title: Dual Stimuli-Activatable Oxidative Stress Amplifying Agent as a Hybrid Anticancer Prodrug.
abstract: Compared to normal cells, cancer cells have a higher level of reactive oxygen species (ROS) due to aberrant metabolism and disruption of redox homeostasis which drive their proliferation and promote progression and metastasis of cancers. The altered redox balance and biological difference between normal cells and cancer cells provide a basis for the development of anticancer agents which are able to generate pharmacological ROS insults to kill cancer cells preferentially. In this study, we report a new hybrid anticancer drug, termed OSamp, which undergoes esterase- and acid-catalyzed hydrolysis to deplete antioxidant glutathione (GSH) and generate ROS, simultaneously. OSamp significantly elevated oxidative stress in cancer cells, leading to enhanced apoptotic cancer cell death through mitochondrial membrane disruption, cytochrome c release, activation of pro-caspase 3, and deactivation of STAT3 (signal transducer and activator of transcription-3). OSamp, administered intravenously, significantly suppressed the tumor growth in a mouse model of tumor xenografts without notable side effects. Oxidative stress amplifying OSamp holds tremendous potential as a new anticancer therapeutic and provides a new therapeutic paradigm which can be extended to development of hybrid anticancer drugs.
authors.affiliation: Department of BIN Convergence Technology and ‡Department of Polymer·Nano Science and Technology, Chonbuk National University , Baekjedaero 567, Jeonju, Chonbuk, 567-756, Republic of Korea.
authors.forename: Eunji
authors.initials: E
authors.lastname: Han
authors.affiliation: Department of BIN Convergence Technology and ‡Department of Polymer·Nano Science and Technology, Chonbuk National University , Baekjedaero 567, Jeonju, Chonbuk, 567-756, Republic of Korea.
authors.forename: Byeongsu
authors.initials: B
authors.lastname: Kwon
authors.affiliation: Department of BIN Convergence Technology and ‡Department of Polymer·Nano Science and Technology, Chonbuk National University , Baekjedaero 567, Jeonju, Chonbuk, 567-756, Republic of Korea.
authors.forename: Donghyuck
authors.initials: D
authors.lastname: Yoo
authors.affiliation: Department of BIN Convergence Technology and ‡Department of Polymer·Nano Science and Technology, Chonbuk National University , Baekjedaero 567, Jeonju, Chonbuk, 567-756, Republic of Korea.
authors.forename: Changsun
authors.initials: C
authors.lastname: Kang
authors.affiliation: Department of BIN Convergence Technology and ‡Department of Polymer·Nano Science and Technology, Chonbuk National University , Baekjedaero 567, Jeonju, Chonbuk, 567-756, Republic of Korea.
authors.forename: Gilson
authors.identifier: 0000-0002-6452-5653
authors.initials: G
authors.lastname: Khang
authors.affiliation: Department of BIN Convergence Technology and ‡Department of Polymer·Nano Science and Technology, Chonbuk National University , Baekjedaero 567, Jeonju, Chonbuk, 567-756, Republic of Korea.
authors.forename: Dongwon
authors.identifier: 0000-0003-3035-6342
authors.initials: D
authors.lastname: Lee
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015195:Drug Design; D006801:Humans; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects*; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D011355:Prodrugs; D017382:Reactive Oxygen Species