prodigiosin and Precursor-Cell-Lymphoblastic-Leukemia-Lymphoma

Tumor suppressor p53 and proto-oncogene survivin are challenging targets for anticancer drugs in acute lymphoblastic leukemia (ALL) which are associated with chemoresistance. Yet, no p53 and survivin-modulating drug with low toxicity and high efficacy has been approved for clinical application in ALL. Consequently, the search for novel compounds which target p53 or survivin is needed to further advance ALL treatment. Prodigiosin, a secondary metabolite of Serratia marcescens induces apoptosis in cancer cells with no toxicity on normal cells. However, the possible potential of prodigiosin as p53- and survivin-modulating agent in ALL cells has not been investigated. Wt-p53 Molt-4 cells were treated with 100 to 600 nM prodigiosin, after which, viability, cell proliferation rates, survivin and p53 protein levels, caspase-3 activation, and apoptosis were evaluated. After 24-, 48-, and 72-h treatments with 100 to 600 nM prodigiosin, cell proliferation rates were measured to be 93.7-77.3%, 75.5-58.3%, and 55-23.3%, respectively. Treatment for 48 hours with 100 to 600 nM prodigiosin resulted in 41-19% decrease in survivin protein levels followed by 450-950% increases in caspase-3 activation levels. Prodigiosin induced remarkably p53 accumulation and increased p53/survivin and caspase-3/survivin ratios by 6.1 to 11.3 and 10.3 to 47.5-fold at 100 to 600 nM, respectively. Survivin protein levels were inversely proportional to p53 accumulation levels. Low survivin protein levels combined with high levels of p53 accumulation were correlated to higher apoptotic rates. P53 and survivin as molecular targets of prodigiosin contribute to caspase-3-dependent apoptosis in ALL cells and this compound represents an attractive p53- and survivin-modulating agent in ALL.

Topics: Antineoplastic Agents; Apoptosis; Caspase 3; Cell Line, Tumor; Cell Proliferation; Cell Survival; Humans; Inhibitor of Apoptosis Proteins; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prodigiosin; Proto-Oncogene Mas; Serratia marcescens; Survivin; Tumor Suppressor Protein p53

Matrix metalloproteinase-9 (MMP-9) and survivin are involved in several steps of carcinogenesis in acute lymphoblastic leukaemia (ALL). Yet, no MMP-9 and survivin-modulating drugs with low toxicity on normal cells but high efficacy against high MMP-9- and survivin-expressing leukaemia cells have been approved for clinical application in ALL. Prodigiosin, a secondary metabolite of Serratia marcescens, induces apoptosis in different kinds of cancer cells with low toxicity on normal cells. However, little is known about the effects of this compound on the high MMP-9- and survivin-expressing leukaemia cells.. The inhibitory effects of prodigiosin on MMP-9 and survivin expression, as well as its pro-apoptotic capacity, represent a novel therapeutic avenue against ALL cells.. These findings provide an important and interesting basis to develop a new therapeutic compound with high potential against ALL cells.

Topics: Apoptosis; Caspase 3; Cell Line, Tumor; Cell Proliferation; Cell Survival; Humans; Inhibitor of Apoptosis Proteins; Matrix Metalloproteinase 9; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prodigiosin; RNA, Messenger; Serratia marcescens; Survivin