A novel mechanism of drug resistance to an anticancer drug, Temoxifen unveiled through interference with iron homeostasis Bhawna Nishal, Anil K. Sharma*, Raman Kumar, Vikas Beniwal and Sardul S. Sandhu Received : August 20 , 2011; Accepted : November 15, 2011 ISSN 2249-4073 Current Trends in Biotechnology and Chemical Research Volume 1, Issue 2, July-December 2011 *Corresponding author: Department of Biotechnology, M.M. University, Mullana-Ambala Introduction Iron is a key trace element for virtually all organisms as it functions as an essential co-factor in central cellular processes. Although iron is highly abundant, its bioavailability is low due to its poor solubility under ambient conditions. Most of the organisms have developed efficient iron uptake systems to meet cellular iron demands [1-3]. For microbial pathogens, acquisition of host iron is frequently crucial for virulence [4,5]. Cellular iron levels must be delicately balanced, as intracellular iron is both a source and an amplifier of reactive oxygen species and thus toxic at higher concentrations. To maintain appropriate cellular iron levels and to avoid iron-loading, cells have developed sophisticated systems for assuring a balanced cellular iron homeostasis. At the cellular level, this balance is achieved through a strict coupling of cellular iron uptake at the plasma membrane to intracellular iron demands and a balanced intracellular distribution of iron between the cellular compartments involved in iron-utilization and storage. A tightly regulated iron metabolism is essential, and disruption or over-expression of iron-related molecules can have significant health consequences. Defects in mammalian proteins involved in iron transport, its regulation, or its utilization in mitochondria are frequently associated with recessive chronic degenerative disorders with either chronic anaemia or systemic iron overload [1,6,7]. In the latter case, the cytotoxic effects of elevated intracellular iron levels result in chronic progressive tissue damage and ultimately failure of the organs involved [3,8]. In the model organism S. cerevisiae, the iron-responsive transcription factors Aft1 and Aft2 play a central role in the regulation of cellular iron homeostasis [2]. Upon iron deprivation, Aft1-Aft2 activate the transcription of the iron regulon, a set of ~ 40 genes encoding cell surface iron transporters and proteins involved in intracellular iron utilization. Aft1 shuttles between the cytosol and nucleus in an iron-responsive manner and acts as transcriptional activator under iron- limiting conditions [2]. It had been reported that an anticancer drug, cisplatin activates Aft1 through the inhibition of iron uptake into the cells, after which the expression of Aft1 target genes involved in iron uptake might be induced [9,10,11]. However the exact mechanism of the iron interference in anticancer drug action is still unknown. There are variety of other mechanisms by virtue of which drug resistance occur in organisms such as by reduced drug accumulation, reduced amount taken up by the cells, cellular excretion, enhanced detoxification mechanisms by high levels of glutathione and Metallothioneines, inhibition of apoptotic signals, altered drug metabolism, enhanced DNA repair, altered drug target etc.[12-16].The present study has been carried out to delineate another possible mechanism of ctbcr@mmumullana.org 127 Dr. Anil K. Sharma Department of Biotechnology, M.M. University, Mullana-Ambala-133207 E-mail: anibiotech18@gmail.com. Abstract Many drug resistance mechanisms have been known in organisms attributed to many factors such as reduced drug accumulation, reduced amount taken up by the cells, cellular excretion, enhanced detoxification mechanisms, inhibition of apoptotic signals, altered drug metabolism, enhanced DNA repair and altered drug target etc. The present investigations have been carried out to delineate another possible mechanism of drug resistance as iron might interfere with anticancer drug, Temoxifen.Temoxifen was introduced into the yeast, Saccharomyces cerevisiae OCY356 strain having Fet3LacZ on the chromosome. Temoxifen not only resulted in decreased growth but also found to chelate iron to some extent which resulted in increased levels of Aft-1 regulated gene expression. Therefore iron levels in the cell may interfere with the drug, Temoxifen pointing towards a novel mechanism of drug resistance. Keywords: Temoxifen, Aft-1, iron interference, drug resistance