1. ¹Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
2. ²The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA
3. ³Faculty of Dentistry, Thammasat University (Rangsit Campus), Pathum-thani, Thailand
4. ⁴Institute for Drug Development, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
5. ⁵Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Correspondence: Professor P Huang, Department of Molecular Pathology, University of Texas, MD Anderson Cancer Center. Box 0951, 1515 Holcombe Boulevard, Houston, TX 77030, USA. E-mail: phuang@mdanderson.org

Received 22 November 2007; Revised 13 February 2008; Accepted 25 February 2008; Published online 3 April 2008.

Abstract

Mutation of Bcr-Abl is an important mechanism by which chronic myelogenous leukemia (CML) cells become resistant to Gleevec. The T315I mutation is clinically significant since CML cells harboring this mutation are insensitive to Gleevec and other Bcr-Abl-targeted drugs. Identification of new agents capable of effectively killing CML cells with T315I mutation would have important therapeutic implications in Gleevec-resistant CML. Here, we showed that -phenylethyl isothiocyanate (PEITC), a natural compound found in vegetables, is effective in killing CML cells expressing T315I BCR-ABL. Treatment of leukemia cell lines harboring wild-type or mutant Bcr-Abl with 10 M PEITC resulted in an elevated ROS stress and a redox-mediated degradation of the BCR-ABL protein, leading to massive death of the leukemia cells. Antioxidant NAC attenuated the PEITC-induced oxidative stress in CML cells and prevented the degradation of BCR-ABL, caspase-3 activation and cell death. We further showed that the ROS-induced degradation of BCR-ABL was mediated partially by caspase-3 and the proteasome pathway. The ability of PEITC to effectively kill T315I-positive CML cells was further confirmed using primary leukemia cells isolated from CML patients. Our results suggest that PEITC is a promising compound capable of killing Gleevec-resistant CML cells through a ROS-mediated mechanism and warrants further investigations.