title: Antitumor and modeling studies of a penetratin-peptide that targets E2F-1 in small cell lung cancer.
abstract: E2F-1, a key transcription factor necessary for cell growth, DNA repair, and differentiation, is an attractive target for development of anticancer drugs in tumors that are E2F "oncogene addicted". We identified a peptide isolated from phage clones that bound tightly to the E2F-1 promoter consensus sequence. The peptide was coupled to penetratin to enhance cellular uptake. Modeling of the penetratin-peptide (PEP) binding to the DNA E2F-1 promoter demonstrated favorable interactions that also involved the participation of most of the penetratin sequence. The penetratin-peptide (PEP) demonstrated potent in vitro cytotoxic effects against a range of cancer cell lines, particularly against Burkitt lymphoma cells and small cell lung cancer (SCLC) cells. Further studies in the H-69 SCLC cell line showed that the PEP inhibited transcription of E2F-1 and also several important E2F-regulated enzymes involved in DNA synthesis, namely, thymidylate synthase, thymidine kinase, and ribonucleotide reductase. As the PEP was found to be relatively unstable in serum, it was encapsulated in PEGylated liposomes for in vivo studies. Treatment of mice bearing the human small cell lung carcinoma H-69 with the PEP encapsulated in PEGylated liposomes (PL-PEP) caused tumor regression without significant toxicity. The liposome encapsulated PEP has promise as an antitumor agent, alone or in combination with inhibitors of DNA synthesis.
authors.affiliation: Department of Pharmacology and Medicine, Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ USA.
authors.forename: Xiaoqi
authors.initials: X
authors.lastname: Xie
authors.forename: John E
authors.initials: JE
authors.lastname: Kerrigan
authors.forename: Tamara
authors.initials: T
authors.lastname: Minko
authors.forename: Olga
authors.initials: O
authors.lastname: Garbuzenko
authors.forename: Kuo-Chieh
authors.initials: KC
authors.lastname: Lee
authors.forename: Alex
authors.initials: A
authors.lastname: Scarborough
authors.forename: Emine Ercikan
authors.initials: EE
authors.lastname: Abali
authors.forename: Tulin
authors.initials: T
authors.lastname: Budak-Alpdogan
authors.forename: Nadine
authors.initials: N
authors.lastname: Johnson-Farley
authors.forename: Debabrata
authors.initials: D
authors.lastname: Banerjee
authors.forename: Kathleen W
authors.initials: KW
authors.lastname: Scotto
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Bertino
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D057846:Cell-Penetrating Peptides; D015536:Down-Regulation; D004354:Drug Screening Assays, Antitumor; D050687:E2F1 Transcription Factor / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D058990:Molecular Targeted Therapy; D010446:Peptide Fragments / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011897:Random Allocation; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D002352:Carrier Proteins; D057846:Cell-Penetrating Peptides; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D010446:Peptide Fragments; D012333:RNA, Messenger; C414409:penetratin
keywords: E2F-1; mouse xenografts; pegylated liposomes; penetratin peptide; small cell lung cancer