Linalool Induces Apoptosis of Lymphoblastic Leukemia Cell Lines ...

[Abstract]

Leukemia is a common malignant neoplasm of hematopoietic system. Its etiology and pathogenesis remain uncertain. Currently, chemotherapy is one of major approaches to treat it. However, the serious side effects of chemotherapy and MDR often lead to relapse of the disease and are eventually responsible for the failure of treatments. Thus, it is imperative to find out novel and more efficient antitumor drugs to improve the cure rate.In this study, we found out that linalool, a small-molecule compound, could inhibit the growth of various human lymphocyte leukemia cell lines significantly. Meanwhile, it showed little toxicity to normal hematopoietic cells. To determine effects of linalool on the growth of a serious of human leukemia cell lines and normal hematopoietic cells and to explore its possible mechanisms, we employed various technologies, including MTT assay, Flow cytometry, Human Cancer PathwayFinder II Gene Array, Western Blot, RT-PCR and so on.Materials and Methods1. Cell culture:?1? Human leukemia cell lines : H9. Molt-4 and Jurkat for T cell leukemia; Raji for Burkitt?s lymphoma; THP1 ? U937 for acute monocytic leukmia; K562 for chronic myelogenous leukemia?CML?; KG-1 for acutemyelogenous leukemia.? 2 ? Normal hematopoietic cells: Including examples of bone marrows and PBMNCs from health donors.2. Growth inhibition assay of leukemia cell lines with MTT assay.3. Effects of linalool on cell cycles of leukemia cell line with Flow cytometry.4. Apoptosis induced by linalool in leukemia cell line with Flow cytometry, and PI/Annexin-V assay.5. Signal molecules in leukemia cell line in different human cancer pathways after treatment with linalool with Human Cancer PathwayFinder II Gene Array6. Assay of mRNA expression in leukemia cell line after treatment with linalool by RT-PCR.7. Assay of protein expression in leukemia cell line after treatment with linalool by Western Blot.Results1. Linalool inhibited the growth of T cell leukemia cell lines H9, Molt-4, Jurkat and Burkitt?s lymphoma cell line Raji significantly. The value of IC50 were 7.09?M? 5.79?M?11.3?M and 6.46?M at 48 hours respectively. In contrast, it displayed no significant inhibition for myelogenous leukemia cell lines THP1, U937 and KG-1, and the value of IC₅₀ were respectively 34.89?M?203.99?M? and 371.69?M at 48 hours. Meanwhile, When the concentration of linalool was 100uM, it showed little toxicity foe normal hematopoietic cells.2. Linalool induced obvious apoptosis of Molt-4 cells ?T-cell acute lymphoblastic leukemia?3. After treatment with linalool , the percentage of G₀/G₁, S, and G₂/M stage in Molt-4 cells declined notably, and the fraction of apoptosis cells increased obviously.4. Linalool could influence signal molecules in Molt-4 ?T-cell acute lymphoblastic leukemia? cells in 15 different human cancer pathways and represent chiefly that itup-regulated P53, P21, P27, P57 and GADD45a and so on.5. Results of Western Blot and RT-PCR revealed that after treatment with linalool, the expressions of P53, P21, P27, P57 and GADD45? were up-regulated and downstream proteins, c-jun and JNK, were activated.Conclusion1. Linalool could inhibit the growth of lymphoblastic leukemia cell lines, and induction of apoptosis is one of mechanisms for its suppression on the growth of these cell lines.2. Activating and up-regulating GADD45a/c-jun/JNK signaling pathway might be one of mechanisms for this apoptosis.3. Linalool could eliminate cells of quiescence effectively, suggesting that it maybe kill leukemia stem cells.

Title: Linalool Induces Apoptosis of Lymphoblastic Leukemia Cell Lines by Activating GADD45?/JNK Pathway

Category: Stomach Cancer

Filename: Linalool Induces Apoptosis of Lymphoblastic Leukemia Cell Lines by Activating GADD45?/JNK Pathway.pdf

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