Nitric oxide is the key mediator of death induced by fisetin in human acute monocytic leukemia cells

Ash, Dipankar and Subramanian, Manikandan and Surolia, Avadhesha and Shaha, Chandrima (2015) Nitric oxide is the key mediator of death induced by fisetin in human acute monocytic leukemia cells. In: AMERICAN JOURNAL OF CANCER RESEARCH, 5 (2). 481-U421.

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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 Ca2+ entry through L-type Ca2+ channels and abrogation of Ca2+ influx reduced caspase activation and cell death. NO increase and increased Ca2+ 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 Ca2+ 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.

Item Type:	Journal Article
Publication:	AMERICAN JOURNAL OF CANCER RESEARCH
Publisher:	E-CENTURY PUBLISHING CORP
Additional Information:	Copy right for this article belongs to the E-CENTURY PUBLISHING CORP, 40 WHITE OAKS LN, MADISON, WI 53711 USA
Keywords:	Fisetin; apoptosis; calcium; nitric oxide; leukemia; mTOR
Department/Centre:	Division of Biological Sciences > Molecular Biophysics Unit
Date Deposited:	06 May 2015 05:27
Last Modified:	06 May 2015 05:27
URI:	http://eprints.iisc.ac.in/id/eprint/51497

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