ABSTRACT
Reactivation of the tumor suppressor activity to mutant p53 should trigger massive apoptosis and eliminate tumors. The low molecular weight compounds PRIMA-1 and the structural analog PRIMA-1MET reactivate human mutant p53 in vitro and suppress growth of human tumor xenografts in SCID mice. However, little is known about their effect on mouse mutant p53 in mouse tumor cells. We have examined the effect of PRIMA-1MET on mouse sarcomas, mammary carcinomas and chemically induced fibrosarcomas. PRIMA-1MET showed potent growth suppression in mutant p53-carrying mouse tumors in vitro and a significant anti-tumor effect in syngeneic mice in vivo. These results demonstrate that PRIMA-1MET targets mouse tumors carrying mutant p53 and provide strong support for the anti-tumor efficiency of PRIMA-1MET in vivo.
Subject(s)
Antineoplastic Agents/pharmacology , Aza Compounds/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Neoplasms, Experimental/drug therapy , Tumor Suppressor Protein p53/drug effects , Animals , Apoptosis/drug effects , Blotting, Western , Cell Line, Tumor , Cell Proliferation/drug effects , Flow Cytometry , In Situ Nick-End Labeling , Methylation , Mice , Neoplasms, Experimental/pathology , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
Reactivation of mutant p53 in human tumor cells should induce cell death by apoptosis and thus eliminate the tumor. Several small molecules that reactivate mutant p53 have been identified. Here we show that STIMA-1, a low molecular weight compound with some structural similarities to the previously identified molecule CP-31398, can stimulate mutant p53 DNA binding in vitro and induce expression of p53 target proteins and trigger apoptosis in mutant p53-expressing human tumor cells. Human diploid fibroblasts are significantly more resistant to STIMA-1 than mutant or wild type p53-carrying tumor cells. STIMA-1 may provide new insights into possible mechanisms of mutant p53 reactivation and thus facilitate the development of novel anticancer drugs that target mutant p53-carrying tumors.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Delivery Systems/methods , Neoplasms/drug therapy , Quinazolinones/pharmacology , Tumor Suppressor Protein p53/drug effects , Tumor Suppressor Protein p53/genetics , Vinyl Compounds/pharmacology , DNA/metabolism , Fibroblasts , Humans , Molecular Weight , Mutant Proteins/drug effects , Mutation , Neoplasms/pathology , Tumor Cells, Cultured , Tumor Suppressor Protein p53/metabolismABSTRACT
Reactivation of mutant p53 is likely to provide important benefits for treatment of chemotherapy- and radiotherapy-resistant tumors. We demonstrate here that the maleimide-derived molecule MIRA-1 can reactivate DNA binding and preserve the active conformation of mutant p53 protein in vitro and restore transcriptional transactivation to mutant p53 in living cells. MIRA-1 induced mutant p53-dependent cell death in different human tumor cells carrying tetracycline-regulated mutant p53. The structural analog MIRA-3 showed antitumor activity in vivo against human mutant p53-carrying tumor xenografts in SCID mice. The MIRA scaffold is a novel lead for the development of anticancer drugs specifically targeting mutant p53.
Subject(s)
Maleimides/pharmacology , Neoplasms/drug therapy , Neoplasms/genetics , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/physiology , Animals , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Separation , DNA/chemistry , Dose-Response Relationship, Drug , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , Glutathione Transferase/metabolism , Humans , Mice , Mice, SCID , Microscopy, Fluorescence , Models, Chemical , Mutation , Neoplasm Transplantation , Plasmids/metabolism , Protein Binding , Protein Conformation , Tetracycline/metabolism , Transcriptional Activation , Tumor Suppressor Protein p53/metabolismABSTRACT
Mutant p53-carrying tumors are often more resistant to chemotherapeutical drugs. We demonstrate here that the mutant p53-reactivating compound PRIMA-1(MET) acts synergistically with several chemotherapeutic drugs to inhibit tumor cell growth. Combined treatment with cisplatin and PRIMA-1(MET) resulted in a synergistic induction of tumor cell apoptosis and inhibition of human tumor xenograft growth in vivo in SCID mice. The induction of mutant p53 levels by chemotherapeutic drugs is likely to increase the sensitivity of tumor cells to PRIMA-1(MET). Thus, the combination of PRIMA-1(MET) with currently used chemotherapeutic drugs may represent a novel and more efficient therapeutic strategy for treatment of mutant p53-carrying tumors.