20(S)-Ginsenoside Rg3 is a novel inhibitor of autophagy and sensitizes hepatocellular carcinoma to doxorubicin

Kim, Dong‐Gun; Jung, Kyung Hee; Lee, Da-Gyum; Yoon, Jong Ho; Choi, Kyeong Sook; Kwon, Sung Won; Shen, Han; Morgan, Michael J.; Hong, Soon‐Sun; Kim, You Sun

doi:10.18632/oncotarget.2034

Cited by 95 publications

(87 citation statements)

References 68 publications

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“…Here we demonstrate that doxorubicin induces protective autophagy in pancreatic cancer cells. Consistently, another report has described doxorubicin induced autophagy during induction of cell death [8]. Furthermore, pharmacologic or genetic inhibition of autophagy by knockdown of Beclin-1 or Atg5 expression augments doxorubicin-induced cell death in multiple myeloma cell lines [28].…”

Section: Discussionmentioning

confidence: 56%

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Inhibition of Autophagy by Deguelin Sensitizes Pancreatic Cancer Cells to Doxorubicin

Zhao

Zhang

et al. 2017

IJMS

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Pancreatic cancer is the fourth most common cause of cancer mortality worldwide. Furthermore, patients with pancreatic cancer experience limited benefit from current chemotherapeutic approaches because of drug resistance. Therefore, an effective therapeutic strategy for patients with pancreatic cancer is urgently required. Deguelin is a natural chemopreventive drug that exerts potent antiproliferative activity in solid tumors by inducing cell death. However, the molecular mechanisms underlying this activity have not been fully elucidated. Here we show that deguelin blocks autophagy and induces apoptosis in pancreatic cancer cells in vitro. Autophagy induced by doxorubicin plays a protective role in pancreatic cancer cells, and suppressing autophagy by chloroquine or silencing autophagy protein 5 enhanced doxorubicin-induced cell death. Similarly, inhibition of autophagy by deguelin also chemosensitized pancreatic cancer cell lines to doxorubicin. These findings suggest that deguelin has potent anticancer effects against pancreatic cancer and potentiates the anti-cancer effects of doxorubicin. These findings provide evidence that combined treatment with deguelin and doxorubicin represents an effective strategy for treating pancreatic cancer.

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Section: Discussionmentioning

confidence: 56%

“…In cancer, autophagy plays important roles both in cell death and survival [7,8]. Autophagy is activated in response to a number of stressors, including cancer chemotherapeutics, facilitating cell survival and leading to treatment resistance.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Autophagy by Deguelin Sensitizes Pancreatic Cancer Cells to Doxorubicin

Zhao

Zhang

et al. 2017

IJMS

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“…Typically, the increased acidification and cathepsin enzyme activity, which are the unique features of autophagosome–lysosome fusion, have also been found to be concomitantly altered . Ro and 20( S )‐Rg3 were identified as novel autophagy inhibitors that blocked the fusion of autophagosome with lysosome. More detailed mechanistic studies revealed that Ro led to ROS generation via ESR2 (estrogen receptor 2) mediated NCF1/p47PHOX (neutrophil cytosolic factor 1) pathway, which resulted in an impairment in both lysosomal acidification and cathepsin activity …”

Section: Cellular Stress Response Mechanisms Regulated By Ginsenosidesmentioning

confidence: 99%

“…Doxorubicin‐induced autophagy plays a protective role in hepatocellular carcinoma (HCC) cells. In addition, 20( S )‐Rg3 treatment synergized with doxorubicin to inhibit tumor growth of HCCs . Ro as a novel autophagy suppressor, enhanced 5‐fluorouracil (5‐Fu)‐induced DNA damage and sensitized chemoresistant esophageal cancer cells to 5‐Fu‐mediated cell death .…”

Section: Cellular Stress Response Mechanisms Regulated By Ginsenosidesmentioning

confidence: 99%

Cellular stress response mechanisms as therapeutic targets of ginsenosides

2017

Medicinal Research Reviews

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Ginseng, one of the most widely used traditional herbal medicines and dietary supplements, has historically been recognized as a tonic herb and adaptogen that can enhance the body's tolerance to various adversities. Ginsenosides are a diverse group of steroidal saponins that comprise the major secondary metabolites of ginseng and are responsible for its multiple pharmacological effects. Emerging evidence suggests that hormetic phytochemicals produced by environmentally stressed plants can activate the moderate cellular stress response mechanisms at a subtoxic level in humans, which may enhance tolerance against severe dysfunction or disease. In this review, we initially describe the role of ginsenosides in the chemical defense of plants from the genus Panax suffering from biotic and abiotic stress. Next, we summarize the diverse evolutionarily conserved cellular stress response pathways regulated by ginsenosides and the subsequent stress tolerance against various dysfunctions or diseases. Finally, the structure-activity relationship involved in the effect of ginsenosides is also analyzed. The evidence presented in this review implicates that ginseng as "the King of all herbs" could be regarded as a well-characterized example of the critical role of cellular stress response mechanisms in understanding the health benefits provided by herbal medicines from an evolutionary and ecological perspective.

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“…22,23 Many molecular mechanisms have been proposed for such anticancer activity, Downloaded by [University of Cambridge] at 17:58 16 June 2016 6 including autophagy regulation. [24][25][26][27] Moreover, autophagy contributes to the neuronal protective effects of ginsenoside Rb1 and compound K. 28,29 However, there is currently no evidence showing a direct connection between autophagy and ginsenoside-induced cell death.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of autophagosome-lysosome fusion by ginsenoside Ro via the ESR2-NCF1-ROS pathway sensitizes esophageal cancer cells to 5-fluorouracil-induced cell death via the CHEK1-mediated DNA damage checkpoint

Zheng

Wang

et al. 2016

Autophagy

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Modulation of autophagy has been increasingly regarded as a promising cancer therapeutic approach. In this study, we screened several ginsenosides extracted from Panax ginseng and identified ginsenoside Ro (Ro) as a novel autophagy inhibitor. Ro blocked the autophagosome-lysosome fusion process by raising lysosomal pH and attenuating lysosomal cathepsin activity, resulting in the accumulation of the autophagosome marker MAP1LC3B/LC3B and SQSTM1/p62 (sequestosome 1) in various esophageal cancer cell lines. More detailed studies demonstrated that Ro activated ESR2 (estrogen receptor 2), which led to the activation of NCF1/p47(PHOX) (neutrophil cytosolic factor 1), a subunit of NADPH oxidase, and subsequent reactive oxygen species (ROS) production. Treatment with siRNAs or inhibitors of the ESR2-NCF1-ROS axis, such as N-acetyl-L-cysteine (NAC), diphenyleneiodonium chloride (DPI), apocynin (ACN), Tiron, and Fulvestrant apparently decreased Ro-induced LC3B-II, GFP-LC3B puncta, and SQSTM1, indicating that ROS instigates autophagic flux inhibition triggered by Ro. More importantly, suppression of autophagy by Ro sensitized 5-fluorouracil (5-Fu)-induced cell death in chemoresistant esophageal cancer cells. 5-Fu induced prosurvival autophagy, and by inhibiting such autophagy, siRNAs against BECN1/beclin 1, ATG5, ATG7, and LC3B enhanced 5-Fu-induced autophagy-associated and apoptosis-independent cell death. We observed that Ro potentiates 5-Fu cytotoxicity via delaying CHEK1 (checkpoint kinase 1) degradation and downregulating DNA replication process, resulting in the delayed DNA repair and the accumulation of DNA damage. In summary, these data suggest that Ro is a novel autophagy inhibitor and could function as a potent anticancer agent in combination therapy to overcome chemoresistance.

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20(S)-Ginsenoside Rg3 is a novel inhibitor of autophagy and sensitizes hepatocellular carcinoma to doxorubicin

Cited by 95 publications

References 68 publications

Inhibition of Autophagy by Deguelin Sensitizes Pancreatic Cancer Cells to Doxorubicin

Inhibition of Autophagy by Deguelin Sensitizes Pancreatic Cancer Cells to Doxorubicin

Cellular stress response mechanisms as therapeutic targets of ginsenosides

Inhibition of autophagosome-lysosome fusion by ginsenoside Ro via the ESR2-NCF1-ROS pathway sensitizes esophageal cancer cells to 5-fluorouracil-induced cell death via the CHEK1-mediated DNA damage checkpoint

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