206
TAM with fungal siderophores, it is possible to transport and utilize Fe for various
functions of the cells. The pathways of Fe acquisition, export and storage are often
disturbed in cancer. Hence, targeting Fe metabolic pathways should be a novel
approach in cancer drug discovery. Although there is close connectivity between Fe
homeostasis and cancer biology, our knowledge remains descriptive and is based
only on the in vitro experimental models or from the in vivo animal models that
employ xenogeneic tumour cell transplantation. The potential role of Fe in cancer
and tumour microenvironment are not completely addressed in human cancer or
patient cohorts. There is toxicity in the excess labile Fe as it acts as a catalyst in the
formation of reactive oxygen species (ROS) via Fenton-/Haber-Weiss chemistry
(Pfeifhofer-Obermair et al. 2018).
Fungal siderophores are useful in cancer therapy: desferrioxamine, a natural siderophore, deferasirox, a synthetic Fe chelator and thiosemicarbazone show promising anti-cancer activity (Kalinowski and Richardson 2005). These siderophores are
validated through clinical trials (Hatcher et al. 2009). Unfortunately, serious side
effects such as abnormalities in the hearing, nephropathy, optic neuropathy and
retarded growth in children are observed as a side effect of cancer treatment with
fungal siderophores and their use is hampered (Nadkarni et al. 2008; Dayani et al.
2004). Several studies target Fe in tumour cells, but there are fewer approaches that
address Fe chelation. Metal chelation therapy is one of the challenges in cancer
treatment although it has systemic iron depletion ability.
12.7 Fungal Siderophores and Pathogenicity
A. fumigatus adjusts to iron limitation by the process of siderophore biosynthesis
through iron upregulation and down regulation of pathways involved in iron consumption (Schrettl and Haas 2011). A. fumigatus causes invasive infection in ImC
populations and is considered to be a serious life-threatening infection worldwide.
Genes such as sidA present in A. fumigatus are found to be involved in hydroxamate
siderophore biosynthesis. The gene sidA causes virulence in A. fumigatus and hence
inhibition of this gene could be a target to treat fungal infection in humans (Hissen
et al. 2005; Wasylnka et al. 2005). A. fumigatus employs extra- and intracellular
siderophores to maintain adequate supply of iron. This helps fungal growth even
during iron starvation. Hence, the fungal siderophore system is highly required for
interaction with the host immune cells and extracellular growth (Schrettl and Haas
2011). Siderophores are also required for storage of iron, resistance to oxidative
stress, asexual/sexual development, iron-induced toxicity protection and virulence
in some fungal organisms (Johnson 2008).
Candida glabrata is a life-threatening human fungal pathogen that causes infections in a number of ImC individuals who are exposed to cancer treatment, HIV
A. Prabahar et al.
TAM with fungal siderophores, it is possible to transport and utilize Fe for various
functions of the cells. The pathways of Fe acquisition, export and storage are often
disturbed in cancer. Hence, targeting Fe metabolic pathways should be a novel
approach in cancer drug discovery. Although there is close connectivity between Fe
homeostasis and cancer biology, our knowledge remains descriptive and is based
only on the in vitro experimental models or from the in vivo animal models that
employ xenogeneic tumour cell transplantation. The potential role of Fe in cancer
and tumour microenvironment are not completely addressed in human cancer or
patient cohorts. There is toxicity in the excess labile Fe as it acts as a catalyst in the
formation of reactive oxygen species (ROS) via Fenton-/Haber-Weiss chemistry
(Pfeifhofer-Obermair et al. 2018).
Fungal siderophores are useful in cancer therapy: desferrioxamine, a natural siderophore, deferasirox, a synthetic Fe chelator and thiosemicarbazone show promising anti-cancer activity (Kalinowski and Richardson 2005). These siderophores are
validated through clinical trials (Hatcher et al. 2009). Unfortunately, serious side
effects such as abnormalities in the hearing, nephropathy, optic neuropathy and
retarded growth in children are observed as a side effect of cancer treatment with
fungal siderophores and their use is hampered (Nadkarni et al. 2008; Dayani et al.
2004). Several studies target Fe in tumour cells, but there are fewer approaches that
address Fe chelation. Metal chelation therapy is one of the challenges in cancer
treatment although it has systemic iron depletion ability.
12.7 Fungal Siderophores and Pathogenicity
A. fumigatus adjusts to iron limitation by the process of siderophore biosynthesis
through iron upregulation and down regulation of pathways involved in iron consumption (Schrettl and Haas 2011). A. fumigatus causes invasive infection in ImC
populations and is considered to be a serious life-threatening infection worldwide.
Genes such as sidA present in A. fumigatus are found to be involved in hydroxamate
siderophore biosynthesis. The gene sidA causes virulence in A. fumigatus and hence
inhibition of this gene could be a target to treat fungal infection in humans (Hissen
et al. 2005; Wasylnka et al. 2005). A. fumigatus employs extra- and intracellular
siderophores to maintain adequate supply of iron. This helps fungal growth even
during iron starvation. Hence, the fungal siderophore system is highly required for
interaction with the host immune cells and extracellular growth (Schrettl and Haas
2011). Siderophores are also required for storage of iron, resistance to oxidative
stress, asexual/sexual development, iron-induced toxicity protection and virulence
in some fungal organisms (Johnson 2008).
Candida glabrata is a life-threatening human fungal pathogen that causes infections in a number of ImC individuals who are exposed to cancer treatment, HIV
A. Prabahar et al.