Subject(s)
COVID-19 , Education, Pharmacy , Pharmacy Residencies , Pharmacy Service, Hospital , Students, Pharmacy , Humans , SARS-CoV-2ABSTRACT
Anoikis is defined as apoptosis, which is induced by inappropriate cell-matrix interactions. Cancer cells with anoikis resistance tend to undergo metastasis, and this phenomenon has been reported to be associated with integrin and FAK activity. HPW-RX40 is a derivative of 3,4-methylenedioxy-ß-nitrostyrene, which is known to prevent platelet aggregation by inhibition of integrin. In the present study, we investigated the effect of HPW-RX40 on an anoikis-resistant human breast cancer cell line MDA-MB-231. HPW-RX40 inhibited cell aggregation and induced cell death in suspending MDA-MB-231 cells, but had only little effect on the monolayer growth of adherent cells. Analysis of caspase activation and poly (ADP-ribose) polymerase (PARP) cleavage confirmed anoikis in HPW-RX40-treated suspending cancer cells. HPW-RX40 also affected the Bcl-2 family proteins in detached cancer cells. Furthermore, HPW-RX40 inhibited detachment-induced activation of FAK and the downstream phosphorylation of Src and paxillin, but did not affect this pathway in adherent cancer cells. We also found that the expression and activation of ß1 integrin in MDA-MB-231 cells were reduced by HPW-RX40. The combination of HPW-RX40 with an EGFR inhibitor led to enhanced anoikis and inhibition of the FAK pathway in breast cancer cells. Taken together, our results suggest that HPW-RX40 restores the anoikis sensitivity in the metastatic breast cancer cells by inhibiting integrin and subsequent FAK activation, and reveal a potential strategy for prevention of tumor metastasis.
Subject(s)
Anoikis/drug effects , Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Chlorobenzoates/pharmacology , Focal Adhesion Kinase 1/metabolism , Integrin beta1/metabolism , Signal Transduction/drug effects , Styrenes/pharmacology , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Apoptosis Regulatory Proteins/metabolism , Breast Neoplasms/enzymology , Breast Neoplasms/pathology , Cell Adhesion/drug effects , Cell Aggregation/drug effects , Cell Line, Tumor , Dose-Response Relationship, Drug , Enzyme Activation , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/metabolism , Female , Humans , Paxillin/metabolism , Phosphorylation , Protein Kinase Inhibitors/pharmacology , Quinazolines/pharmacology , Tyrphostins/pharmacology , src-Family Kinases/metabolismABSTRACT
Our previous studies demonstrated that two cytotoxic ß-nitrostyrene derivatives, 3,4-methylenedioxy-ß-nitrostyrene (MNS) and 4-O-benzoyl-3-methoxy-ß-nitrostyrene (BMNS) exhibit potent anti-platelet activities. In this study, a series of ß-nitrostyrenes were synthesized and subjected to anti-platelet aggregation assay and cytotoxicity assay. The mono- and di-substitutions on the B ring of BMNS tended to increase the anti-platelet activity and decrease the cytotoxic activity. Of these, compounds 19 and 24 exhibited the most potent inhibitory effects on thrombin- and collagen-induced platelet aggregation (IC(50)≤0.7 µM) without significant cytotoxicity on a human cancer cell line (up to 20 µM). Further studies indicated that compounds 19 and 24 inhibited platelet aggregation via prevention of glycoprotein IIb/IIIa activation. The potent and novel effects of BMNS derivatives make them attractive candidates for the development of new anti-platelet agents.