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Figure 6. Progression of angiogenesis and the inhibitory mechanism of curcumin. Curcumin is capable of functioning through a myriad of
mechanisms, but this figure illustrates down-regulation of factors involved in tumor initiation such as NF-κB, COX-2, cyclin D1, p53 and
Akt/PI3k, and proliferation factors such as STAT, MAPK EGFR. The progression phase of tumorigenesis is also inhibited, for example, by
alteration of VEGF expression, leading to reduced angiogenesis and metastasis. NF-κB: nuclear factor-κB; COX: cyclooxygenase; PI3K:
phosphatidylinositol-3-kinase; MAPK: mitogen-activated protein kinase

mg along with chemotherapy [189] . In addition, topical application of curcumin along with other herbal
preparations for 30 consecutive days resulted in significant clearance of HPV. However, vaginal curcumin
capsules did not show any statistical difference [190] . Oral administration of curcumin (8000 mg) is well
tolerated in patients diagnosed with advanced pancreatic cancer [191] . And, in a Phase II clinical trial, despite
its limited absorption, curcumin exerted biological activity in a few patients, such as down-regulation of
transcription factor NF-κB and reduced COX-2 (8,000 mg/day dosage) [192] .

Mechanism of anti-carcinogenesis
VEGF
Since VEGF is a crucial regulator for angiogenesis, the use of potentially active phytochemicals including
curcumin as an anti-angiogenic compound has been explored [193] . With the H22 HCC cell line, curcumin
[194]
inhibited the proliferation of cells in vitro and reduced VEGF expression and PI3K/AKT signaling in vivo .
Curcumin reduced high mobility group box 1 and VEGF-D expression in gastric cancer AGC and SGC-
7901 cell lines, and induced cell apoptosis through caspase-3 activation, in a dose-dependent manner [195] .

Role of curcumin in cell-cycle arrest
Curcumin inhibits the expression of cyclin E and cyclin D1 that enable cell-cycle arrest at the G1/S phase
in LNCaP and PC-3 cell lines [196] . In another in vitro study, with human osteosarcoma cells, cell-cycle arrest
by curcumin at the G1/S phase was related to a reduction of cyclin D1 [197] . Human mantle cell lymphoma is
characterized by overexpression of cyclin D1, which up-regulates NF-κB and several genes such as, bcl-2,
COX-2 and IL-6. However, on treatment with curcumin, cyclin D1 expression was down-regulated, along
with AKT activation [198] . Curcumin also improves the efficacy of chemotherapeutic agents such as cisplatin