Pilot Study of Oral Anthocyanins for Colorectal Cancer Chemoprevention

Thomasset, Sarah; Berry, David P.; Cai, Hong; West, Kevin; Marczylo, Tim; Marsden, Debbie A.; Brown, Karen; Dennison, Ashley R.; Garcea, Giuseppe; Miller, Andrew M.; Hemingway, David; Steward, William P.; Gescher, Andreas J.

doi:10.1158/1940-6207.capr-08-0201

Cited by 114 publications

(82 citation statements)

References 28 publications

(38 reference statements)

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“…Repeated consumption of fruits and vegetables containing high levels of anthocyanins reduces the risk of tumor development in breast and colon cancers. In addition, anthocyanin intake inhibits tumor proliferation in patients with colorectal cancer (6,10). Studies have also indicated that various anthocyanins derived from fruits and vegetables are effective in the prevention or reduction of solid tumor development in animal models (11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

Anthocyanins are novel AMPKα1 stimulators that suppress tumor growth by inhibiting mTOR phosphorylation

Lee

Lee²,

Kim³

et al. 2010

Oncol Rep

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Abstract. AMP-activated protein kinase (AMPK) has emerged as a therapeutic target of cancer. AMPK functions as an upstream regulator of proliferative signals such as mammalian target of rapamycin (mTOR), tuberous sclerosis complex (TSC), p70S6 and elongation factor-2, indicating that AMPK can be applied for the inhibition of cancer cell proliferation via modulating the proliferative signaling network. The Akt/mTOR signaling pathway is activated in colon cancer. The well known mTOR inhibitor rapamycin has a disadvantage of feedback stimulation of Akt. Anthocyanins are naturally-occurring mTOR inhibitor possessing Akt inhibitory activities. We have investigated the mTOR inhibitory effect of anthocyanins through the activation of AMPK. In this study, anthocyanins were applied to colon cancer cells and tumor-bearing xenograft models to investigate their anti-proliferative and pro-apoptotic effects, and elucidate the mechanisms that link AMP-activated protein kinase (AMPK) ·1 activation to the survival signal of mTOR. Our results indicated that anthocyanins significantly decreased phospho-mTOR comparable to rapamycin, a synthetic mTOR inhibitor, and this inhibitory effect of anthocyanins on mTOR was completely abrogated by inactivating AMPK·1. Furthermore, suppression of cell growth with anthocyanins was also alleviated in the absence of noticeable AMPK·1 activities. For the first time we have found anthocyanins as novel AMPK·1 activators, and in conditions of AMPK·1 inactivation, anthocyanins lost their ability to inhibit mTOR in HT-29 colon cancer cells. The activation of AMPK·1, and the deactivation of mTOR and Akt were observed in anthocyanins-treated tumor-bearing xenograft models. The results from this study suggest that there is a complex interaction between AMPK·1 and mTOR signaling, and anthocyanins are powerful AMPK·1 activators that inhibit cancer cell growth by inhibiting mTOR phosphorylation.

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Section: Introductionmentioning

confidence: 99%

Anthocyanins are novel AMPKα1 stimulators that suppress tumor growth by inhibiting mTOR phosphorylation

Lee

Lee²,

Kim³

et al. 2010

Oncol Rep

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“…This autophagy-inducing activity of ATCs could explain the chemopreventive effect of ATCs reported in the esophagus and the colon (11,12), although the autophagyinducing activity of ATCs in non-transformed cells remains to be determined. A metabolic shift to aerobic glycolysis has generally been regarded as a driving force for carcinogenesis (35,36), and dysregulated metabolic homeostasis and obesity have been reported to increase the risk of certain types of cancer, such as breast cancer (37).…”

Section: Discussionmentioning

confidence: 96%

“…This anti-inflammatory activity of ATCs was shown to be effective in vivo to subside circulatory and multiple organ failures due to endotoxemia (8). Based on these apoptosis-inducing and anti-inflammatory as well as anti-invasive and anti-angiogenic effects (9,10), attempts have been made to develop ATCs as a chemopreventive agent, and promising results of pilot studies in rodent models of esophageal and colorectal cancers and human colorectal cancer patients have provided support for this hypothesis (11,12). In addition to inducing apoptosis, it has been suggested that ATCs induce autophagy in cancer and glial cells (13,14), although the mechanism for this remains to be clarified.…”

Section: Anthocyanins In the Black Soybean (Glycine Max L) Protect Umentioning

confidence: 99%

Anthocyanins in the black soybean (Glycine max L.) protect U2OS cells from apoptosis by inducing autophagy via the activation of adenosyl monophosphate-dependent protein kinase

Choe

et al. 2012

Oncology Reports

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Abstract. Anthocyanins (ATCs) have been reported to induce apoptosis in various types of cancer cells, stimulating the development of ATCs as a cancer chemotherapeutic or chemopreventive agent. It was recently reported that ATCs can induce autophagy, however, the mechanism for this remains unclear. In the present report, we carried out mechanistic studies of the mechanism involved in ATC-induced autophagy using ATCs extracted from black soybeans (cv. Cheongja 3, Glycine max L.). ATCs clearly induced hallmarks of autophagy, including LC3 puncta formation and the conversion of LC3-I to LC3-II in U2OS human osteosarcoma cells. The induction of autophagy was accompanied by the phosphorylation of multiple protein kinases including extracellular signal-regulated kinase (ERK)1/2, p38 mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK), protein kinase B (AKT) and adenosyl mono phosphate-dependent protein kinase (AMPK). While chemical inhibitors against ERK1/2, p38 MAPK, JNK and AKT failed to inhibit ATC-induced autophagy, the suppression of AMPK by compound C (CC) as well as siRNA against AMPK reduced ATC-induced autophagy. The treatment of ATCs resulted in a decrease in intracellular ATP contents and the activation of AMPK by AICAR treatment also induced autophagy. It is noteworthy that the reduction of autophagy via the inhibition of AMPK resulted in enhanced apoptosis in ATC-treated cells. In addition, siRNA against forkhead box O3A (FOXO3a), a downstream target of AMPK, suppressed ATC-induced autophagy and p27 KIP1 siRNA increased apoptosis in ATC-treated cells. Collectively, it can be concluded that ATCs induce autophagy in U2OS cells via activation of the AMPK-FOXO3a pathway and protect cells from ATC-induced apoptosis via the AMPK-p27 KIP1 pathway. These results also suggest that autophagy-modulating agents could contribute to the efficient development of ATCs as anticancer therapy.

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“…However, in the absence of a zero dose control group, authors couldn't determine if this increase could, at least, to some extent, be the consequence of inherent procedural differences in measurements. Nevertheless, the pharmacodynamic changes observed seemed to be more prominent in patients at a dose of anthocyanins, which elicited target tissue levels below the detection limit, than at higher one, which furnished detectable anthocyanin levels in colorectal tissue (Thomasset et al, 2009). However, an Italian study aimed at investigating the relationship between anthocyanidins intake and risk for oral or pharyngeal cancer did not show any significant association (Rossi et al, 2007).…”

Section: Cytotoxicity In Colon and Other Cancer Cell Linesmentioning

confidence: 98%