ABSTRACT
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.
Subject(s)
Antineoplastic Agents/pharmacology , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Bradykinin/antagonists & inhibitors , Oligopeptides/pharmacology , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Guinea Pigs , Humans , Ileum/drug effects , Matrix Metalloproteinase Inhibitors , Mice , Mice, Nude , Oligopeptides/administration & dosage , Oligopeptides/chemistry , Phenylalanine/analogs & derivatives , Phenylalanine/pharmacology , Rabbits , Rats , Structure-Activity Relationship , Tyrosine/analogs & derivatives , Tyrosine/pharmacologyABSTRACT
Bradykinin (BK) is an autocrine growth factor for lung and prostate cancers. BK also facilitates tumor extension by increasing tissue permeability and stimulating angiogenesis. Peptide BK antagonists are in development as potential new drugs for lung cancer. Newer nonpeptide BK antagonists have even higher potency against lung cancer, in vitro and in vivo. These compounds have now been applied to the study of prostate cancers, and have been found to be effective. Prostate cancer cell line PC3 is derived from a late-stage, hormone-independent, metastatic tumor; its growth is difficult to inhibit. Our established BK antagonists, while less effective against this line of prostate cancer in xenografts in nude mice than against lung cancer, are active and have led the way to development of new peptide and nonpeptide agents for prostate cancer. In addition to inhibiting cancer cell growth directly, they inhibit angiogenesis mediated by vascular endothelial growth factor, and inhibit increased tissue permeability mediated by membrane metalloproteases in these tumors. This class of compounds offers hope for development of new drugs for refractory prostate cancer.
Subject(s)
Angiogenesis Inhibitors/therapeutic use , Antineoplastic Agents/therapeutic use , Bradykinin Receptor Antagonists , Prostatic Neoplasms/drug therapy , Protease Inhibitors/therapeutic use , Angiogenesis Inhibitors/chemistry , Animals , Antineoplastic Agents/chemistry , Cell Membrane/enzymology , Endothelium, Vascular/cytology , Endothelium, Vascular/drug effects , Endothelium, Vascular/metabolism , Humans , Inhibitory Concentration 50 , Male , Metalloendopeptidases/antagonists & inhibitors , Mice , Mice, Nude , Neoplasm Transplantation , Prostatic Neoplasms/enzymology , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Protease Inhibitors/chemistry , Receptors, Bradykinin/biosynthesis , Structure-Activity Relationship , Tumor Cells, Cultured , Umbilical Cord/cytology , Umbilical Cord/drug effects , Umbilical Cord/metabolismABSTRACT
Bradykinin (BK) (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) is an important growth factor for small-cell lung cancer (SCLC) and prostate cancer (PC). These cancers have cells of neuroendocrine origin and express receptors for a variety of neuropeptides. BK receptors are expressed on almost all lung cancer cell lines and on many PC cells. Our very potent BK antagonist B9430 (D-Arg-Arg-Pro-Hyp-Gly-lgl-Ser-D-Igl-Oic-Arg) (Hyp, trans-4-hydroxy-L-proline; Ig1, alpha-2-indanylglycine; Oic, octahydroindole-2-carboxylic acid) is a candidate anti-inflammatory drug but does not inhibit growth of SCLC or PC. When B9430 is dimerized by N-terminal cross-linking with a suberimide linker, the product B9870 is a potent growth inhibitor for SCLC both in vitro and in vivo in athymic nude mice. Daily i.p. injection at 5 mg x kg(-1) day(-1) beginning on day 8 after SCLC SHP-77 cell implantation gave 65% inhibition of tumor growth. B9870 stimulates apoptosis in SCLC by a novel "biased agonist" action. We have also developed new small mimetic antagonists. BKM-570 (F5C-OC2Y-Atmp) (F5C, pentafluorocinnamic acid; OC2Y, O-2,6-dichlorobenzyl tyrosine; Atmp, 4-amino-2,2,6,6-tetramethylpiperidine) is very potent for inhibition of SHP-77 growth in nude mice. When injected daily i.p. at 5 mg x kg(-1), M-570 gave 90% suppression of tumor growth. M-570 is more potent than the well-known anticancer drug cisPlatin (60% inhibition) or the recently developed SU5416 (40% inhibition) in this model. M-570 also showed activity against various other cancer cell lines in vitro (SCLC, non-SCLC, lung, prostate, colon, cervix) and inhibited growth of prostate cell line PC3 in nude mice. M-570 and related compounds evidently act in vivo through pathways other than BK receptors. These compounds have clinical potential for treatment of human lung and prostate cancers.
