PRIMA-1 inhibits growth of breast cancer cells by re-activating mutant p53 protein.
Mutation of the p53 tumor suppressor gene is a common event in many types of tumors, including breast cancers. Mutant p53 (mtp53) protein is thought to promote tumor cell survival and resistance to chemotherapeutic drugs. Therefore, restoring p53 function by converting existing mtp53 to the wild-type p53 (wtp53) conformation is being pursued as one strategy to promote apoptosis of tumor cells. PRIMA-1 (p53 re-activation and induction of massive apoptosis) is a non-toxic small molecule that converts mtp53 to the active conformation and induces apoptosis in tumor cells. Here we examined whether PRIMA-1 activates mtp53 and induces cell death in vitro and in vivo in estrogen-responsive breast cancer cell lines that express mtp53 (BT-474, HCC-1428, and T47-D). Fluorescent staining with conformation-specific p53 antibodies demonstrated that PRIMA-1 converted mtp53 into the wtp53 conformation. In vitro treatment of tumor cells with PRIMA-1 (0-50 microM) led to a dose-dependent loss of cell viability and induced cell death markers. In contrast, PRIMA-1 had no effect on the viability of MCF-7 cells, normal breast cells, and endothelial cells, all of which express wtp53 protein. PRIMA-1 treatment of mice inhibited the growth of tumors from xenografts of BT-474, HCC-1428, and T47-D cells but did not influence xenografts obtained from MCF-7 cells. Mechanistic studies showed that PRIMA-1 induced the mitochondrial-dependent apoptotic pathway in mtp53-expressing breast cancer cells. Our findings suggest that PRIMA-1 renews the susceptibility of mtp53-expressing breast tumors to apoptosis and should be investigated for use in breast cancer therapy.
Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO 65211, USA.
Yayun
Y
Liang
Cynthia
C
Besch-Williford
Salman M
SM
Hyder
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001372:Aza Compounds / Q000494:pharmacology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D001372:Aza Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D016159:Tumor Suppressor Protein p53; C451219:2,2-bis(hydroxymethyl)-1-azabicyclo(2,2,2,)octan-3-one