proportion of HNSCC cells in the G1 phase, decreased cyclin D1 protein expression
and increased the levels of p21WAF1/CIP1 and p27KIP1 proteins [52]. Many
recent studies have demonstrated that EGCG triggers cell growth arrest pathways
at the G1 stage of the cell cycle through regulation of cyclin D1, CDK4, CDK6,
p21/WAF1/CIP1, and p27/KIP1, and induced apoptosis through generation of ROS
and activation of caspase-3 and caspase-9 [89]. Treatment of human colorectal
carcinoma HT-29 cells with EGCG resulted in nuclear condensation, DNA fragmentation, caspase activation, disruption of mitochondrial membrane potential, and
cytochrome c release, which all appeared to be mediated by the JNK pathway [91].
It has been pointed out that the ability of resveratrol to be proapoptotic,
antiproliferative and anti-inflammatory make it a potent anticancer agent [92].
GSE is also reported to have anticancer potential against an array of cancers
such as prostate, breast, oral, colorectal cancers, leukemia, and glioblastoma
multiforme [93, 94].
2.4 Anti-angiogenic Effect
Anti-angiogenesis is one of the fundamental methods of cancer treatment. Angiogenesis is regulated by a variety of pro-angiogenic genes and signaling molecules,
including vascular endothelial growth factor (VEGF), basic fibroblast growth factor
(bFGF), epidermal growth factor (EGF), platelet-derived growth factors (PDGFs),
hypoxia-inducible factors, angiopoetin-1 and angiopoetin-2, and matrix metalloproteinases [95]. Curcumin has demonstrated to have an anti-angiogenic effect
in vivo in xenograft models of various tumors including glioblastoma, hepatocelluar
carcinoma, and prostate and ovarian carcinomas. Curcumin has been shown to
regulate a variety of pro-angiogenic growth factors, enzymes, and transcription
factors (including bFGF, VEGF, angiopoetins 1 and 2, COX-2, MMP-9, AP-1,
and NF-kB), inhibit the angiogenic response to FGF-2 stimulation in mouse
endothelial cells, and decrease the expression of MMP-9 [13].
Silymarin is reported to upregulate Kip1/p27, Cip1/p21, and p53; cause mitochondrial apoptosis and caspase activation; downregulate survivin and inhibit Akt
and NF-kB signaling; and induce MMP-2 secretions. These reactions affected the
growth and survival of human umbilical vein endothelial cells (HUVECs) by
inhibiting capillary tube formation and inducing cell cycle arrest, apoptosis, invasion, and migration [66, 73, 80]. Silymarin reduced VEGF levels in prostate
(DU145), breast (MCF) and MDA-MB-468 cancer cells and downregulated
MMP-2 and CD34 in human hepatoma cell lines [96], causing anti-angiogenic
effects.
EGCG inhibits angiogenesis by enhancing FOXO transcriptional activity. Inhibition of AKT and MEK kinases synergistically induced FOXO transcriptional
activity, which was further enhanced in the presence of EGCG. Phosphorylationdeficient mutants of FOXO induced FOXO transcriptional activity and inhibited
HUVEC cell migration and capillary tube formation. Inhibition of FOXO
Phytomedicine-Loaded Polymeric Nanomedicines: Potential Cancer Therapeutics
213
and increased the levels of p21WAF1/CIP1 and p27KIP1 proteins [52]. Many
recent studies have demonstrated that EGCG triggers cell growth arrest pathways
at the G1 stage of the cell cycle through regulation of cyclin D1, CDK4, CDK6,
p21/WAF1/CIP1, and p27/KIP1, and induced apoptosis through generation of ROS
and activation of caspase-3 and caspase-9 [89]. Treatment of human colorectal
carcinoma HT-29 cells with EGCG resulted in nuclear condensation, DNA fragmentation, caspase activation, disruption of mitochondrial membrane potential, and
cytochrome c release, which all appeared to be mediated by the JNK pathway [91].
It has been pointed out that the ability of resveratrol to be proapoptotic,
antiproliferative and anti-inflammatory make it a potent anticancer agent [92].
GSE is also reported to have anticancer potential against an array of cancers
such as prostate, breast, oral, colorectal cancers, leukemia, and glioblastoma
multiforme [93, 94].
2.4 Anti-angiogenic Effect
Anti-angiogenesis is one of the fundamental methods of cancer treatment. Angiogenesis is regulated by a variety of pro-angiogenic genes and signaling molecules,
including vascular endothelial growth factor (VEGF), basic fibroblast growth factor
(bFGF), epidermal growth factor (EGF), platelet-derived growth factors (PDGFs),
hypoxia-inducible factors, angiopoetin-1 and angiopoetin-2, and matrix metalloproteinases [95]. Curcumin has demonstrated to have an anti-angiogenic effect
in vivo in xenograft models of various tumors including glioblastoma, hepatocelluar
carcinoma, and prostate and ovarian carcinomas. Curcumin has been shown to
regulate a variety of pro-angiogenic growth factors, enzymes, and transcription
factors (including bFGF, VEGF, angiopoetins 1 and 2, COX-2, MMP-9, AP-1,
and NF-kB), inhibit the angiogenic response to FGF-2 stimulation in mouse
endothelial cells, and decrease the expression of MMP-9 [13].
Silymarin is reported to upregulate Kip1/p27, Cip1/p21, and p53; cause mitochondrial apoptosis and caspase activation; downregulate survivin and inhibit Akt
and NF-kB signaling; and induce MMP-2 secretions. These reactions affected the
growth and survival of human umbilical vein endothelial cells (HUVECs) by
inhibiting capillary tube formation and inducing cell cycle arrest, apoptosis, invasion, and migration [66, 73, 80]. Silymarin reduced VEGF levels in prostate
(DU145), breast (MCF) and MDA-MB-468 cancer cells and downregulated
MMP-2 and CD34 in human hepatoma cell lines [96], causing anti-angiogenic
effects.
EGCG inhibits angiogenesis by enhancing FOXO transcriptional activity. Inhibition of AKT and MEK kinases synergistically induced FOXO transcriptional
activity, which was further enhanced in the presence of EGCG. Phosphorylationdeficient mutants of FOXO induced FOXO transcriptional activity and inhibited
HUVEC cell migration and capillary tube formation. Inhibition of FOXO
Phytomedicine-Loaded Polymeric Nanomedicines: Potential Cancer Therapeutics
213