Induction of apoptosis in human leukemia cells by MCS-C2 via caspase-dependent Bid cleavage and cytochrome c release

Kim, Min Kyoung; Cho, Youl-Hee; Kim, Jung Mogg; Chun, Moon Woo; Lee, Seung Ki; Lim, Yoongho; Lee, Chul-Hoon

doi:10.1016/j.canlet.2004.10.045

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Volume 223, Issue 2 , Pages 239-247, 8 June 2005

Induction of apoptosis in human leukemia cells by MCS-C2 via caspase-dependent Bid cleavage and cytochrome c release

Min Kyoung Kim
- Department of Medical Genetics and Institute of Biomedical Science, Hanyang University College of Medicine, Seoul 133-791, South Korea
Youl-Hee Cho
- Department of Medical Genetics and Institute of Biomedical Science, Hanyang University College of Medicine, Seoul 133-791, South Korea
Jung Mogg Kim
- Department of Microbiology, Hanyang University College of Medicine, Seoul 133-791, South Korea
Moon Woo Chun
- College of Pharmacy, Seoul National University, Seoul 151-742, South Korea
Seung Ki Lee
- College of Pharmacy, Seoul National University, Seoul 151-742, South Korea
Yoongho Lim
- Department of Applied Biology and Chemistry, Bio/Molecular Informatics Center, Konkuk University, Seoul 143-701, South Korea
Chul-Hoon Lee
- Department of Medical Genetics and Institute of Biomedical Science, Hanyang University College of Medicine, Seoul 133-791, South Korea
- Corresponding author. Tel.: +82 2 2290 0673; fax: +82 2 2298 5737.

Received 20 January 2004; received in revised form 13 September 2004; accepted 20 October 2004.

Abstract

The purpose of the present study was to investigate the anti-proliferative and apoptotic effects of MCS-C2, a novel synthetic analogue of the pyrrolo[2,3-d]pyrimidine nucleoside toyocamycin and sangivamycin, in human promyelocytic leukemia (HL-60) cells. When treated with 5μM MCS-C2, inhibited proliferation associated with apoptotic induction was found in the HL-60 cells in a concentration-dependent and time-dependent manner, plus nuclear DAPI staining revealed the typical nuclear features of apoptosis. However, MCS-C2 showed almost no antiproliferative effect and no apoptotic induction in normal lymphocyte cells used as a control when compared with those in HL-60 cancer cells. Moreover, a flow cytometric analysis of the HL-60 cells using FITC-dUTP and propidium iodide (PI) showed that the apoptotic cell population increased gradually from <1% at 0h to 34% at 12h after exposure to 5μM MCS-C2. This apoptotic induction was associated with the cleavage of Bid and a release of cytochrome c from mitochondria into the cytosol, followed by the activation of caspase-3 and inactivation of poly(ADP-ribose) polymerase (PARP). However, there was no significant change in any other mitochondrial membrane proteins, such as Bcl-2 and Bax. Consequently, the current findings suggest that the mitochondrial pathway was primarily involved in the MCS-C2-induced apoptosis in the human promyelocytic leukemia HL-60 cells.