Sulforaphane potentiates the efficacy of imatinib against chronic leukemia cancer stem cells through enhanced abrogation of Wnt/β-catenin function.
Sulforaphane (SFN) has been indicated for the prevention and suppression of tumorigenesis in solid tumors. Herein, we evaluated SFN's effects on imatinib (IM)-resistant leukemia stem cells (LSCs). CD34(+)/CD38(-) and CD34(+)/CD38(+) LSCs were isolated from KU812 cell line flowcytometrically. Isolated LSCs showed high expression of Oct4, CD133, β-catenin, and Sox2 and IM resistance. Differentially, CD34(+)/CD38(-) LSCs demonstrated higher BCR-ABL and β-catenin expression and imatinib (IM) resistance than CD34(+)/CD38(+) counterparts. IM and SFN combined treatment sensitized CD34(+)/CD38(-) LSCs and induced apoptosis, shown by increased caspase 3, PARP, and Bax while decreased Bcl-2 expression. Additionally, the combined treatment reduced BCR-ABL and β-catenin and MDR-1 protein expression. Mechanistically, IM and SFN combined treatment resensitized LSCs by inducing intracellular reactive oxygen species (ROS). Importantly, β-catenin-silenced LSCs exhibited reduced glutathione S-transferase pi 1 (GSTP1) expression and intracellular GSH level, which led to increased sensitivity toward IM and SFN. We demonstrated that IM and SFN combined treatment effectively eliminated CD34(+)/CD38(-) LSCs. Since SFN has been shown well tolerated in both animals and human, this regimen could be considered for clinical trials.
Department of Radiation Oncology, Chi-Mei Foundation Medical Center, Tainan, Taiwan.
Li-Ching
LC
Lin
Chi-Tai
CT
Yeh
Chia-Chun
CC
Kuo
Chi-Ming
CM
Lee
Gow-Chin
GC
Yen
Liang-Shun
LS
Wang
Chih-Hsiung
CH
Wu
Wei-Chung Vivian
WC
Yang
Alexander T H
AT
Wu
D051997:ADP-ribosyl Cyclase 1 / Q000032:analysis; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D018952:Antigens, CD34 / Q000032:analysis; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005786:Gene Expression Regulation / Q000187:drug effects; D005978:Glutathione / Q000032:analysis; D051549:Glutathione S-Transferase pi / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D017879:Isothiocyanates; D007938:Leukemia / Q000188:drug therapy / Q000276:immunology / Q000473:pathology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D014411:Neoplastic Stem Cells / Q000737:chemistry / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D013454:Sulfoxides; D013861:Thiocyanates / Q000494:pharmacology*; D060449:Wnt Signaling Pathway / Q000187:drug effects* / Q000502:physiology*; D051176:beta Catenin / Q000037:antagonists & inhibitors
D016588:Anticarcinogenic Agents; D018952:Antigens, CD34; D000970:Antineoplastic Agents; D001549:Benzamides; D017879:Isothiocyanates; D010879:Piperazines; D011743:Pyrimidines; D013454:Sulfoxides; D013861:Thiocyanates; D051176:beta Catenin; D000068877:Imatinib Mesylate; D051549:Glutathione S-Transferase pi; D051997:ADP-ribosyl Cyclase 1; C016766:sulforaphane; D005978:Glutathione