A
recent
study
reported
that
gedunin
derivatives,
3-a-acetoxydihydrodeoxygedunin (3-a-DOG) were partial agonist towards adhesion G protein coupled receptors (aGPCR) GPR56/ADGRG1 (Stoveken et al.
2018). aGPCRs is broadly distributed in various tumor cells and has become
prominent as a potential therapeutic target in various neurological diseases and
cancers (Paavola and Hall 2012). The activating mechanism of most aGPCRs have
only been recently characterized and limited modulatory compound are being
defined. Hence, 3-a-DOG and possibly other gedunin derivatives as partial agonist
to aGPCRs could indicate an invaluable area for further research.
16.2.1.1 Combinatorial Treatment Using Gedunin Enhances
Anti-cancer Properties
The complex pathway of tumorigenesis has significant impact on the efficacy of
anti-cancer drugs. Many studies have demonstrated that combinatorial treatments
using multiple agent have proven to improve the clinical therapeutic efficacy of
anti-cancer drugs as compared to single agent regimen. Specifically, gedunin in
neem has been shown to synergize with other anti-cancer drugs apart from its
anti-cancer properties as a single agent. (Sharma et al. 2014; Gupta et al. 2017;
Bodduluru et al. 2014; Kamath et al. 2009).
Combinatory treatment with gedunin and epalrestat has shown to attenuate the
Aldose Reductase (AR) enzyme in the SCC131 oral cancer cell line (Tanagala et al.
2018). Inhibition of diabetic associated enzymes Aldose Reductase (AR) are correlated to the inhibition of SCC131 cell proliferation, apoptosis evasion and
angiogenesis through enervating downstream PI3K/Akt/mTOR/ERK/NF-jB signalling axis. It is reported that the combinatory treatment resulted in diversion of
cell death in favor of apoptosis in the treated cell lines. Further, pro-invasive and
proangiogenic proteins were downregulated in treated groups, hence inhibiting
cancer cell migration. In all events, combined treatment of gedunin and epalrestat
was reported to be more effective than single agents. In a similar study, Kishore and
the team (2016) suggested that the abrogation of AR enzyme, PI3K/Akt and NF-jB
pathways by gedunin has downregulated the expression of miR-21, hypoxia
inducible factor-1 alpha (HIF-1a) and the pro-angiogenic factors vascular
endothelial growth factor in a hamster model of oral carcinogenesis, which inhibited angiogenesis (Kishore et al. 2016).
Interestingly, gedunin acted synergistically with the chemotherapy agents cisplatin (C30, CP75) and paclitaxel (ID8TaxR) at doses as low as 2.5 lM, which
have no effect on the chemoresistant cancer cell lines when treated alone (Johnson
et al. 2014). In a similar study, the anti-cancer effect of neem-derived gedunin alone
and in combination with cisplatin was also tested against SKOV3, OVCAR4, and
OVCAR8 ovarian cancer cell lines. Gedunin reduced cell proliferation by 20%
when treated alone. When treat synergistically with cisplatin, further 47% decrease
in cell proliferation was reported (Kamath et al. 2009).
576
Y. S. Ong et al.
recent
study
reported
that
gedunin
derivatives,
3-a-acetoxydihydrodeoxygedunin (3-a-DOG) were partial agonist towards adhesion G protein coupled receptors (aGPCR) GPR56/ADGRG1 (Stoveken et al.
2018). aGPCRs is broadly distributed in various tumor cells and has become
prominent as a potential therapeutic target in various neurological diseases and
cancers (Paavola and Hall 2012). The activating mechanism of most aGPCRs have
only been recently characterized and limited modulatory compound are being
defined. Hence, 3-a-DOG and possibly other gedunin derivatives as partial agonist
to aGPCRs could indicate an invaluable area for further research.
16.2.1.1 Combinatorial Treatment Using Gedunin Enhances
Anti-cancer Properties
The complex pathway of tumorigenesis has significant impact on the efficacy of
anti-cancer drugs. Many studies have demonstrated that combinatorial treatments
using multiple agent have proven to improve the clinical therapeutic efficacy of
anti-cancer drugs as compared to single agent regimen. Specifically, gedunin in
neem has been shown to synergize with other anti-cancer drugs apart from its
anti-cancer properties as a single agent. (Sharma et al. 2014; Gupta et al. 2017;
Bodduluru et al. 2014; Kamath et al. 2009).
Combinatory treatment with gedunin and epalrestat has shown to attenuate the
Aldose Reductase (AR) enzyme in the SCC131 oral cancer cell line (Tanagala et al.
2018). Inhibition of diabetic associated enzymes Aldose Reductase (AR) are correlated to the inhibition of SCC131 cell proliferation, apoptosis evasion and
angiogenesis through enervating downstream PI3K/Akt/mTOR/ERK/NF-jB signalling axis. It is reported that the combinatory treatment resulted in diversion of
cell death in favor of apoptosis in the treated cell lines. Further, pro-invasive and
proangiogenic proteins were downregulated in treated groups, hence inhibiting
cancer cell migration. In all events, combined treatment of gedunin and epalrestat
was reported to be more effective than single agents. In a similar study, Kishore and
the team (2016) suggested that the abrogation of AR enzyme, PI3K/Akt and NF-jB
pathways by gedunin has downregulated the expression of miR-21, hypoxia
inducible factor-1 alpha (HIF-1a) and the pro-angiogenic factors vascular
endothelial growth factor in a hamster model of oral carcinogenesis, which inhibited angiogenesis (Kishore et al. 2016).
Interestingly, gedunin acted synergistically with the chemotherapy agents cisplatin (C30, CP75) and paclitaxel (ID8TaxR) at doses as low as 2.5 lM, which
have no effect on the chemoresistant cancer cell lines when treated alone (Johnson
et al. 2014). In a similar study, the anti-cancer effect of neem-derived gedunin alone
and in combination with cisplatin was also tested against SKOV3, OVCAR4, and
OVCAR8 ovarian cancer cell lines. Gedunin reduced cell proliferation by 20%
when treated alone. When treat synergistically with cisplatin, further 47% decrease
in cell proliferation was reported (Kamath et al. 2009).
576
Y. S. Ong et al.