Beom Suk Lee1, Yong Woo Cho1, Gui Chul Kim1, Do Hee Lee1, Chang Jin Kim1, Hee Seup Kil1, Dae Yoon Chi1, Youngro Byun1, Soon Hong Yuk1, Kwangmeyung Kim1, In-San Kim1, Ick Chan Kwon2, Sang Yoon Kim2. 1. Department of Otolaryngology (BSL, GCK, SYK) and Department of Neurosurgery (DHL, CJK), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea (BSL, YWC, KK, ISK, ICK, SYK); Department of Chemical Engineering, Hanyang University, Gyeonggido, Republic of Korea (YWC); Department of Chemistry, Sogang University, Seoul, Republic of Korea (HSK, DYC); Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergent Science and Technology, Seoul National University, Seoul, Republic of Korea (YB); College of Pharmacy, Korea University, Sejong, Republic of Korea (SHY); Department of Biochemistry and Cell Biology, School of Medicine and Cell and Matrix Research Institute, Kyungpook National University, Daegu, Republic of Korea (ISK); KU-KIST School, Korea University, Seoul, Republic of Korea (ICK). 2. Department of Otolaryngology (BSL, GCK, SYK) and Department of Neurosurgery (DHL, CJK), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea (BSL, YWC, KK, ISK, ICK, SYK); Department of Chemical Engineering, Hanyang University, Gyeonggido, Republic of Korea (YWC); Department of Chemistry, Sogang University, Seoul, Republic of Korea (HSK, DYC); Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergent Science and Technology, Seoul National University, Seoul, Republic of Korea (YB); College of Pharmacy, Korea University, Sejong, Republic of Korea (SHY); Department of Biochemistry and Cell Biology, School of Medicine and Cell and Matrix Research Institute, Kyungpook National University, Daegu, Republic of Korea (ISK); KU-KIST School, Korea University, Seoul, Republic of Korea (ICK). sykim2@amc.seoul.kr ikwon@kist.re.kr.
Abstract
BACKGROUND: Tumor heterogeneity and evolutionary complexity may underlie treatment failure in spite of the development of many targeted agents. We suggest a novel strategy termed induced phenotype targeted therapy (IPTT) to simplify complicated targets because of tumor heterogeneity and overcome tumor evolutionary complexity. METHODS: We designed a caspase-3 specific activatable prodrug, DEVD-S-DOX, containing doxorubicin linked to a peptide moiety (DEVD) cleavable by caspase-3 upon apoptosis. To induce apoptosis locally in the tumor, we used a gamma knife, which can irradiate a very small, defined target area. The in vivo antitumor activity of the caspase-3-specific activatable prodrug combined with radiation was investigated in C3H/HeN tumor-bearing mice (n = 5 per group) and analyzed with the Student's t test or Mann-Whitney U test. All statistical tests were two-sided. We confirmed the basic principle using a caspase-sensitive nanoprobe (Apo-NP). RESULTS: A single exposure of radiation was able to induce apoptosis in a small, defined region of the tumor, resulting in expression of caspase-3. Caspase-3 cleaved DEVD and activated the prodrug. The released free DOX further activated DEVD-S-DOX by exerting cytotoxic effects on neighboring tumor or supporting cells, which repetitively induced the expression of caspase-3 and the activation of DEVD-S-DOX. This sequential and repetitive process propagated the induction of apoptosis. This novel therapeutic strategy showed not only high efficacy in inhibiting tumor growth (14-day tumor volume [mm(3)] vs radiation alone: 848.21 ± 143.24 vs 2511.50 ± 441.89, P < .01) but also low toxicity to normal cells and tissues. CONCLUSION: Such a phenotype induction strategy represents a conceptually novel approach to overcome tumor heterogeneity and complexity as well as to substantially improve current conventional chemoradiotherapy with fewer sequelae and side effects.
BACKGROUND:Tumor heterogeneity and evolutionary complexity may underlie treatment failure in spite of the development of many targeted agents. We suggest a novel strategy termed induced phenotype targeted therapy (IPTT) to simplify complicated targets because of tumor heterogeneity and overcome tumor evolutionary complexity. METHODS: We designed a caspase-3 specific activatable prodrug, DEVD-S-DOX, containing doxorubicin linked to a peptide moiety (DEVD) cleavable by caspase-3 upon apoptosis. To induce apoptosis locally in the tumor, we used a gamma knife, which can irradiate a very small, defined target area. The in vivo antitumor activity of the caspase-3-specific activatable prodrug combined with radiation was investigated in C3H/HeN tumor-bearing mice (n = 5 per group) and analyzed with the Student's t test or Mann-Whitney U test. All statistical tests were two-sided. We confirmed the basic principle using a caspase-sensitive nanoprobe (Apo-NP). RESULTS: A single exposure of radiation was able to induce apoptosis in a small, defined region of the tumor, resulting in expression of caspase-3. Caspase-3 cleaved DEVD and activated the prodrug. The released free DOX further activated DEVD-S-DOX by exerting cytotoxic effects on neighboring tumor or supporting cells, which repetitively induced the expression of caspase-3 and the activation of DEVD-S-DOX. This sequential and repetitive process propagated the induction of apoptosis. This novel therapeutic strategy showed not only high efficacy in inhibiting tumor growth (14-day tumor volume [mm(3)] vs radiation alone: 848.21 ± 143.24 vs 2511.50 ± 441.89, P < .01) but also low toxicity to normal cells and tissues. CONCLUSION: Such a phenotype induction strategy represents a conceptually novel approach to overcome tumor heterogeneity and complexity as well as to substantially improve current conventional chemoradiotherapy with fewer sequelae and side effects.
Authors: Shilpa Bhatia; Kellen Hirsch; Jaspreet Sharma; Ayman Oweida; Anastacia Griego; Stephen Keysar; Antonio Jimeno; David Raben; Valery Krasnoperov; Parkash S Gill; Elena B Pasquale; Xiao-Jing Wang; Sana D Karam Journal: Sci Rep Date: 2016-12-12 Impact factor: 4.379