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Introduction
Apigenin (4’,5,7-trihydroxyflavone; Fig. 1A), a naturally occurring flavone, it is widely distributed in many fruits and vegetables such as parsley, onions, apples, tea and chamomile. In recent years, apigenin has been increasingly recognized as a cancer chemopreventive agent. The chemopreventive aspects of apigenin have been evaluated both in vitro and in vivo. Apigenin has been shown to be growth inhibitory in a variety of human cancer cell lines including colon, pancreatic, oral squamous, lung and leukemia cells (1–5). An important effect of apigenin is to increase the stability of the tumor suppressor p53 gene in normal cells. It has been shown that apigenin induced G2/M cell cycle arrest in colon cancer cells (1), and in vivo it is involved in p21CIP1/WAF1-independent pathway for inhibitory phosphorylation of p34 (Cdc2) and concomitant G2/M arrest in mouse keratinocytes (6). Apigenin was shown to induce apoptosis in a variety of cancer cells (3,4,7,8). Apigenin has shown to inhibit tumor cell invasion and metastases by regulating the hypoxia-inducible factor 1-α protein level and to inhibit transforming growth factor β 1-induced vascular endothelial growth factor expression in human prostate cancer cells (9). Moreover, apigenin has been reported to potentiate the effect of tumor necrosis factor-related apoptosis-inducing ligand, paclitaxel, ABT-263, 5-fluorouracil (5-FU) and cisplatin against various human cancers (10–13).
Autophagy, an evolutionarily conserved process, sequesters and degrades long-lived cellular proteins and organelles through the lysosomal machinery (14,15). The purpose of autophagy is the recycling of cellular components to sustain metabolism under stress conditions such as nutrient deprivation and to prevent accumulation of damaged proteins and organelles (16). The first evidence for a role of autophagy in cancer was found by Liang et al (17). The autophagy-promoting activity of beclin-1 in human breast cancer cells is associated with inhibition of MCF7 cellular proliferation (17). It is reported that beclin-1, a phylo-genetically conserved protein that is essential for autophagy, can inhibit tumorigenesis and is expressed at decreased levels in human breast carcinoma. Recent evidence indicates that the phosphoinositide 3-kinase (PI3K), Akt and mammalian target of rapamycin (mTOR) pathway, which is activated in many types of cancer (18) is important in autophagy regulation, especially through activating mTOR kinase, leading to suppression of autophagy (15). Recently, increasing evidence indicates that autophagy...