previously revealed that UTX-121, which converted the sulfonamide of celecoxib to methyl ester, has more potent MMP-2/9 inhibitory activity than celecoxib. Based on these findings, we identified compounds with improved MMP inhibitory activity through a structure-activity relationship (SAR) study, using UTX-121 as a lead compound. Among them, compounds 9c and 10c, in which the methyl group of the p-tolyl group was substituted for Cl or F, showed significantly higher antitumor activity than UTX-121, and suppressed the expression of MMP-2/9 and activation of pro MMP-2. Our findings suggest that compounds 9c and 10c may be potent lead compounds for the development of more effective antitumor drugs targeting MMP.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Development , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/metabolism , Matrix Metalloproteinase Inhibitors/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Matrix Metalloproteinase Inhibitors/chemical synthesis , Matrix Metalloproteinase Inhibitors/chemistry , Molecular Structure , Structure-Activity RelationshipABSTRACT
[This corrects the article DOI: 10.1016/j.bbrep.2021.101072.].
ABSTRACT
Matrix metalloproteinase (MMP)-2 and MMP-9, also known as gelatinases or type IV collagenases, are recognized as major contributors to the proteolytic degradation of extracellular matrix during tumor invasion. Latent MMP-2 (proMMP-2) is activated by membrane type 1 MMP (MT1-MMP) on the cell surface of tumor cells. We previously reported that cell-bound proMMP-9 is activated by the MT1-MMP/MMP-2 axis in HT1080 cells treated with concanavalin A in the presence of exogenous proMMP-2. However, the regulatory mechanism of proMMP-9 activation remains largely unknown. Transforming growth factor (TGF)-ß1 is frequently overexpressed in tumor tissues and is associated with tumor aggressiveness and poor prognosis. In this study, we examined the role of TGF-ß1 on MT1-MMP-mediated proMMP-9 activation using human oral squamous cell carcinoma cells. TGF-ß1 significantly increased the expression of MMP-9. By adding exogenous proMMP-2, TGF-ß1-induced proMMP-9 was activated during collagen gel culture, which was suppressed by the inhibition of TGF-ß1 signaling or MT1-MMP activity. This MT1-MMP-mediated proMMP-9 activation was needed to facilitate TGF-ß1-induced cell invasion into collagen gel. Thus, TGF-ß1 may facilitate MT1-MMP-mediated MMP-9 activation and thereby stimulate invasion of tumor cells in collaboration with MT1-MMP and MMP-2.
ABSTRACT
Various radiosensitizers are being developed to increase the radiation sensitivity of hypoxic cancer cells, which show resistance to radiation. Previously, we demonstrated that an acetyl glucose-modified nitroimidazole derivative showed a high radiosensitizing effect by inhibiting glucose uptake and glycolysis. Based on this finding, we designed and synthesized novel sugar hybrid radiosensitizers, wherein acetyl glucose was introduced into gefitinib. Among them, UTX-114 had higher autophosphorylation and radiosensitizing activity than gefitinib and inhibited glucose uptake. This result supports our hypothesis that an acetyl glucose moiety improves the radiosensitizing effect of the drug, and UTX-114 can be expected to be a leading compound with a radiosensitizing effect.
Subject(s)
Antineoplastic Agents/chemistry , Gefitinib/chemistry , Glucose/chemistry , Nitroimidazoles/chemistry , Radiation-Sensitizing Agents/chemistry , Antineoplastic Agents/pharmacology , Biomedical Enhancement , Cell Line, Tumor , Cell Membrane Permeability , ErbB Receptors/metabolism , Gefitinib/pharmacology , Glucose Transport Proteins, Facilitative/metabolism , Glycolysis/drug effects , Humans , Monosaccharide Transport Proteins/metabolism , Phosphorylation , Radiation-Sensitizing Agents/pharmacologyABSTRACT
We designed and synthesized a celecoxib derivative UTX-121 to enhance its anti-tumor activity. Similar to celecoxib, this compound could also inhibit matrix metalloproteinase (MMP)-9 activity. In addition, UTX-121 suppressed membrane-type 1 MMP (MT1-MMP)-mediated pro-MMP-2 activation by disturbing the cell surface expression of MT1-MMP. UTX-121 also impeded the glycosylation of cell surface proteins, resulting in the suppression of cell attachment to fibronectin. This inhibition by UTX-121 caused the reduction of fibronectin-stimulated focal adhesion kinase activation, Akt activation, and cell migration. Consequently, UTX-121 treatment significantly inhibited fibronectin-induced HT1080â¯cell invasion into the Matrigel. UTX-121 may be a potent lead compound that can be used to develop a novel anti-tumor drug.
