Enhanced targeting and killing of tumor cells expressing the CXC chemokine receptor 4 by transducible anticancer peptides.
Protein transduction domains (PTDs), such as the TAT PTD, have been shown to deliver a wide variety of cargo in cell culture and to treat preclinical models of cancer and cerebral ischemia. The TAT PTD enters cells by a lipid raft-dependent macropinocytosis mechanism that all cells perform. Consequently, PTDs resemble small-molecule therapeutics in their lack of pharmacologic tissue specificity in vivo. However, several human malignancies overexpress specific receptors, including HER2 in breast cancer, GnRH in ovarian carcinomas, and CXC chemokine receptor 4 (CXCR4) in multiple malignancies. To target tumor cells that overexpress the CXCR4 receptor, we linked the CXCR4 DV3 ligand to two transducible anticancer peptides: a p53-activating peptide (DV3-TATp53C') and a cyclin-dependent kinase 2 antagonist peptide (DV3-TAT-RxL). Treatment of tumor cells expressing the CXCR4 receptor with either the DV3-TATp53C' or DV3-TAT-RxL targeted peptides resulted in an enhancement of tumor cell killing compared with treatment with nontargeted parental peptides. In contrast, there was no difference between DV3 targeted peptide and nontargeted, parental peptide treatment of non-CXCR4-expressing tumor cells. These observations show that a multidomain approach can be used to further refine and enhance the tumor selectivity of biologically active, transducible macromolecules for treating cancer.
Snyder
Eric L
EL
Howard Hughes Medical Institute and Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, California 92037-0686, USA.
Saenz
Cheryl C
CC
Denicourt
Catherine
C
Meade
Bryan R
BR
Cui
Xian-Shu
XS
Kaplan
Ian M
IM
Dowdy
Steven F
SF
D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D015696:Gene Products, tat / Q000494:pharmacology*; D006801:Humans; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D019718:Receptors, CXCR4 / Q000096:biosynthesis* / Q000235:genetics; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000494:pharmacology*
D015696:Gene Products, tat; D010446:Peptide Fragments; D019718:Receptors, CXCR4; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53