4.5 Role of Phytochemicals in Cancer Cure Via Necrosis
Induction
Phytochemicals have been shown to protect cells by interfering with their molecular
pathways that regulate the cell cycle, survival, angiogenesis and cell death. These
properties made phytochemicals an essential source of drug for the prevention and
treatment of cancer. Many anticancer drugs such as paclitaxel and vinblastine are
derived from phytochemicals, and still, many more are under investigation.
Notably, most of these compounds target the apoptotic mechanism mainly by
interfering with caspase-dependent pathways (Ashraf 2020). However, other
non-apoptotic cell death pathways such as necrosis also play an essential role in
checking neoplastic cells and destroying tumour cells. Inducing necrosis is a known
mechanism of some anticancer drugs such as DNA-alkylating agents in treating
human cancers (Cho and Park 2014). Therefore, understanding the role of phytochemicals in signalling cascades involved in the induction of necrotic cell death will
allow us to develop a novel drug to treat cancer.
Depending on the physiological and pathological conditions, a cell would either
take the apoptotic or necrotic pathway. Unlike apoptosis, necrosis does not have a
dedicated molecular pathway, instead it overlaps with many of those
caspase-independent apoptotic pathways, which culminates in disruption of organelle
and loss of membrane integrity resulting in the spillover of cellular contents (Lee et al.
2018). In a tumour microenvironment, induction of necrotic pathway would cause
more damage as it destroys the cells around, and the contents released from these cells
create a pro-inflammatory environment (Lee et al. 2018). Phytochemicals with
enhanced necrosis may help to exert more effective tumour suppression property.
Well-controlled, a programmed form of necrosis is known as necroptosis, which
is mainly triggered by extracellular stimuli similar to the extrinsic apoptotic pathway. Necroptosis is primarily orchestrated by serine/threonine kinase
receptor-interacting protein 1/3 (RIP1 and RIP3) to induce necrotic cell death. RIP1
and RIP3 can be activated by signalling via tumour necrotic factor receptor 1/2
(TNF-R1/2), Toll-like receptor 3/4 (TLR3/4), DNA damage-induced Poly
[ADP-ribose] polymerase 1 (PARP1) pathways, especially when caspase-8 is either
downregulated, non-responsive or inactivated by other regulators (De Giffoni De
Carvalho et al. 2019). Finally, RIP1 and RIP3 form a dimer which is one of the
ways of induction of necroptosis by the activation of mixed lineage kinase
domain-like protein (MLKL) that destroys the integrity of plasma membrane or via
activation of mitochondrial protein phosphatases PGAM5 and Drp1 (mitochondrial
fission protein) which lead to mitochondrial dysregulation (Fig. 4.5) (Mishra et al.
2018). However, progression depends on the level of caspase-8 and Fas-associated
protein with death domain (FADD) that regulates RIP1/RIP3 levels. Experiments
have demonstrated downregulation of Caspase 8 and FADD promotes
RIP3-dependent necrosis (Wattanathamsan et al. 2019). Further, reactive oxygen
species (ROS), advanced glycation end products (AGE), calcium, cyclophilin D
(CypD), NO/NOS, phospholipase A2 (PLA2), calpains, cathepsin B, ceramide,
4 The Role of Phytochemicals in Cancer Prevention and Cure
135
Induction
Phytochemicals have been shown to protect cells by interfering with their molecular
pathways that regulate the cell cycle, survival, angiogenesis and cell death. These
properties made phytochemicals an essential source of drug for the prevention and
treatment of cancer. Many anticancer drugs such as paclitaxel and vinblastine are
derived from phytochemicals, and still, many more are under investigation.
Notably, most of these compounds target the apoptotic mechanism mainly by
interfering with caspase-dependent pathways (Ashraf 2020). However, other
non-apoptotic cell death pathways such as necrosis also play an essential role in
checking neoplastic cells and destroying tumour cells. Inducing necrosis is a known
mechanism of some anticancer drugs such as DNA-alkylating agents in treating
human cancers (Cho and Park 2014). Therefore, understanding the role of phytochemicals in signalling cascades involved in the induction of necrotic cell death will
allow us to develop a novel drug to treat cancer.
Depending on the physiological and pathological conditions, a cell would either
take the apoptotic or necrotic pathway. Unlike apoptosis, necrosis does not have a
dedicated molecular pathway, instead it overlaps with many of those
caspase-independent apoptotic pathways, which culminates in disruption of organelle
and loss of membrane integrity resulting in the spillover of cellular contents (Lee et al.
2018). In a tumour microenvironment, induction of necrotic pathway would cause
more damage as it destroys the cells around, and the contents released from these cells
create a pro-inflammatory environment (Lee et al. 2018). Phytochemicals with
enhanced necrosis may help to exert more effective tumour suppression property.
Well-controlled, a programmed form of necrosis is known as necroptosis, which
is mainly triggered by extracellular stimuli similar to the extrinsic apoptotic pathway. Necroptosis is primarily orchestrated by serine/threonine kinase
receptor-interacting protein 1/3 (RIP1 and RIP3) to induce necrotic cell death. RIP1
and RIP3 can be activated by signalling via tumour necrotic factor receptor 1/2
(TNF-R1/2), Toll-like receptor 3/4 (TLR3/4), DNA damage-induced Poly
[ADP-ribose] polymerase 1 (PARP1) pathways, especially when caspase-8 is either
downregulated, non-responsive or inactivated by other regulators (De Giffoni De
Carvalho et al. 2019). Finally, RIP1 and RIP3 form a dimer which is one of the
ways of induction of necroptosis by the activation of mixed lineage kinase
domain-like protein (MLKL) that destroys the integrity of plasma membrane or via
activation of mitochondrial protein phosphatases PGAM5 and Drp1 (mitochondrial
fission protein) which lead to mitochondrial dysregulation (Fig. 4.5) (Mishra et al.
2018). However, progression depends on the level of caspase-8 and Fas-associated
protein with death domain (FADD) that regulates RIP1/RIP3 levels. Experiments
have demonstrated downregulation of Caspase 8 and FADD promotes
RIP3-dependent necrosis (Wattanathamsan et al. 2019). Further, reactive oxygen
species (ROS), advanced glycation end products (AGE), calcium, cyclophilin D
(CypD), NO/NOS, phospholipase A2 (PLA2), calpains, cathepsin B, ceramide,
4 The Role of Phytochemicals in Cancer Prevention and Cure
135