extensively for its in vitro anti-cancer properties against a variety of cancers such as
colon (Uddin et al. 2007), ovarian (Johnson et al. 2014; Patwardhan et al. 2013),
mammary (Brandt et al. 2008; Kikuchi et al. 2011), pancreatic (Boopalan et al.
2013; Subramani et al. 2017), lung, stomach cancers, melanoma and leukemic
(Kikuchi et al. 2011) (Table 16.1). The anti-cancer activities of neem compounds
including gedunin in gynecological cancers (breast, cervical and ovarian) was
recently reviewed by Moga et al. (2018). A number of literatures reported gedunin
showed notable anti-cancer mechanisms such as induction of autophagy, apoptosis,
mitotic arrest and inhibition of metastasis (Fig. 16.1). The compound exhibited a
promising in vitro efficacy with IC 50 values in a range of 3.22–30 µM; in which the
efficacy was more prominent in breast cancer cell lines (MCF-7 and SkBr3) and
leukemia cell line (HL60).
In 2006, a research group led by Lamb et al. (2006) discovered that the
anti-proliferative property of gedunin was modulated by the 90-kDa heat shock
protein (Hsp90) through connectivity map. Hsp90 is a molecular chaperone that is
responsible for the stability and function of a wide variety of client proteins for cells
growths and survivals. In cancerous cells, these client proteins are frequently
mutated or/and overexpressed, henceforth it is being actively pursued as individual
therapeutic target (Garg et al. 2016). Hsp90 is essential for normal cellular
homeostasis. It is also known to play an important role in several pathological
conditions. Hsp90 and its co-chaperones (which help to regulate the function of the
Hsp90 protein-folding machine) are extensively studied in tumorigenesis. Hsp90
inhibitors bind and inactivate Hsp90 N-terminal ATP-binding site, causing proteasomal degradation of Hsp90-dependent client protein (Patwardhan et al. 2013).
Unlike most of the drug inhibitor of Hsp90, gedunin interacted with Hsp90 without
the involvement of competitive inhibitor of ATP, suggesting that a novel and
unique mechanism of Hsp90 modulation (Hieronymus et al. 2006).
Through Hsp90 inhibition, gedunin has been further investigated for the
downstream mechanisms of action responsible for its anti-cancer effect. Research
revealed that gedunin inhibited cancerous cell proliferation by inducing mitotic
arrest between metaphase and anaphase. The significant overexpressed of checkpoint kinase-1 (CHK1) and polo-like kinase-1 (PLK1) in the cancerous cells has led
to the mitotic halt. In a study performed with pancreatic cancer cells, gedunin has
shown to exhibit anti-proliferative effect by suppressing mTOR and 4EBP, which
are the key phosphoproteins responsible for protein translation.
Induction of apoptosis in cancerous cells has been the main strategy in cancer
treatment (Ong et al. 2018). Several studies reported that treatment with gedunin
has induced apoptosis and autophagy in various cancer cells through modulation of
cell death executors such as LC3B, WIPI-1, VMP-1, pJNK, caspases and
PARP. Gedunin demonstrated its potential as effective agent against pancreatic
cancer which currently lacks of effective treatment. In vitro study by Subramani and
colleagues showed that gedunin at 25 µM has induced high percentage of apoptotic
cell death in three pancreatic cancer cell lines HPAC (46.5%), MIAPaCa-2 (37.6%)
and PANC-1 (44.7%), but it was relatively safe against non-cancerous pancreatic
cell (hTERT-HPNE). In addition, gedunin induced apoptosis through intrinsic and
566
Y. S. Ong et al.
colon (Uddin et al. 2007), ovarian (Johnson et al. 2014; Patwardhan et al. 2013),
mammary (Brandt et al. 2008; Kikuchi et al. 2011), pancreatic (Boopalan et al.
2013; Subramani et al. 2017), lung, stomach cancers, melanoma and leukemic
(Kikuchi et al. 2011) (Table 16.1). The anti-cancer activities of neem compounds
including gedunin in gynecological cancers (breast, cervical and ovarian) was
recently reviewed by Moga et al. (2018). A number of literatures reported gedunin
showed notable anti-cancer mechanisms such as induction of autophagy, apoptosis,
mitotic arrest and inhibition of metastasis (Fig. 16.1). The compound exhibited a
promising in vitro efficacy with IC 50 values in a range of 3.22–30 µM; in which the
efficacy was more prominent in breast cancer cell lines (MCF-7 and SkBr3) and
leukemia cell line (HL60).
In 2006, a research group led by Lamb et al. (2006) discovered that the
anti-proliferative property of gedunin was modulated by the 90-kDa heat shock
protein (Hsp90) through connectivity map. Hsp90 is a molecular chaperone that is
responsible for the stability and function of a wide variety of client proteins for cells
growths and survivals. In cancerous cells, these client proteins are frequently
mutated or/and overexpressed, henceforth it is being actively pursued as individual
therapeutic target (Garg et al. 2016). Hsp90 is essential for normal cellular
homeostasis. It is also known to play an important role in several pathological
conditions. Hsp90 and its co-chaperones (which help to regulate the function of the
Hsp90 protein-folding machine) are extensively studied in tumorigenesis. Hsp90
inhibitors bind and inactivate Hsp90 N-terminal ATP-binding site, causing proteasomal degradation of Hsp90-dependent client protein (Patwardhan et al. 2013).
Unlike most of the drug inhibitor of Hsp90, gedunin interacted with Hsp90 without
the involvement of competitive inhibitor of ATP, suggesting that a novel and
unique mechanism of Hsp90 modulation (Hieronymus et al. 2006).
Through Hsp90 inhibition, gedunin has been further investigated for the
downstream mechanisms of action responsible for its anti-cancer effect. Research
revealed that gedunin inhibited cancerous cell proliferation by inducing mitotic
arrest between metaphase and anaphase. The significant overexpressed of checkpoint kinase-1 (CHK1) and polo-like kinase-1 (PLK1) in the cancerous cells has led
to the mitotic halt. In a study performed with pancreatic cancer cells, gedunin has
shown to exhibit anti-proliferative effect by suppressing mTOR and 4EBP, which
are the key phosphoproteins responsible for protein translation.
Induction of apoptosis in cancerous cells has been the main strategy in cancer
treatment (Ong et al. 2018). Several studies reported that treatment with gedunin
has induced apoptosis and autophagy in various cancer cells through modulation of
cell death executors such as LC3B, WIPI-1, VMP-1, pJNK, caspases and
PARP. Gedunin demonstrated its potential as effective agent against pancreatic
cancer which currently lacks of effective treatment. In vitro study by Subramani and
colleagues showed that gedunin at 25 µM has induced high percentage of apoptotic
cell death in three pancreatic cancer cell lines HPAC (46.5%), MIAPaCa-2 (37.6%)
and PANC-1 (44.7%), but it was relatively safe against non-cancerous pancreatic
cell (hTERT-HPNE). In addition, gedunin induced apoptosis through intrinsic and
566
Y. S. Ong et al.