title: Mitochondrial targeted β-lapachone induces mitochondrial dysfunction and catastrophic vacuolization in cancer cells.
abstract: Mitochondria play important roles in tumor cell physiology and survival by providing energy and metabolites for proliferation and metastasis. As part of their oncogenic status, cancer cells frequently produce increased levels of mitochondrial-generated reactive oxygen species (ROS). However, extensive stimulation of ROS generation in mitochondria has been shown to be able to induce cancer cell death, and is one of the major mechanisms of action of many anticancer agents. We hypothesized that enhancing mitochondrial ROS generation through direct targeting of a ROS generator into mitochondria will exhibit tumor cell selectivity, as well as high efficacy in inducing cancer cell death. We thus synthesized a mitochondrial targeted version of β-lapachone (XJB-Lapachone) based on our XJB mitochondrial targeting platform. We found that the mitochondrial targeted β-lapachone is more efficient in inducing apoptosis compared to unconjugated β-lapachone, and the tumor cell selectivity is maintained. XJB-Lapachone also induced extensive cellular vacuolization and autophagy at a concentration not observed with unconjugated β-lapachone. Through characterization of mitochondrial function we revealed that XJB-Lapachone is indeed more capable of stimulating ROS generation in mitochondria, which led to a dramatic mitochondrial uncoupling and autophagic degradation of mitochondria. Taken together, we have demonstrated that targeting β-lapachone accomplishes higher efficacy through inducing ROS generation directly in mitochondria, resulting in extensive mitochondrial and cellular damage. XJB-Lapachone will thus help to establish a novel platform for the design of next generation mitochondrial targeted ROS generators for cancer therapy.
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, and Hillman Cancer Center, University of Pittsburgh Cancer Institute, 5117 Centre Avenue, Pittsburgh, PA 15213, United States; Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College of HuaZhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, PA 15260, United States; Accelerated Chemical Discovery Center, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, PA 15260, United States.
authors.forename: Chaemin
authors.initials: C
authors.lastname: Lim
authors.affiliation: Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, PA 15260, United States.
authors.forename: Joshua R
authors.initials: JR
authors.lastname: Sacher
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, and Hillman Cancer Center, University of Pittsburgh Cancer Institute, 5117 Centre Avenue, Pittsburgh, PA 15213, United States.
authors.forename: Bennett
authors.initials: B
authors.lastname: Van Houten
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, and Hillman Cancer Center, University of Pittsburgh Cancer Institute, 5117 Centre Avenue, Pittsburgh, PA 15213, United States. Electronic address: qianw@upmc.edu.
authors.forename: Wei
authors.initials: W
authors.lastname: Qian
authors.affiliation: Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, PA 15260, United States; Accelerated Chemical Discovery Center, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, PA 15260, United States. Electronic address: pwipf@pitt.edu.
authors.forename: Peter
authors.initials: P
authors.lastname: Wipf
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D015394:Molecular Structure; D009285:Naphthoquinones / Q000494:pharmacology*; D009369:Neoplasms / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship; D014617:Vacuoles / Q000187:drug effects*
chemical_list: D009285:Naphthoquinones; D017382:Reactive Oxygen Species; C014638:beta-lapachone
keywords: Cytotoxicity; Lapachone; Mitochondria; Mitophagy; ROS; Vacuolization; XJB-5-131