title: T315 Decreases Acute Myeloid Leukemia Cell Viability through a Combination of Apoptosis Induction and Autophagic Cell Death.
abstract: T315, an integrin-linked kinase (ILK) inhibitor, has been shown to suppress the proliferation of breast cancer, stomach cancer and chronic lymphocytic leukemia cells. Here we demonstrate that T315 decreases cell viability of acute myeloid leukemia (AML) cell lines (HL-60 and THP-1) and primary leukemia cells from AML patients in a dose-responsive manner. Normal human bone marrow cells are less sensitive than leukemia cells to T315. T315 down regulates protein kinase B (Akt) and p-Akt and induces caspase activation, poly-ADP-ribose polymerase (PARP) cleavage, apoptosis and autophagy through an ILK-independent manner. Interestingly, pretreatment with autophagy inhibitors rescues cells from apoptosis and concomitant PARP cleavage, which implicates a key role of autophagic cell death in T315-mediated cytotoxicity. T315 also demonstrates efficacy in vivo, suppressing the growth of THP-1 xenograft tumors in athymic nude mice when administered intraperitoneally. This study shows that autophagic cell death and apoptosis cooperatively contribute to the anticancer activity of T315 in AML cells. In conclusion, the complementary roles of apoptotic and autophagic cell death should be considered in the future assessment of the translational value of T315 in AML therapy.
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung 40447, Taiwan. d5686@mail.cmuh.org.tw.|Cancer Center, China Medical University Hospital, Taichung 40447, Taiwan. d5686@mail.cmuh.org.tw.|College of Medicine, School of Medicine, China Medical University, Taichung 40402, Taiwan. d5686@mail.cmuh.org.tw.
authors.forename: Chang-Fang
authors.initials: CF
authors.lastname: Chiu
authors.affiliation: Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 80424, Taiwan. columnster@gmail.com.|Department of Biological Science and Technology, China Medical University, Taichung 40402, Taiwan. columnster@gmail.com.
authors.forename: Jing-Ru
authors.initials: JR
authors.lastname: Weng
authors.affiliation: Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA. appaso06@gmail.com.
authors.forename: Appaso
authors.initials: A
authors.lastname: Jadhav
authors.affiliation: Department of Biological Science and Technology, China Medical University, Taichung 40402, Taiwan. kelen0523@yahoo.com.tw.
authors.forename: Chia-Yung
authors.initials: CY
authors.lastname: Wu
authors.affiliation: Charles River Laboratories, Preclinical Services, Spencerville, OH 45887, USA. aaron.Sargeant@crl.com.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Sargeant
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung 40447, Taiwan. lybai6@gmail.com.|College of Medicine, School of Medicine, China Medical University, Taichung 40402, Taiwan. lybai6@gmail.com.
authors.forename: Li-Yuan
authors.initials: LY
authors.lastname: Bai
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D018922:HL-60 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000099200:Scaffold Protein ILK
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000099200:Scaffold Protein ILK
keywords: T315; acute myeloid leukemia; apoptosis; autophagic cell death; autophagy