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Cryptotanshinone enhances TNF-α-induced apoptosis in chronic myeloid leukemia KBM-5 cells

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Abstract

Cryptotanshinone is a biologically active compound from the root of Salvia miltiorrhiza. In the present study, we investigated the molecular mechanisms by which cryptotanshinone is in synergy with tumor necrosis factor-alpha (TNF-α) for the induction of apoptosis in human chronic myeloid leukemia (CML) KBM-5 cells. The co-treatment of cryptotanshinone with TNF-α reduced the viability of the cells [combination index (CI) < 1]. Concomitantly, the co-treatment of cryptotanshinone and TNF-α elicited apoptosis, manifested by enhanced the number of terminal deoxynucleotide transferase-mediated dUTP-nick-end labeling (TUNEL)-positive cells, the sub-G1 cell populations, and the activation of caspase-8 and -3, in comparison with the treatment with either drug alone. The treatment with cryptotanshinone further suppressed TNF-α-mediated expression of c-FLIPL, Bcl-xL, but the increased level of tBid (a caspase-8 substrate). Furthermore, cryptotanshinone activated p38 but not NF-κB in TNF-α-treated KBM-5 cells. The addition of a specific p38 MAPK inhibitor SB203580 significantly attenuated cryptotanshinone/TNF-α-induced apoptosis. The combination treatment of cryptotanshinone and TNF-α also stimulated the reactive oxygen species (ROS) generation. N-acetyl-l-cysteine (NAC, a ROS scavenger) was not only able to block cryptotanshinone/TNF-α-induced ROS production but also the activation of caspase-8 and p38 MAPK. Overall, our findings suggest that cryptotanshinone can sensitize TNF-α-induced apoptosis in human myeloid leukemia KBM-5 cells, which appears through ROS-dependent activation of caspase-8 and p38.

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Acknowledgments

The present study was supported by the Korea Science and Engineering Foundation (KOSEF) grant funded by the Korea government (MEST) (No. 2011-0063466). We thank to Dr. Aggarwal (The University of Texas M.D. Anderson Cancer Center) for providing KBM-5 cell line.

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Authors and Affiliations

  1. Cancer Preventive Material Development Research Center, College of Oriental Medicine, Kyung Hee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul, 130-701, South Korea

    Ji-Hyun Kim, Soo-Jin Jeong, Tae-Rin Kwon, Sun-Mi Yun, Ji Hoon Jung, Hyo-Jung Lee, Seong Gyu Ko & Sung-Hoon Kim

  2. College of Dental Medicine, Tufts University, Boston, MA, 02111, USA

    Minseok Kim

  3. College of Life Sciences and Biotechnology, Kyung Hee University, Seoul, 130-701, Republic of Korea

    Min-Ho Lee

  4. Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA

    Chang-Yan Chen

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  1. Ji-Hyun Kim
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Correspondence to Ji-Hyun Kim.

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Ji-Hyun Kim, Soo-Jin Jeong contributed equally to this work.

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Kim, JH., Jeong, SJ., Kwon, TR. et al. Cryptotanshinone enhances TNF-α-induced apoptosis in chronic myeloid leukemia KBM-5 cells. Apoptosis 16, 696–707 (2011). https://doi.org/10.1007/s10495-011-0605-1

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