methylglyoxal and high mobility group box 1 (HMGB1), act as important mediators in the necrotic pathway. In addition, the necrotic pathway can be triggered by
oncogenic metabolic stress and hypoxia by inducing transcription factors Snail and
Dlx-2 (Lee et al. 2018). Polymorphisms and defects in necroptosis regulators such
as RIP3 have been shown to have a positive correlation with tumour progression in
non-Hodgkin’s lymphoma (Mishra et al. 2018). There is also increasing evidence of
impaired necroptosis in cancer cells (Lalaoui and Brumatti, 2017). Hence, targeting
necroptosis is very promising to treat various cancers, and trials of repurposing
anticancer drugs for inducing necroptosis has been explored (Fulda 2018).
Moreover, phytochemicals have been shown to induce necrosis by targeting many
of the above mediators. Therefore, it is imperative to evaluate the effects of phytochemicals on the above molecular mediators to understand their role in inducing
necrosis/necroptosis.
It is beginning to unravel mounting evidence on the molecular regulation of
phytochemicals by RIP1/RIP3 upregulation of mitochondrial disruption by ROS
generation, ATP depletion and fragmentation. Several in vitro and in vivo studies
have reported the involvement of phytochemicals in necrotic/necroptotic signalling
in cancer (Fig. 4.5). For example, Solamargine has shown to induce necrosis in
melanoma and non-melanoma skin cell lines by targeting the lysosomal mitochondrial death pathway in lung cancer, breast cancer, squamous cell carcinoma
and leukemia cell lines (Al Sinani et al. 2016). Similarly, Phenethyl isothiocyanate
and Shikonin induce necroptosis in lung cancer cells via ROS, and b-Lapachone
induces necroptosis in human hepatocellular carcinoma SK-Hep1 cells through the
RIP1-PARP-AIF-dependent pathway (Diederich and Cerella 2016).
Green tea polyphenol is shown to induce necroptosis in p53-deficient Hep3B
cells through mitochondrial-associated signalling via activation of Bax/Bak
translocation (Lin and Tongyi 2014). Polyphenols resveratrol and analogs from
roots of Fallopia japonica has shown to induce necrosis in MCF-7 breast cancer and
C6 glioma cell lines. Curcumin and analogs have shown to induce necrosis in
prostate (DU-145) cancer cells by generating ROS, and in bladder cancer xenografts by downregulating NF-kB, cyclin D1 with increased p21 expression.
Genistein from Genista tinctorial has shown to cause necrosis in cervical cancer
(HeLa) cell lines (Gali-Muhtasib et al. 2015). Alkaloids such as berberine and
analogs showed necrosis in melanoma (B16) Prostate (RM-1) cell lines. Colchicin
and analogs inhibit cell division and cause necrosis in Lung, colorectal, ovarian,
prostate and breast mouse model. Terpenoids parthenolide and analogs were shown
to cause necrosis in leukemia (HL60, Jurkat), breast (MDA-MB-231) cancer cell
lines by ROS generation, induce dissolution of mitochondria membrane potential
and RIP1 activation. Organosulfur sulforaphane and analogs induce necrosis in the
breast (MCF-7), Colorectal (Caco-2) cancer cells by regulating CDK1
(Gali-Muhtasib H et al. 2015). Flavonoids such as quercetin shown to promote
necroptosis in MCF-7 cells. Artemisinin (ARS) derivatives such as artemether
(ARM) has been shown to exert necrosis in PG 100 gastric cancer cell line and
artesunate (ART) induce necroptosis in RT4 schwannoma cell line (Efferth 2017).
136
B. Cilwyn et al.
oncogenic metabolic stress and hypoxia by inducing transcription factors Snail and
Dlx-2 (Lee et al. 2018). Polymorphisms and defects in necroptosis regulators such
as RIP3 have been shown to have a positive correlation with tumour progression in
non-Hodgkin’s lymphoma (Mishra et al. 2018). There is also increasing evidence of
impaired necroptosis in cancer cells (Lalaoui and Brumatti, 2017). Hence, targeting
necroptosis is very promising to treat various cancers, and trials of repurposing
anticancer drugs for inducing necroptosis has been explored (Fulda 2018).
Moreover, phytochemicals have been shown to induce necrosis by targeting many
of the above mediators. Therefore, it is imperative to evaluate the effects of phytochemicals on the above molecular mediators to understand their role in inducing
necrosis/necroptosis.
It is beginning to unravel mounting evidence on the molecular regulation of
phytochemicals by RIP1/RIP3 upregulation of mitochondrial disruption by ROS
generation, ATP depletion and fragmentation. Several in vitro and in vivo studies
have reported the involvement of phytochemicals in necrotic/necroptotic signalling
in cancer (Fig. 4.5). For example, Solamargine has shown to induce necrosis in
melanoma and non-melanoma skin cell lines by targeting the lysosomal mitochondrial death pathway in lung cancer, breast cancer, squamous cell carcinoma
and leukemia cell lines (Al Sinani et al. 2016). Similarly, Phenethyl isothiocyanate
and Shikonin induce necroptosis in lung cancer cells via ROS, and b-Lapachone
induces necroptosis in human hepatocellular carcinoma SK-Hep1 cells through the
RIP1-PARP-AIF-dependent pathway (Diederich and Cerella 2016).
Green tea polyphenol is shown to induce necroptosis in p53-deficient Hep3B
cells through mitochondrial-associated signalling via activation of Bax/Bak
translocation (Lin and Tongyi 2014). Polyphenols resveratrol and analogs from
roots of Fallopia japonica has shown to induce necrosis in MCF-7 breast cancer and
C6 glioma cell lines. Curcumin and analogs have shown to induce necrosis in
prostate (DU-145) cancer cells by generating ROS, and in bladder cancer xenografts by downregulating NF-kB, cyclin D1 with increased p21 expression.
Genistein from Genista tinctorial has shown to cause necrosis in cervical cancer
(HeLa) cell lines (Gali-Muhtasib et al. 2015). Alkaloids such as berberine and
analogs showed necrosis in melanoma (B16) Prostate (RM-1) cell lines. Colchicin
and analogs inhibit cell division and cause necrosis in Lung, colorectal, ovarian,
prostate and breast mouse model. Terpenoids parthenolide and analogs were shown
to cause necrosis in leukemia (HL60, Jurkat), breast (MDA-MB-231) cancer cell
lines by ROS generation, induce dissolution of mitochondria membrane potential
and RIP1 activation. Organosulfur sulforaphane and analogs induce necrosis in the
breast (MCF-7), Colorectal (Caco-2) cancer cells by regulating CDK1
(Gali-Muhtasib H et al. 2015). Flavonoids such as quercetin shown to promote
necroptosis in MCF-7 cells. Artemisinin (ARS) derivatives such as artemether
(ARM) has been shown to exert necrosis in PG 100 gastric cancer cell line and
artesunate (ART) induce necroptosis in RT4 schwannoma cell line (Efferth 2017).
136
B. Cilwyn et al.