title: Nitric oxide is the key mediator of death induced by fisetin in human acute monocytic leukemia cells.
abstract: Nitric oxide (NO) has been shown to be effective in cancer chemoprevention and therefore drugs that help generate NO would be preferable for combination chemotherapy or solo use. This study shows a new evidence of NO as a mediator of acute leukemia cell death induced by fisetin, a promising chemotherapeutic agent. Fisetin was able to kill THP-1 cells in vivo resulting in tumor shrinkage in the mouse xenograft model. Death induction in vitro was mediated by an increase in NO resulting in double strand DNA breaks and the activation of both the extrinsic and the intrinsic apoptotic pathways. Double strand DNA breaks could be reduced if NO inhibitor was present during fisetin treatment. Fisetin also inhibited the downstream components of the mTORC1 pathway through downregulation of levels of p70 S6 kinase and inducing hypo-phosphorylation of S6 Ri P kinase, eIF4B and eEF2K. NO inhibition restored phosphorylation of downstream effectors of mTORC1 and rescued cells from death. Fisetin induced Ca(2+) entry through L-type Ca(2+) channels and abrogation of Ca(2+) influx reduced caspase activation and cell death. NO increase and increased Ca(2+) were independent phenomenon. It was inferred that apoptotic death of acute monocytic leukemia cells was induced by fisetin through increased generation of NO and elevated Ca(2+) entry activating the caspase dependent apoptotic pathways. Therefore, manipulation of NO production could be viewed as a potential strategy to increase efficacy of chemotherapy in acute monocytic leukemia.
authors.affiliation: Cell Death and Differentiation Research Laboratory, National Institute of Immunology New Delhi-110067, India.
authors.forename: Dipankar
authors.initials: D
authors.lastname: Ash
authors.affiliation: Cell Death and Differentiation Research Laboratory, National Institute of Immunology New Delhi-110067, India.
authors.forename: Manikandan
authors.initials: M
authors.lastname: Subramanian
authors.affiliation: Indian Institute of Science Bangalore, India.
authors.forename: Avadhesha
authors.initials: A
authors.lastname: Surolia
authors.affiliation: Cell Death and Differentiation Research Laboratory, National Institute of Immunology New Delhi-110067, India.
authors.forename: Chandrima
authors.initials: C
authors.lastname: Shaha
keywords: Fisetin; apoptosis; calcium; leukemia; mTOR; nitric oxide