title: Combination of the PI3K inhibitor ZSTK474 with a PSMA-targeted immunotoxin accelerates apoptosis and regression of prostate cancer.
abstract: The phosphoinositide 3-kinase (PI3K) pathway is activated in most advanced prostate cancers, yet so far treatments with PI3K inhibitors have been at best tumorostatic in preclinical cancer models and do not show significant antitumor efficacy in clinical trials. Results from tissue culture experiments in prostate cancer cells suggest that PI3K inhibitors should be combined with other cytotoxic agents; however, the general toxicity of such combinations prevents translating these experimental data into preclinical and clinical models. We investigated the emerging concept of tumor-targeted synthetic lethality in prostate cancer cells by using the pan-PI3K inhibitor ZSTK474 and the immunotoxin J591PE, a protein chimera between the single-chain variable fragment of the monoclonal antibody J591 against the prostate-specific membrane antigen (PSMA) and the truncated form of the Pseudomonas aeruginosa exotoxin A (PE38QQR). The combination of ZSTK474 and J591PE increased apoptosis within 6 hours and cell death (monitored at 24-48 hours) in the PSMA-expressing cells LNCaP, C4-2, and C4-2Luc but not in control cells that do not express PSMA (PC3 and BT549 cells). Mechanistic analysis suggested that induction of apoptosis requires Bcl-2-associated death promoter (BAD) dephosphorylation and decreased expression of myeloid leukemia cell differentiation protein 1 (MCL-1). A single injection of ZSTK474 and J591PE into engrafted prostate cancer C4-2Luc cells led to consistent and stable reduction of luminescence within 6 days. These results suggest that the combination of a PI3K inhibitor and a PSMA-targeted protein synthesis inhibitor toxin represents a promising novel strategy for advanced prostate cancer therapy that should be further investigated.
authors.affiliation: Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: Daniele
authors.initials: D
authors.lastname: Baiz
authors.forename: Sazzad
authors.initials: S
authors.lastname: Hassan
authors.forename: Young A
authors.initials: YA
authors.lastname: Choi
authors.forename: Anabel
authors.initials: A
authors.lastname: Flores
authors.forename: Yelena
authors.initials: Y
authors.lastname: Karpova
authors.forename: Dana
authors.initials: D
authors.lastname: Yancey
authors.forename: Ashok
authors.initials: A
authors.lastname: Pullikuth
authors.forename: Guangchao
authors.initials: G
authors.lastname: Sui
authors.forename: Michel
authors.initials: M
authors.lastname: Sadelain
authors.forename: Waldemar
authors.initials: W
authors.lastname: Debinski
authors.forename: George
authors.initials: G
authors.lastname: Kulik
mesh_terms: D036002:ADP Ribose Transferases / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology; D000954:Antigens, Surface / Q000276:immunology*; D017209:Apoptosis; D001427:Bacterial Toxins / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D005098:Exotoxins / Q000235:genetics / Q000276:immunology*; D043425:Glutamate Carboxypeptidase II / Q000276:immunology*; D064593:Heterografts; D006801:Humans; D000922:Immunotoxins / Q000235:genetics / Q000276:immunology*; D008297:Male; D008807:Mice, Inbred BALB C; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011471:Prostatic Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D011550:Pseudomonas aeruginosa; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D057127:Single-Chain Antibodies / Q000235:genetics / Q000276:immunology; D014227:Triazines / Q000494:pharmacology*; D037521:Virulence Factors / Q000235:genetics / Q000276:immunology*; D000097668:Pseudomonas aeruginosa Exotoxin A
chemical_list: D036002:ADP Ribose Transferases; D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D001427:Bacterial Toxins; D005098:Exotoxins; D043425:Glutamate Carboxypeptidase II; D000922:Immunotoxins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011993:Recombinant Fusion Proteins; D057127:Single-Chain Antibodies; D014227:Triazines; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C579095:MCL1 protein, human; C510150:ZSTK474; C473848:FOLH1 protein, human