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Hormetic Effect of Berberine Attenuates the Anticancer Activity of Chemotherapeutic Agents.

Bao J, Huang B, Zou L, Chen S, Zhang C, Zhang Y, Chen M, Wan JB, Su H, Wang Y, He C - PLoS ONE (2015)

Bottom Line: Hormesis is a phenomenon of biphasic dose response characterized by exhibiting stimulatory or beneficial effects at low doses and inhibitory or toxic effects at high doses.This study aims to investigate the hormetic effect of berberine and its influence on the anticancer activities of chemotherapeutic agents.These results provided important information to understand the potential side effects of hormesis, and suggested cautious application of natural compounds and relevant herbs in adjuvant treatment of cancer.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao, China.

ABSTRACT
Hormesis is a phenomenon of biphasic dose response characterized by exhibiting stimulatory or beneficial effects at low doses and inhibitory or toxic effects at high doses. Increasing numbers of chemicals of various types have been shown to induce apparent hormetic effect on cancer cells. However, the underlying significance and mechanisms remain to be elucidated. Berberine, one of the major active components of Rhizoma coptidis, has been manifested with notable anticancer activities. This study aims to investigate the hormetic effect of berberine and its influence on the anticancer activities of chemotherapeutic agents. Our results demonstrated that berberine at low dose range (1.25 ~ 5 μM) promoted cell proliferation to 112% ~170% of the untreated control in various cancer cells, while berberine at high dose rage (10 ~ 80 μM) inhibited cell proliferation. Further, we observed that co-treatment with low dose berberine could significantly attenuate the anticancer activity of chemotherapeutic agents, including fluorouracil (5-FU), camptothecin (CPT), and paclitaxel (TAX). The hormetic effect and thereby the attenuated anticancer activity of chemotherapeutic drugs by berberine may attributable to the activated protective stress response in cancer cells triggered by berberine, as evidenced by up-regulated MAPK/ERK1/2 and PI3K/AKT signaling pathways. These results provided important information to understand the potential side effects of hormesis, and suggested cautious application of natural compounds and relevant herbs in adjuvant treatment of cancer.

No MeSH data available.


Related in: MedlinePlus

Western blot analysis of protein expression levels of p-ERK, ERK, p-AKT and AKT.B16-F10 cells were treated with low dose of BER (5 μM) (A) and high dose of BER (40 μM) (B) for 0.5 h, 1 h and 3 h, respectively. Total protein of cell lysates was extracted and subjected to Western blot analysis. The density of each band was quantified by Quantity One Software, and the relative density ratio of each protein was calculated accordingly. β-actin was used as the internal control. Data are expressed as mean ± SD (n ≥ 3). * P < 0.05, ** P < 0.01 compared to untreated control.
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pone.0139298.g003: Western blot analysis of protein expression levels of p-ERK, ERK, p-AKT and AKT.B16-F10 cells were treated with low dose of BER (5 μM) (A) and high dose of BER (40 μM) (B) for 0.5 h, 1 h and 3 h, respectively. Total protein of cell lysates was extracted and subjected to Western blot analysis. The density of each band was quantified by Quantity One Software, and the relative density ratio of each protein was calculated accordingly. β-actin was used as the internal control. Data are expressed as mean ± SD (n ≥ 3). * P < 0.05, ** P < 0.01 compared to untreated control.

Mentions: MAPK/ERK1/2 and PI3K/AKT pathways play an important role in cell proliferation and survival [23, 24], and adaptive oxidative response [25, 26]. We hypothesized that MAPK/ERK and PI3K/AKT signaling pathways were involved in the hormetic effect induced by low dose BER. Hence, we examined the phosphorylated and total protein levels of ERK1/2 and AKT in B16-F10 cells treated with low (5 μM) and high doses (40 μM) of BER. Representative results from each group were presented in Fig 3. Density analysis showed that ratios of phosphorylated ERK to total ERK were significantly increased with a peak increase of about 40% after treatment with 5 μM BER for 1 h (Fig 3A). However, the expression of phosphorylated ERK in B16-F10 cells decreased sharply over time after treatment with high dose of BER (40 μM) (Fig 3B). The relative density ratio of phosphorylated AKT to total AKT was also increased after treatment of 5 μM BER, and had a rapid decline when treated with high dose BER. These results indicated that low dose BER activated MAPK/ERK and PI3K/AKT signaling pathways, which might be responsible for the hormetic effect and inhibition of anticancer activity of chemotherapeutic agents by BER.


Hormetic Effect of Berberine Attenuates the Anticancer Activity of Chemotherapeutic Agents.

Bao J, Huang B, Zou L, Chen S, Zhang C, Zhang Y, Chen M, Wan JB, Su H, Wang Y, He C - PLoS ONE (2015)

Western blot analysis of protein expression levels of p-ERK, ERK, p-AKT and AKT.B16-F10 cells were treated with low dose of BER (5 μM) (A) and high dose of BER (40 μM) (B) for 0.5 h, 1 h and 3 h, respectively. Total protein of cell lysates was extracted and subjected to Western blot analysis. The density of each band was quantified by Quantity One Software, and the relative density ratio of each protein was calculated accordingly. β-actin was used as the internal control. Data are expressed as mean ± SD (n ≥ 3). * P < 0.05, ** P < 0.01 compared to untreated control.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4589364&req=5

pone.0139298.g003: Western blot analysis of protein expression levels of p-ERK, ERK, p-AKT and AKT.B16-F10 cells were treated with low dose of BER (5 μM) (A) and high dose of BER (40 μM) (B) for 0.5 h, 1 h and 3 h, respectively. Total protein of cell lysates was extracted and subjected to Western blot analysis. The density of each band was quantified by Quantity One Software, and the relative density ratio of each protein was calculated accordingly. β-actin was used as the internal control. Data are expressed as mean ± SD (n ≥ 3). * P < 0.05, ** P < 0.01 compared to untreated control.
Mentions: MAPK/ERK1/2 and PI3K/AKT pathways play an important role in cell proliferation and survival [23, 24], and adaptive oxidative response [25, 26]. We hypothesized that MAPK/ERK and PI3K/AKT signaling pathways were involved in the hormetic effect induced by low dose BER. Hence, we examined the phosphorylated and total protein levels of ERK1/2 and AKT in B16-F10 cells treated with low (5 μM) and high doses (40 μM) of BER. Representative results from each group were presented in Fig 3. Density analysis showed that ratios of phosphorylated ERK to total ERK were significantly increased with a peak increase of about 40% after treatment with 5 μM BER for 1 h (Fig 3A). However, the expression of phosphorylated ERK in B16-F10 cells decreased sharply over time after treatment with high dose of BER (40 μM) (Fig 3B). The relative density ratio of phosphorylated AKT to total AKT was also increased after treatment of 5 μM BER, and had a rapid decline when treated with high dose BER. These results indicated that low dose BER activated MAPK/ERK and PI3K/AKT signaling pathways, which might be responsible for the hormetic effect and inhibition of anticancer activity of chemotherapeutic agents by BER.

Bottom Line: Hormesis is a phenomenon of biphasic dose response characterized by exhibiting stimulatory or beneficial effects at low doses and inhibitory or toxic effects at high doses.This study aims to investigate the hormetic effect of berberine and its influence on the anticancer activities of chemotherapeutic agents.These results provided important information to understand the potential side effects of hormesis, and suggested cautious application of natural compounds and relevant herbs in adjuvant treatment of cancer.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao, China.

ABSTRACT
Hormesis is a phenomenon of biphasic dose response characterized by exhibiting stimulatory or beneficial effects at low doses and inhibitory or toxic effects at high doses. Increasing numbers of chemicals of various types have been shown to induce apparent hormetic effect on cancer cells. However, the underlying significance and mechanisms remain to be elucidated. Berberine, one of the major active components of Rhizoma coptidis, has been manifested with notable anticancer activities. This study aims to investigate the hormetic effect of berberine and its influence on the anticancer activities of chemotherapeutic agents. Our results demonstrated that berberine at low dose range (1.25 ~ 5 μM) promoted cell proliferation to 112% ~170% of the untreated control in various cancer cells, while berberine at high dose rage (10 ~ 80 μM) inhibited cell proliferation. Further, we observed that co-treatment with low dose berberine could significantly attenuate the anticancer activity of chemotherapeutic agents, including fluorouracil (5-FU), camptothecin (CPT), and paclitaxel (TAX). The hormetic effect and thereby the attenuated anticancer activity of chemotherapeutic drugs by berberine may attributable to the activated protective stress response in cancer cells triggered by berberine, as evidenced by up-regulated MAPK/ERK1/2 and PI3K/AKT signaling pathways. These results provided important information to understand the potential side effects of hormesis, and suggested cautious application of natural compounds and relevant herbs in adjuvant treatment of cancer.

No MeSH data available.


Related in: MedlinePlus