title: Chemically and biologically synthesized CPP-modified gelonin for enhanced anti-tumor activity.
abstract: The ineffectiveness of small molecule drugs against cancer has generated significant interest in more potent macromolecular agents. Gelonin, a plant-derived toxin that inhibits protein translation, has attracted much attention in this regard. Due to its inability to internalize into cells, however, gelonin exerts only limited tumoricidal effect. To overcome this cell membrane barrier, we modified gelonin, via both chemical conjugation and genetic recombination methods, with low molecular weight protamine (LMWP), a cell-penetrating peptide (CPP) which was shown to efficiently ferry various cargoes into cells. Results confirmed that gelonin-LMWP chemical conjugate (cG-L) and recombinant gelonin-LMWP chimera (rG-L) possessed N-glycosidase activity equivalent to that of unmodified recombinant gelonin (rGel); however, unlike rGel, both gelonin-LMWPs were able to internalize into cells. Cytotoxicity studies further demonstrated that cG-L and rG-L exhibited significantly improved tumoricidal effects, with IC50 values being 120-fold lower than that of rGel. Moreover, when tested against a CT26 s.c. xenograft tumor mouse model, significant inhibition of tumor growth was observed with rG-L doses as low as 2 μg/tumor, while no detectable therapeutic effects were seen with rGel at 10-fold higher doses. Overall, this study demonstrated the potential of utilizing CPP-modified gelonin as a highly potent anticancer drug to overcome limitations of current chemotherapeutic agents.
authors: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnosis, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China; Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 428 Church St., Ann Arbor, 48109, USA.
authors: Meong Cheol
authors: MC
authors: Shin
authors: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnosis, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China; Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 428 Church St., Ann Arbor, 48109, USA.
authors: Jian
authors: J
authors: Zhang
authors: Department of Chemical Engineering, Auburn University, Auburn, AL 36849, USA.
authors: Allan E
authors: AE
authors: David
authors: Department of Chemistry, TU Kaiserslautern, P.O. Box 3049, D-67653 Kaiserslautern, Germany.
authors: Wolfgang E
authors: WE
authors: Trommer
authors: Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, 3200 S. University Dr., Ft. Lauderdale, FL 33328, USA.
authors: Young Min
authors: YM
authors: Kwon
authors: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 428 Church St., Ann Arbor, 48109, USA.
authors: Kyoung Ah
authors: KA
authors: Min
authors: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 428 Church St., Ann Arbor, 48109, USA.
authors: Jin H
authors: JH
authors: Kim
authors: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnosis, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China; Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 428 Church St., Ann Arbor, 48109, USA. Electronic address: vcyang@umich.edu.
authors: Victor C
authors: VC
authors: Yang
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D057846:Cell-Penetrating Peptides / Q000737:chemistry / Q000235:genetics / Q000627:therapeutic use; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000627:therapeutic use; D054789:Ribosome Inactivating Proteins, Type 1 / Q000737:chemistry* / Q000235:genetics / Q000627:therapeutic use*; D029843:Suregada / Q000737:chemistry
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D057846:Cell-Penetrating Peptides; D011993:Recombinant Fusion Proteins; D054789:Ribosome Inactivating Proteins, Type 1; C025674:GEL protein, Gelonium multiflorum
keywords: Cancer; Cell penetrating peptide; Gelonin; LMWP; Ribosome-inactivating protein; Toxin
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