Abstract
6,8-dihydroxy-7-methoxy-1-methyl-azafluorenone (DMMA), a purified compound from Polyalthia cerasoides roots, is cytotoxic to various cancer cell lines. The aims of this study were to demonstrate the type of cancer cell death and the mechanism(s) involved. DMMA inhibited cell growth and induced apoptotic death in human leukemic cells (HL-60, U937, MOLT-4), human breast cancer MDA-MB231 cells and human hepatocellular carcinoma HepG2 cells in a dose dependent manner, with IC50 values ranging between 20-55 muM DMMA also decreased cell viability of human peripheral blood mononuclear cells. The morphology of cancer cells induced by the compound after staining with propidium iodide and examined under a fluorescence microscope was condensed nuclei and apoptotic bodies. Mitochondrial transmembrane potential (MTP) was decreased after 24h exposure in all five types of cancer cells. DMMA-induced caspase-3, -8, and -9 activity was strongly induced in human leukemic HL-60 and MOLT-4 cells, while in U937-, MDA-MB231- and HepG2-treated cells there was partial induction of caspase. In conclusion, DMMA-induced activation of caspase-8 and -9 resulted in execution of apoptotic cell death in human leukemic HL-60 and MOLT-4 cell lines via extrinsic and intrinsic pathways.
Highlights
Cancer is the first cause of death in the developed countries and the second cause of death in developing countries due to the life style changes, such as smoking, lacking of exercise and taking of western food
Apoptosis is a programmed cell death controlled by genes to keep homeostasis and development of multicellular organisms
The aims of this study were to determine the cytotoxic effect of DMMA and the mechanism of cell death in human cancer cell lines including leukemia, hepatocellular carcinoma and breast cancer
Summary
Cancer is the first cause of death in the developed countries and the second cause of death in developing countries due to the life style changes, such as smoking, lacking of exercise and taking of western food. Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among females (Jemal et al, 2011). Liver cancer is the fifth most frequently found cancer in male (Siegel et al, 2012). Leukemia incidence and curable rate are low compared to other kinds of cancer, which might be due to genetic information and apoptosis resistance. Apoptosis is a programmed cell death controlled by genes to keep homeostasis and development of multicellular organisms. Inappropriate control of apoptosis is occurred in several diseases such as acute myocardial infarct and cancer (Gewies, 2003). E.g., p53 and oncogenes, such as myc control apoptosis on various aspects. Anti-apoptotic (e.g. Bcl-2, Bcl-xL, Mcl-1) and pro-apoptotic proteins (e.g. Bax, Bak, Bad) play pivotal roles on apoptosis induction
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