title: Tandem-multimeric F3-gelonin fusion toxins for enhanced anti-cancer activity for prostate cancer treatment.
abstract: Despite significant progress in prostate cancer treatment, yet, it remains the leading diagnosed cancer and is responsible for high incidence of cancer related deaths in the U.S. Because of the insufficient efficacy of small molecule anti-cancer drugs, significant interest has been drawn to more potent macromolecular agents such as gelonin, a plant-derived ribosome inactivating protein (RIP) that efficiently inhibits protein translation. However, in spite of the great potency to kill tumor cells, gelonin lacks ability to internalize tumor cells and furthermore, cannot distinguish between tumor and normal cells. To address this challenge, we genetically engineered gelonin fusion proteins with varied numbers of F3 peptide possessing homing ability to various cancer cells and angiogenic blood vessels. The E. coli produced F3-gelonin fusion proteins possessed equipotent activity to inhibit protein translation in cell-free protein translation systems to unmodified gelonin; however, they displayed higher cell uptake that led to significantly augmented cytotoxicity. Compared with gelonin fusion with one F3 peptide (F3-Gel), tandem-multimeric F3-gelonins showed even greater cell internalization and tumor cell killing ability. Moreover, when tested against LNCaP s.c. xenograft tumor bearing mice, more significant tumor growth inhibition was observed from the mice treated with tandem-multimeric F3-gelonins. Overall, this research demonstrated the potential of utilizing tandem multimeric F3-modified gelonin as highly effective anticancer agents to overcome the limitations of current chemotherapeutic drugs.
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, 501 Jinju Daero, Jinju, Gyeongnam, 660-751, Republic of Korea; 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, MI 48109, USA.
authors.forename: Meong Cheol
authors.initials: MC
authors.lastname: Shin
authors.affiliation: 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, MI 48109, USA; College of Pharmacy and Inje Institute of Pharmaceutical Sciences and Research, Inje University, 197 Injero, Gimhae, Gyeongnam, 621-749, Republic of Korea.
authors.forename: Kyoung Ah
authors.initials: KA
authors.lastname: Min
authors.affiliation: Comparative Biomedicine Research Branch, Division of Cancer Biology, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi-do, 10408, Republic of Korea.
authors.forename: Heesun
authors.initials: H
authors.lastname: Cheong
authors.affiliation: College of Pharmacy, Sunchon National University, 255 Jungang-ro, Suncheon, Jeonnam 57922, Republic of Korea.
authors.forename: Cheol
authors.initials: C
authors.lastname: Moon
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Hai-ke Rd, Shanghai 201203, China.
authors.forename: Yongzhuo
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnosis, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Huining
authors.initials: H
authors.lastname: He
authors.affiliation: 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, MI 48109, USA. Electronic address: vcyang@umich.edu.
authors.forename: Victor C
authors.initials: VC
authors.lastname: Yang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004926:Escherichia coli; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy*; D010940:Plant Proteins / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D054788:Ribosome Inactivating Proteins / Q000494:pharmacology*; D054789:Ribosome Inactivating Proteins, Type 1 / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D010940:Plant Proteins; D011993:Recombinant Fusion Proteins; D054789:Ribosome Inactivating Proteins, Type 1; C025674:GEL protein, Gelonium multiflorum; D054788:Ribosome Inactivating Proteins
keywords: F3 peptide; Gelonin; Multimeric; Prostate cancer; Ribosome inactivating protein