Synergistic Tumor-Killing Effect of Radiation and Berberine Combined Treatment in Lung Cancer: The Contribution of Autophagic Cell Death

Peng, Pei-Ling; Kuo, Wu‐Hsien; Tseng, Hsien-Chun; Chou, Fen‐Pi

doi:10.1016/j.ijrobp.2007.08.034

Cited by 123 publications

(95 citation statements)

References 24 publications

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“…These results shed further light on the antineoplastic activity of berberine and are in agreement with other recent reports. (16,33) It is interesting that co-incubation of cells with both 3-MA and z-DEVD-fmk did not completely prevent berberine-induced cell death. This suggests that berberine induces not only autophagic cell death and apoptosis, but also some other types of death, such as necrosis.…”

Section: Discussionmentioning

confidence: 99%

Berberine induces cell death in human hepatoma cells in vitro by downregulating CD147

Hou

Xu²,

Liu

et al. 2011

Cancer Science

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The isoquinoline plant alkaloid berberine has anti-tumor effects on a variety of carcinoma cells, mainly through inhibition of cell proliferation, apoptosis induction and cell cycle arrest. However, the mechanisms underlying its role in tumor progression are unknown. In the present study, we investigated the molecular mechanisms involved in berberine-induced cell death in human hepatoma carcinoma cell (HCC) lines HepG2 and SMMC7721. Our results showed that berberine inhibited tumor cell viability in a dose-and time-dependent manner, and induced cell death via apoptosis and autophagy. Moreover, berberine treatment significantly inhibited CD147 expression by HCC cells in a dosedependent manner. Overexpression of CD147 protein markedly reduced berberine-induced cell death. Our data provide the first experimental evidence that berberine induces cell death in HCC cells via downregulation of CD147 and suggest a new mechanism to explain its anti-tumor effects. (Cancer Sci 2011; 102: 1287-1292 B erberine is an isoquinoline alkaloid found in a number of important medicinal plant species such as Berberis aristata and Berberis aquifolium, and has antibacterial,(1) anti-hypertensive, (2) anti-inflammatory, (3) anti-diabetic (4) and anti-hyperlipidemic effects.(5) Recently, researchers have become interested in the anti-neoplastic activities of berberine and have demonstrated its anticancer effects against a variety of human cancer cells both in vitro and in vivo through suppression of tumor cell proliferation, induction of tumor cell apoptosis, and inhibition of both tumor invasion and metastasis.(6,7) These findings suggest that berberine is a promising candidate for clinical use in cancer chemotherapy.Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide and the third leading cause of death from cancer because of its very poor prognosis. More than 1 million cases of HCC occur in the world each year.(8) Hepatocellular carcinoma is highly resistant to conventional systemic therapies and the prognosis for patients with advanced HCC remains poor. Although a lot of progress has been made in terms of chemotherapy, which provides significant survival benefits for patients with HCC, it is associated with significant side-effects, highlighting the need for therapeutic strategies that target tumor cells without compromising normal tissue function.(9,10) Thus, the development of novel systemic agents from natural products with low toxicity and few side-effects is being actively pursued. (11)(12)(13) Previous studies confirm the anti-tumor effects of berberine on HCC. (14)(15)(16) Berberine acts by inhibiting proliferation and inducing apoptosis in HCC cells. It can also inhibit the migration of HCC cells by downregulating the Rho ⁄ ROCK signaling pathway.(17) However, the exact mechanisms underlying the anti-tumor effects of berberine are still unknown. CD147, a glycosylated immunoglobulin super family transmembrane protein, is highly expressed by HCC cells. Several in vitro studies suggest that CD147 promotes...

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Section: Discussionmentioning

confidence: 99%

Berberine induces cell death in human hepatoma cells in vitro by downregulating CD147

Hou

Xu²,

Liu

et al. 2011

Cancer Science

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“…However, co-treatment of berberine and radiation caused a dose-dependent (5-10 μM) autophagic cell death and cell cycle arrest, while little percentage of apoptosis was observed in A549 cell lines. 88 Furthermore, the possible therapeutic application of berberine to enhance radiotherapy was demonstrated by the Lewis lung carcinoma model in mice, showing that berberine with irradiation resulted in autophagic cell death and in a substantial shrinkage of tumor volume, whereas radiation and berberine as single modalities only delayed tumor growth. 88 Albert et al showed that radiation alone (3 Gy) or combined with a ABT-888, a Poly(ADP-ribose) polumerase-1 (PARP-1) inhibitor, induces autophagic cell death up to 7.3 fold and apoptosis up to 2.8 fold in H460 lung cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…88 Furthermore, the possible therapeutic application of berberine to enhance radiotherapy was demonstrated by the Lewis lung carcinoma model in mice, showing that berberine with irradiation resulted in autophagic cell death and in a substantial shrinkage of tumor volume, whereas radiation and berberine as single modalities only delayed tumor growth. 88 Albert et al showed that radiation alone (3 Gy) or combined with a ABT-888, a Poly(ADP-ribose) polumerase-1 (PARP-1) inhibitor, induces autophagic cell death up to 7.3 fold and apoptosis up to 2.8 fold in H460 lung cancer cells. 89 Also, co-treatment with ABT-888/irradiation improved tumor growth delay in a H460 lung cancer xenografts.…”

Section: Discussionmentioning

confidence: 99%

Radiation-induced autophagy in normal and cancer cells: Towards novel cytoprotection and radio-sensitization policies?

Zois¹,

Koukourakis²

2009

Autophagy

124

101

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Autophagy or Type II programmed cell death (PCD) is a major intracellular pathway for the degradation and recycling of proteins, ribosomes and entire organelles. The role of this pathway in the antitumor effect of radiotherapy and in radiation toxicity is obscure. A complicated machinery of genes and proteins is involved in the regulation of autophagy as a response to a variety of stress factors including hypoxia, nutrient deprivation, cytotoxic agents and radiotherapy. Continuously accumulating data suggest that autophagic response of cancer cells to radiotherapy is a major pathway which, in contrast to apoptosis that leads to death, may lead to either death or cellular survival. A variety of agents have been recognized that induce or block autophagy, directly interfering with the cytotoxic effect of radiotherapy. Simultaneous targeting of autophagy and apoptosis during radiotherapy seems to further augment the antitumor effect. Radiobiology research should focus on the differential effect of fractionation on the induction of autophagy in different tumors and on the manipulation of this with autophagy triggering agents. Whether manipulation of this pathway in normal tissues may be used to confer cytoprotection also deserves thorough investigation. Moreover, the role of pretreatment autophagic indices in tumor cells in predicting radiotherapy and chemotherapy outcome should be examined in translational studies.

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“…Statistical significance was determined by using Student's t-test for comparison between the means or one-way analysis of variance with post-hoc Dunnett's test [26]. Differences were considered to be significant when p,0.05.…”

Section: Discussionmentioning

confidence: 99%

Effects of arsenite on macropinocytotic and autophagic activities in CHO-K1 cells

Wang

Chiu

Chen

et al. 2012

Understanding the Geological and Medical Interface of Arsenic - As 2012

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Prostate cancer is the most common malignancy in men. In the present study, LNCaP (androgen-sensitive human prostate cancer cells) and PC-3 cells (androgen-independent human prostate cancer cells) were used to investigate the anti-cancer effects of ionizing radiation (IR) combined with arsenic trioxide (ATO) and to determine the underlying mechanisms in vitro and in vivo. We found that IR combined with ATO increases the therapeutic efficacy compared to individual treatments in LNCaP and PC-3 human prostate cancer cells. In addition, combined treatment showed enhanced reactive oxygen species (ROS) generation compared to treatment with ATO or IR alone in PC-3 cells. Combined treatment induced autophagy and apoptosis in LNCaP cells, and mainly induced autophagy in PC-3 cells. The cell death that was induced by the combined treatment was primarily the result of inhibition of the Akt/mTOR signaling pathways. Furthermore, we found that the combined treatment of cells pre-treated with 3-MA resulted in a significant change in AO-positive cells and cytotoxicity. In an in vivo study, the combination treatment had anti-tumor growth effects. These novel findings suggest that combined treatment is a potential therapeutic strategy not only for androgen-dependent prostate cancer but also for androgenindependent prostate cancer.

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Synergistic Tumor-Killing Effect of Radiation and Berberine Combined Treatment in Lung Cancer: The Contribution of Autophagic Cell Death

Cited by 123 publications

References 24 publications

Berberine induces cell death in human hepatoma cells in vitro by downregulating CD147

Berberine induces cell death in human hepatoma cells in vitro by downregulating CD147

Radiation-induced autophagy in normal and cancer cells: Towards novel cytoprotection and radio-sensitization policies?

Effects of arsenite on macropinocytotic and autophagic activities in CHO-K1 cells

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