We recently isolated and characterized new cellular models resistant to clinically relevant doses of ??radiations derived from HL60, a human acute myeloid leukemia cell line, and HG3, a chronic lymphocytic leukemia cell line. We named the resistant clones HL60CL2 and HG3CL3, respectively. The new radioresistant leukemic cell lines have been employed to study the kinetics of intracellular reactive oxygen species (ROS) following treatments with ionizing radiation. We also characterized these cells, comparing them to the relative parental ones in terms of expression of cell cycle/senescence-related markers (p27/Kip1), anti-apoptotic (Bcl-XL) and antioxidant response (NQO1) related factors. Here, the radioresistant leukemic cells, as a consequence of an adaptive phenotypic response, were characterized by high resistance to oxidative stress and expressed higher levels of p27kip/1, Bcl-XL and NQO1 proteins, commonly associated with cell cycle alterations, senescence induction and resistance to apoptosis [1]. Then, we evaluated the redox status and cytotoxic role of natural flavonoids, such as quercetin (Q) and fisetin (F), well known as senolytic agents and capable of selectively eliminating senescent cells and bypassing resistance to genotoxic stress [1-3], in HL60CL2 and HG3CL3 cells. We hypothesized that the mechanisms responsible for the radiosensitising effects of Q and F were linked to changes in the intracellular ROS concentrations in response to genotoxic stress. This event can induce forms of resistance to cell death, through multiple biochemical pathways of signal transduction (e.g. PI3K/AKT, ERK/MAPK) targeted by natural flavonoids. We demonstrated, by immunoblot analysis, that Q and F affect the phosphorylation status of ERK1/2. Fisetin, differently than Q, was a potent activator of ERK1/2 and AKT in parental and radioresistant leukemic cells. These data confirm the role of senolytic flavonoids in mediating cancer resistance and stimulating future investigations. [1] Kirkland et al. J Intern Med. 2020 288:518 [2] Russo al. Int. J. Mol. Sci. 2022, 23:301 [3] Li et al. Mech Ageing Dev. 2019, 181:1
NATURAL FLAVONOIDS ENHANCE CELL DEATH IN NEW HUMAN LEUKEMIA RADIORESISTANT CELL LINES
Maria Russo;Stefania Moccia;Carmela Spagnuolo;GianLuigi Russo
2022
Abstract
We recently isolated and characterized new cellular models resistant to clinically relevant doses of ??radiations derived from HL60, a human acute myeloid leukemia cell line, and HG3, a chronic lymphocytic leukemia cell line. We named the resistant clones HL60CL2 and HG3CL3, respectively. The new radioresistant leukemic cell lines have been employed to study the kinetics of intracellular reactive oxygen species (ROS) following treatments with ionizing radiation. We also characterized these cells, comparing them to the relative parental ones in terms of expression of cell cycle/senescence-related markers (p27/Kip1), anti-apoptotic (Bcl-XL) and antioxidant response (NQO1) related factors. Here, the radioresistant leukemic cells, as a consequence of an adaptive phenotypic response, were characterized by high resistance to oxidative stress and expressed higher levels of p27kip/1, Bcl-XL and NQO1 proteins, commonly associated with cell cycle alterations, senescence induction and resistance to apoptosis [1]. Then, we evaluated the redox status and cytotoxic role of natural flavonoids, such as quercetin (Q) and fisetin (F), well known as senolytic agents and capable of selectively eliminating senescent cells and bypassing resistance to genotoxic stress [1-3], in HL60CL2 and HG3CL3 cells. We hypothesized that the mechanisms responsible for the radiosensitising effects of Q and F were linked to changes in the intracellular ROS concentrations in response to genotoxic stress. This event can induce forms of resistance to cell death, through multiple biochemical pathways of signal transduction (e.g. PI3K/AKT, ERK/MAPK) targeted by natural flavonoids. We demonstrated, by immunoblot analysis, that Q and F affect the phosphorylation status of ERK1/2. Fisetin, differently than Q, was a potent activator of ERK1/2 and AKT in parental and radioresistant leukemic cells. These data confirm the role of senolytic flavonoids in mediating cancer resistance and stimulating future investigations. [1] Kirkland et al. J Intern Med. 2020 288:518 [2] Russo al. Int. J. Mol. Sci. 2022, 23:301 [3] Li et al. Mech Ageing Dev. 2019, 181:1I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
