Hao Ban1, Olga Uchakina1, Robert James McKallip2. 1. Division of Basic Medical Sciences, Mercer University School of Medicine, Macon, GA, U.S.A. 2. Division of Basic Medical Sciences, Mercer University School of Medicine, Macon, GA, U.S.A. mckallip_r@mercer.edu.
Abstract
BACKGROUND: As an inhibitor of hyaluronic acid (HA) synthesis, 4-methylumbelliferone (4-MU) has been shown to induce apoptosis of various types of cancer cells. However, the potential impact of 4-MU-induced apoptosis on leukemia cells via modulation of HA is not well-known. MATERIALS AND METHODS: We examined apoptosis of chronic myelogenous leukemia (CML) cells after treatment with 4-MU using annexin V/propidium iodide (V/PI) analysis and poly (ADP-ribose) polymerase (PARP) cleavage. We further examined the mechanisms of 4-MU-induced apoptosis by measuring mitochondrial membrane potential and reactive oxygen species generation. Using real-time PCR, and western blot analysis we examined signaling pathways involved in apoptosis. RESULTS: The current study demonstrated that treatment of CML cells with 4-MU led to induction of apoptosis through PARP cleavage and loss of mitochondria membrane potential. Mechanistically, 4-MU led to increased p53 mRNA expression, elevated cytoplasmic protein levels of cytochrome c and B-cell lymphoma-2-associated X (BAX) and reduced levels of B-cell lymphoma-2 (BCL2) expression. Addition of exogenous soluble HA was able to protect 4-MU-exposed cells from apoptosis. CONCLUSION: Our findings suggest that 4-MU induces apoptosis in CML cells by activating components associated with the intrinsic apoptosis pathway. Copyright
BACKGROUND: As an inhibitor of hyaluronic acid (HA) synthesis, 4-methylumbelliferone (4-MU) has been shown to induce apoptosis of various types of cancer cells. However, the potential impact of 4-MU-induced apoptosis on leukemia cells via modulation of HA is not well-known. MATERIALS AND METHODS: We examined apoptosis of chronic myelogenous leukemia (CML) cells after treatment with 4-MU using annexin V/propidium iodide (V/PI) analysis and poly (ADP-ribose) polymerase (PARP) cleavage. We further examined the mechanisms of 4-MU-induced apoptosis by measuring mitochondrial membrane potential and reactive oxygen species generation. Using real-time PCR, and western blot analysis we examined signaling pathways involved in apoptosis. RESULTS: The current study demonstrated that treatment of CML cells with 4-MU led to induction of apoptosis through PARP cleavage and loss of mitochondria membrane potential. Mechanistically, 4-MU led to increased p53 mRNA expression, elevated cytoplasmic protein levels of cytochrome c and B-cell lymphoma-2-associated X (BAX) and reduced levels of B-cell lymphoma-2 (BCL2) expression. Addition of exogenous soluble HA was able to protect 4-MU-exposed cells from apoptosis. CONCLUSION: Our findings suggest that 4-MU induces apoptosis in CML cells by activating components associated with the intrinsic apoptosis pathway. Copyright
Authors: Noor A Lokman; Zoe K Price; Emily K Hawkins; Anne M Macpherson; Martin K Oehler; Carmela Ricciardelli Journal: Cancers (Basel) Date: 2019-08-15 Impact factor: 6.639