Enhanced anti-tumor effect of combination therapy with gemcitabine and apigenin in pancreatic cancer

Lee, Sang Hyub; Ryu, Ji Kon; Lee, Kyeung Yeup; Woo, Sang Myung; Park, Joo Kyung; Yoo, Ji Won; Kim, Young-Tae; Yoon, Yong Bum

doi:10.1016/j.canlet.2007.09.015

Cited by 95 publications

(64 citation statements)

References 30 publications

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“…Activation of the transcription factor NF-κB after gemcitabine treatment has been found in studies of pancreatic cancer (31,32). Consistent with these results, our study demonstrated that gemcitabine alone elevated NF-κB activation.…”

Section: Discussionsupporting

confidence: 92%

Antitumor and apoptosis-promoting properties of emodin, an anthraquinone derivative from Rheum officinale Baill, against pancreatic cancer in mice via inhibition of Akt activation

Wei

Chen²,

Ni³

et al. 2011

Int J Oncol

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Abstract. Pancreatic adenocarcinoma is one of the most common malignancies worldwide. Gemcitabine is currently the standard first-line chemotherapeutic agent for pancreatic cancer. However, gemcitabine can induce activation of Akt and nuclear factor-κB (NF-κB), which is associated with its chemoresistance. It has been reported that gemcitabine combination therapies result in improved survival outcomes in pancreatic cancer. Therefore, agents that can either enhance the effects of gemcitabine or overcome chemoresistance to the drug are needed for the treatment of pancreatic cancer. Emodin is an active component of Chinese medicinal herbs and can inhibit the activation of Akt and NF-κB. In this study, we investigated whether emodin could enhance the anticancer effect of gemcitabine on pancreatic cancer in vivo. We demonstrated that treatment of gemcitabine combined with emodin efficiently suppressed tumor growth in mice inoculated with pancreatic tumor cells. This treatment paradigm promoted apoptotic cell death and mitochondrial fragmentation. Furthermore, it reduced phosphorylated-Akt (p-Akt) level, NF-κB activation and Bcl-2/Bax ratio, increased caspase-9 and -3 activation, Cytochrome C (CytC) release occurred in combination therapy. Collectively, emodin enhanced the activity of gemcitabine in tumor growth suppression via inhibition of Akt and NF-κB activation, thus promoting the mitochondrial-dependent apoptotic pathway. Therefore, our findings may provide new insights into understanding the pharmacological regulation of emodin on gemcitabine-mediated proapoptosis in pancreatic cancer and may aid in the design of new therapeutic strategies for the intervention of human pancreatic cancers.

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Section: Discussionsupporting

confidence: 92%

Antitumor and apoptosis-promoting properties of emodin, an anthraquinone derivative from Rheum officinale Baill, against pancreatic cancer in mice via inhibition of Akt activation

Wei

Chen²,

Ni³

et al. 2011

Int J Oncol

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show abstract

“…A prevalent mechanism by which activated NF-κB induces chemoresistance in PDAC (pancreatic ductal adenocarcinoma) is by increased expression of cellular inhibitors of apoptosis, including cIAP1, cIAP2, TRAF1, TRAF2, and Survivin (33,34). Activation of the transcription factor NF-κB after gemcitabine treatment has been found in several studies of pancreatic cancer (35,36).…”

Section: Discussionmentioning

confidence: 99%

Emodin potentiates the antitumor effects of gemcitabine in PANC-1 pancreatic cancer xenograft model in vivo via inhibition of inhibitors of apoptosis

Guo

Luo

et al. 2012

Int J Oncol

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Abstract. Pancreatic cancer is a highly aggressive malignant disease. Gemcitabine is currently the standard first-line chemotherapeutic agent for pancreatic cancer. As members of apoptosis inhibitors, Survivin and XIAP play an important role in chemotherapy resistance in pancreatic cancer. Emodin has therapeutic potential against cancers. This study was designed to investigate whether combination therapy with gemcitabine and emodin enhanced antitumor efficacy in pancreatic cancer. The application of the combination therapy triggered significantly higher frequency of pancreatic cancer cell apoptosis. Our research demonstrated that the combination of emodin and gemcitabine resulted in significantly reduced tumor volumes compared to gemcitabine or emodin treatment alone. Immunohistochemistry and western immunoblot analyses showed that Survivin and XIAP expression were downregulated in emodin and the combination groups compared to the other two groups. Reverse transcriptase polymerase chain reaction analyses showed that Survivin and XIAP mRNA expression in emodin and the combination groups were downregulated significantly compared to the other two groups. Furthermore, the expression of the nuclear transcription factor κB (NF-κB) protein and NF-κB mRNA were downregulated in the emodin and the combination groups. DNA-binding activity of NF-κB was inhibited in emodin and combination groups compared to the other groups. This study suggests that emodin potentiates the antitumor effects of gemcitabine in PANC-1 cell xenografts via promotion of apoptosis and IAP suppression.

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“…As a new strategy, gemcitabine combined with naturally occurring nontoxic flavonoid compounds has been reported to overcome tumor cell resistance to apoptosis without increasing toxicity [23,24,25,26,27]. Chemoresistance of pancreatic carcinoma cell lines is associated with two antiapoptotic signal transduction pathways, PI3K/Akt and nuclear factor-ĸB (NF-ĸB), which are believed to be attractive targets for cancer treatment [28].…”

Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of Standardized Allergen-Removed <i>Rhus verniciflua</i> Stokes Extract in Patients with Advanced or Metastatic Pancreatic Cancer: A Korean Single-Center Experience

et al. 2011

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Background: Pancreatic cancer has the worst prognosis because of poor response to conventional therapy. We investigated the clinical feasibility of the standardized allergen-removed Rhus verniciflua Stokes (aRVS) extract as a potential therapeutic agent for advanced or metastatic pancreatic cancer. Patients and Methods: From July 2006 to June 2010, patients with advanced or metastatic pancreatic adenocarcinoma were checked in our institution. After applying inclusion/exclusion criteria, 42 patients were eligible for the final analysis. Overall survival, clinical benefit and adverse events of these patients treated with aRVS in the aftercare period were determined. Results: In May 2011, 39 patients had died and the remaining 3 patients were alive with evidence of disease. The mean RVS administration period was 3.86 months (95% confidence interval 2.52–5.20). The median overall survival for the entire population was 7.87 months (95% confidence interval 5.14–10.59), and the 1-year survival rate was 26.2%, which is compatible with external controls. Using univariate and multivariate analyses, aRVS treatment including performance status and prognostic index significantly affected overall survival. A clinical benefit response was also shown by aRVS treatment which was not dependent on concurrent chemotherapy. Adverse reactions to aRVS treatment were mostly mild and self-limiting. Conclusions: The standardized aRVS extract might be beneficial for patients with advanced or metastatic pancreatic cancer since it positively affected overall survival and clinical symptoms without significant adverse effects.

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Enhanced anti-tumor effect of combination therapy with gemcitabine and apigenin in pancreatic cancer

Cited by 95 publications

References 30 publications

Antitumor and apoptosis-promoting properties of emodin, an anthraquinone derivative from Rheum officinale Baill, against pancreatic cancer in mice via inhibition of Akt activation

Antitumor and apoptosis-promoting properties of emodin, an anthraquinone derivative from Rheum officinale Baill, against pancreatic cancer in mice via inhibition of Akt activation

Emodin potentiates the antitumor effects of gemcitabine in PANC-1 pancreatic cancer xenograft model in vivo via inhibition of inhibitors of apoptosis

Efficacy and Safety of Standardized Allergen-Removed <i>Rhus verniciflua</i> Stokes Extract in Patients with Advanced or Metastatic Pancreatic Cancer: A Korean Single-Center Experience

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