These authors contributed equally to this work.
Antitumor effects with apoptotic death in human promyelocytic leukemia HL-60 cells and suppression of leukemia xenograft tumor growth by irinotecan HCl
Version of Record online: 29 JAN 2014
© 2014 Wiley Periodicals, Inc.
Volume 30, Issue 7, pages 803–815, July 2015
How to Cite
Chen, Y.-L., Chueh, F.-S., Yang, J.-S., Hsueh, S.-C., Lu, C.-C., Chiang, J.-H., Lee, C.-S., Lu, H.-F. and Chung, J.-G. (2015), Antitumor effects with apoptotic death in human promyelocytic leukemia HL-60 cells and suppression of leukemia xenograft tumor growth by irinotecan HCl. Environ. Toxicol., 30: 803–815. doi: 10.1002/tox.21959
- Issue online: 12 JUN 2015
- Version of Record online: 29 JAN 2014
- Manuscript Accepted: 9 JAN 2014
- Manuscript Received: 15 APR 2013
- China Medical University and by the Taiwan Department of Health. Grant Number: CMU100-ASIA-4
- China Medical University Hospital Cancer Research Center of Excellence. Grant Number: DOH101-TD-C-111-005
- National Science Council of the Republic of China (Taiwan). Grant Number: NSC100-2320-B-039-004-
- irinotecan HCl;
- in vitro;
- tumor xenograft model
Irinotecan HCl (CPT-11) is an anticancer prodrug, but there is no available information addressing CPT-11-inhibited leukemia cells in in vitro and in vivo studies. Therefore, we investigated the cytotoxic effects of CPT-11 in promyelocytic leukemia HL-60 cells and in vivo and tumor growth in a leukemia xenograft model. Effects of CPT-11 on HL-60 cells were determined using flow cytometry, immunofluorescence staining, comet assay, real-time PCR, and Western blotting. CPT-11 demonstrated a dose- and time-dependent inhibition of cell growth, induction of apoptosis, and cell-cycle arrest at G0/G1 phase in HL-60 cells. CPT-11 promoted the release of AIF from mitochondria and its translocation to the nucleus. Bid, Bax, Apaf-1, caspase-9, AIF, Endo G, caspase-12, ATF-6b, Grp78, CDK2, Chk2, and cyclin D were all significantly upregulated and Bcl-2 was down-regulated by CPT-11 in HL-60 cells. Induction of cell-cycle arrest by CPT-11 was associated with changes in expression of key cell-cycle regulators such as CDK2, Chk2, and cyclin D in HL-60 cells. To test whether CPT-11 could augment antitumor activity in vivo, athymic BALB/cnu/nu nude mice were inoculated with HL-60 cells, followed by treatment with either CPT-11. The treatments significantly inhibited tumor growth and reduced tumor weight and volume in the HL-60 xenograft mice. The present study demonstrates the schedule-dependent antileukemia effect of CPT-11 using both in vitro and in vivo models. CPT-11 could potentially be a promising agent for the treatment of promyelocytic leukemia and requires further investigation. © 2014 Wiley Periodicals, Inc. Environ Toxicol 30: 803–815, 2015.