Abstract
Drug resistance and human leukocyte antigen (HLA) matching limit conventional treatment of acute myeloid leukemia (AML). Although several small molecule drugs are clinically used, single drug administration is not sufficient to cure AML, which has a high molecular diversity. Metabolic homeostasis plays a key role in determining cellular fate. Appropriate levels of reactive oxygen species (ROS) maintain the redox system balance, and excessive amounts of ROS cause oxidative damage, thus providing a strategy to eliminate cancer cells. CPPTL is a novel analogue of parthenolide that exhibited significant cytotoxicity to AML cells in vitro and induced apoptosis in a dose-dependent manner. Additionally, CPPTL's prodrug DMA-CPPTL decreased the burden of AML engraftment and prolonged survival in a mouse model administered human primary AML cells in vivo. CPPTL induced apoptosis of AML cells by stimulating ROS production, and accumulation of ROS then activated the JNK pathway, thereby promoting mitochondrial damage. These results demonstrated that CPPTL effectively eradicated AML cells in vitro and in vivo and suggested that CPPTL may be a novel candidate for auxiliary AML therapy.
Highlights
Acute myeloid leukemia (AML) is the most common hematological malignancy in adults [1]
CPPTL induced apoptosis of acute myeloid leukemia (AML) cells by stimulating reactive oxygen species (ROS) production, and accumulation of ROS activated the JNK pathway, thereby promoting mitochondrial damage. These results demonstrated that CPPTL effectively eradicated AML cells in vitro and in vivo and suggested that CPPTL may be a novel candidate for auxiliary AML therapy
To determine whether CPPTL had anti-leukemic effects, we determined its effects on five typical leukemia cell lines: HL-60 (APL cell line), HL-60/ADR (ADR-resistant acute promyelocytic leukemia (APL) cell line), K562 (CML cell line), K562/ADR (ADRresistant chronic myelogenous leukemia (CML) cell line) and KG1a (AML cell line)
Summary
Acute myeloid leukemia (AML) is the most common hematological malignancy in adults [1]. Chemotherapy and hematopoietic stem cell (HSC) transplantation are conventional treatments for AML [2, 3]. Approximately 30%-40% of AML patients cannot receive HSC transplantation, because of human leukocyte antigen (HLA) matching limitation. The sequelae of autologous or allogeneic HSC transplantation can affect patient quality of life [4]. Some patients are resistant to chemotherapeutics [5, 6], and high-dose chemotherapy drugs can cause severe side effects. Screening selective small molecule drugs for AML treatment is necessary and urgent
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