Shin Meong Cheol, Min Kyoung Ah, Cheong Heesun, Moon Cheol, Huang Yongzhuo, He Huining, Yang Victor C
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.
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.
Int J Pharm. 2017 May 30;524(1-2):101-110. doi: 10.1016/j.ijpharm.2017.03.072. Epub 2017 Mar 27.
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.
尽管前列腺癌治疗取得了显著进展，但它仍是美国诊断出的主要癌症，且导致癌症相关死亡的发生率很高。由于小分子抗癌药物疗效不足，人们对更有效的大分子药物产生了浓厚兴趣，比如相思豆毒素，一种植物来源的核糖体失活蛋白（RIP），它能有效抑制蛋白质翻译。然而，尽管相思豆毒素具有强大的杀死肿瘤细胞的能力，但它缺乏内化肿瘤细胞的能力，而且无法区分肿瘤细胞和正常细胞。为应对这一挑战，我们通过基因工程构建了具有不同数量F3肽的相思豆毒素融合蛋白，这些F3肽对各种癌细胞和血管生成血管具有归巢能力。大肠杆菌产生的F3-相思豆毒素融合蛋白在无细胞蛋白质翻译系统中抑制蛋白质翻译的活性与未修饰的相思豆毒素相当；然而，它们表现出更高的细胞摄取率，从而导致细胞毒性显著增强。与含有一个F3肽的相思豆毒素融合蛋白（F3-Gel）相比，串联多聚体F3-相思豆毒素表现出更强的细胞内化和肿瘤细胞杀伤能力。此外，在用携带LNCaP皮下异种移植瘤的小鼠进行测试时，用串联多聚体F3-相思豆毒素治疗的小鼠观察到更显著的肿瘤生长抑制。总体而言，这项研究证明了利用串联多聚体F3修饰的相思豆毒素作为高效抗癌药物来克服当前化疗药物局限性的潜力。
