T315 Decreases Acute Myeloid Leukemia Cell Viability through a Combination of Apoptosis Induction and Autophagic Cell Death

International Journal of Molecular Sciences

Aaron M. Sargeant¹  Chia-Yung Wu²  Jing-Ru Weng³  Li-Yuan Bai⁴  Chang-Fang Chiu⁴  Appaso Jadhav⁵ 

[1] Charles River Laboratories, Preclinical Services, Spencerville, OH 45887, USA;Department of Biological Science and Technology, China Medical University, Taichung 40402, Taiwan;Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 80424, Taiwan;Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung 40447, Taiwan;Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA;

关键词: T315;    acute myeloid leukemia;    apoptosis;    autophagy;    autophagic cell death;   

DOI  :  10.3390/ijms17081337

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown