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Am J Transl Res 2013;5(6):622-633
Original Article
A novel piperazine derivative potently induces caspase-dependent
apoptosis of cancer cells via inhibition of multiple cancer signaling
pathways
Edward X She, Zhonglin Hao
Cancer Center and Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta,
Georgia
Received September 5, 2013; Accepted September 15, 2013; Epub September 25, 2013; Published September
30, 2013
Abstract: Despite rapid progress in anticancer drug development and improvement in clinical outcomes, the
survival rate for many types of cancer is still unacceptably low. Therefore, it is crucial to discover novel anticancer
drugs to both prevent and treat the disease. In recent years, the advent of combinatorial chemistry allows the
design and parallel synthesis of millions of small compounds that have drug-like properties. In vitro high
throughput screening of such compound libraries has allowed the identification of many new drug candidates
that may be further evaluated for their efficacy and mechanism of action. The overall objective of this study was to
identify small molecule compounds as candidates for anti-cancer drug development. We first used cell
proliferation and cytotoxicity assays to identify compounds exhibiting anti-cancer activity in vitro in a leukemia cell
line (K562). Six top compounds selected from the initial screening of a library of 2,560 compounds were further
evaluated in multiple cancer cell lines to rank the drug candidates. The top candidate was further investigated to
elucidate the molecular mechanism underlying its anticancer activity. Our studies suggest that this piperazine
derivative effectively (GI50 = 0.06-0.16 µM) inhibits cancer cell proliferation and induces caspase-dependent
apoptosis via inhibiting multiple cancer signaling pathways including the PI3K/AKT, the Src family kinases and
the BCR-ABL pathways. (AJTR1309005).
Keywords: Drug discovery, high throughput screening, apoptosis, piperazine, cancer, leukemia
Address correspondence to: Edward X She or Dr. Zhonglin Hao, Cancer Center and Department of Medicine,
Medical College of Georgia, Georgia Regents University, 1120 15th Street, Room CN2132, Augusta, GA 30912,
USA. E-mail: eshe@gru.edu (EXS); zhao@gru.edu (ZH)
Original Article
A novel piperazine derivative potently induces caspase-dependent
apoptosis of cancer cells via inhibition of multiple cancer signaling
pathways
Edward X She, Zhonglin Hao
Cancer Center and Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta,
Georgia
Received September 5, 2013; Accepted September 15, 2013; Epub September 25, 2013; Published September
30, 2013
Abstract: Despite rapid progress in anticancer drug development and improvement in clinical outcomes, the
survival rate for many types of cancer is still unacceptably low. Therefore, it is crucial to discover novel anticancer
drugs to both prevent and treat the disease. In recent years, the advent of combinatorial chemistry allows the
design and parallel synthesis of millions of small compounds that have drug-like properties. In vitro high
throughput screening of such compound libraries has allowed the identification of many new drug candidates
that may be further evaluated for their efficacy and mechanism of action. The overall objective of this study was to
identify small molecule compounds as candidates for anti-cancer drug development. We first used cell
proliferation and cytotoxicity assays to identify compounds exhibiting anti-cancer activity in vitro in a leukemia cell
line (K562). Six top compounds selected from the initial screening of a library of 2,560 compounds were further
evaluated in multiple cancer cell lines to rank the drug candidates. The top candidate was further investigated to
elucidate the molecular mechanism underlying its anticancer activity. Our studies suggest that this piperazine
derivative effectively (GI50 = 0.06-0.16 µM) inhibits cancer cell proliferation and induces caspase-dependent
apoptosis via inhibiting multiple cancer signaling pathways including the PI3K/AKT, the Src family kinases and
the BCR-ABL pathways. (AJTR1309005).
Keywords: Drug discovery, high throughput screening, apoptosis, piperazine, cancer, leukemia
Address correspondence to: Edward X She or Dr. Zhonglin Hao, Cancer Center and Department of Medicine,
Medical College of Georgia, Georgia Regents University, 1120 15th Street, Room CN2132, Augusta, GA 30912,
USA. E-mail: eshe@gru.edu (EXS); zhao@gru.edu (ZH)
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