Fish-Oil-Derived DHA-mediated Enhancement of Apoptosis in Acute Lymphoblastic Leukemia Cells is Associated with Accumulation of p53, Downregulation of Survivin, and Caspase-3 Activation

Abstract

In acute lymphoblastic leukemia (ALL), resistance to chemotherapy is associated with inactivation of p53 and upregulation of survivin. Thus, targeting the p53 and survivin expression may provide an attractive strategy for ALL treatment. It has been shown that fish-oil-derived docosahexaenoic acid (DHA) activates several antitumorigenic mechanisms in tumor cells, but little is known regarding the role of DHA on modulating p53 and survivin expression in ALL cells. In this study, we investigated the alterations of the p53 and survivin expression and induction of apoptosis in DHA-treated Molt-4 cells that serve as a model for ALL cells. Molt-4 cells were treated with 50, 100, 150, and 200 μM DHA after which cell proliferation, survivin mRNA and protein levels, p53 protein level, caspase-3 activation, and apoptotic rates were evaluated by different cellular and molecular techniques. After 48- and 72-h treatments with DHA at concentrations ranging from 50 to 200 μM, cell proliferation rates were measured to be 80.5-44.4%, and 73.4-14.4%, respectively, compared to untreated cells. We also found that treatment for 48 h with 200 μM DHA resulted in 10.8- and 3.6-fold increase in p53 protein level and caspase-3 activation followed by 4.7-and 1.6-fold decrease in survivin mRNA and protein levels, respectively, compared to untreated cells. Treatment of cells with different concentrations of DHA dramatically increased the p53/survivin and caspase-3/survivin ratios by 2.8- to 16.9-fold and 3.3 to 5.6-fold increases, respectively, compared to untreated cells. A decrease in the number of cells ranging from 16% to 70% and an increase in the number of apoptotic cells ranging from 9.3% to 93% was also observed with increasing DHA concentrations. In conclusion, p53 and survivin may provide promising targets of DHA in ALL cells and this compound with high proapoptotic capacity represents the possibility of its therapeutic application for ALL treatment.

Omega-3 fatty acid DHA modulates p53, survivin, and microRNA-16-1 expression in KRAS-mutant colorectal cancer stem-like cells

“…In the present study, we found that DHA decreased survivin expression at both the transcript and protein levels and this followed by accumulation of Wt-p53, caspase-3 activation, and apoptosis, suggesting a role of survivin in p53-dependent apoptosis in HCT-116 cells. In line with the present results, previous reports showed that DHA decreases survivin expression in the LS174T human CRC cell line with stem cell-like properties [ 53 ] and induces Wt-p53 accumulation in the acute lymphoblastic leukemia (ALL) Molt-4 cell line [ 54 ]. However, these interesting results were mainly descriptive without any mechanistic approach.…”

Dietary Fat and Cancer—Which Is Good, Which Is Bad, and the Body of Evidence

“…Both DHA and EPA induced a dose-dependent decrease in cell viability in five acute myeloid leukaemia cell lines; cell death was associated with the mitochondrial glycolytic switch and nuclear factor erythroid 2-related factor 2 (Nrf2) pathway activation [241]. DHA showed pro-apoptotic activity in Molt-4 acute lymphoblastic leukaemia cells, which was associated with p53 accumulation, survivin downregulation, and caspase-3 activation [242].…”

Chemical evaluation and cytotoxic mechanism investigation of Clinacanthus nutans extract in lymphoma SUP‐T1 cells

“…Caspase are hydrolysis enzymes which play an important role in apoptotic cell death. Many studies shown that induction of caspase protein could trigger apoptosis in cancer cells . Therefore, it is estimated that some key biomarkers like caspase‐3, ‐7, and ‐8 can prove if MHA could induce caspase‐dependent cell death.…”