Combination cancer chemotherapy with one compound: pluripotent bradykinin antagonists.
Lung and prostate cancers are major health problems worldwide. Treatments with standard chemotherapy agents are relatively ineffective. Combination chemotherapy gives better treatment than a single agent because the drugs can inhibit the cancer in different pathways, but new therapeutic agents are needed for the treatment of both tumor types. Bradykinin (BK) antagonists offer advantages of combination therapy in one compound. These promising multitargeted anti-cancer compounds selectively stimulate apoptosis in cancers and also inhibit both angiogenesis and matrix metalloprotease (MMP) action in treated lung and prostate tumors in nude mice. The highly potent, metabolism-resistant bradykinin antagonist peptide dimer, B-9870 [SUIM-(DArg-Arg-Pro-Hyp-Gly-Igl-Ser-DIgl-Oic-Arg)2] (SUIM=suberimidyl; Hyp=4-hydroxyproline; Igl=alpha-(2-indanyl)glycine; Oic=octahydroindole-2-carboxylic acid) and its non-peptide mimetic, BKM-570 [2,3,4,5,6-pentafluorocinnamoyl-(o-2,6-dichlorobenzyl)-L-tyrosine-N-(4-amino-2,2,6,6-tetramethylpiperidyl)amide] are superior to the widely used but toxic chemotherapeutic drugs cisplatin and taxotere. In certain combinations, they act synergistically with standard anti-cancer drugs. Due to its structure and biological activity, BKM-570 is an attractive lead compound for derivatization and evaluation for lung and prostate cancer drugs.
Stewart
John M
JM
Department of Biochemistry and Molecular Genetics, Cancer Center, and Pulmonary Hypertension Center, University of Colorado Health Sciences Center, Denver, CO 80262, USA. john.stewart@uchsc.edu
Gera
Lajos
L
Chan
Daniel C
DC
York
Eunice J
EJ
Simkeviciene
Vitalija
V
Bunn
Paul A
PA
Taraseviciene-Stewart
Laimute
L
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001920:Bradykinin / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006168:Guinea Pigs; D006801:Humans; D007082:Ileum / Q000187:drug effects; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008819:Mice, Nude; D009842:Oligopeptides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology; D005466:Fluorocarbons
D000970:Antineoplastic Agents; D001920:Bradykinin; D061965:Matrix Metalloproteinase Inhibitors; D009842:Oligopeptides; D010649:Phenylalanine; D014443:Tyrosine; C506334:BKM-1174; C506333:BKM-570; D005466:Fluorocarbons; C466459:CU201