Metformin Increases Sensitivity of Pancreatic Cancer Cells to Gemcitabine by Reducing CD133+ Cell Populations and Suppressing ERK/P70S6K Signaling

Chai, Xiangping; Chu, Hongpeng; Yang, Xuan; Meng, Yunlong; Shi, Pengfei; Gou, Shanmiao

doi:10.1038/srep14404

Cited by 63 publications

(41 citation statements)

References 52 publications

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“…In line with these findings, the administration of anti-CD44 monoclonal antibody to a human PC xenograft mouse model increased Gemcitabine sensitivity[120]. Additionally, Metformin enhanced the capacity of Gemcitabine to inhibit the proliferation of PC cells by inhibiting the proliferation of CD133 + cells[121]. Side population PCSC identified by Van der Broeck in 2012[111] are resistant to Gemcitabine.…”

Section: Pancreatic Cancer Stem Cellsmentioning

confidence: 96%

Leptin signaling and cancer chemoresistance: Perspectives

Candelaria¹,

Rampoldi²,

Harbuzariu³

et al. 2017

WJCO

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Obesity is a major health problem and currently is endemic around the world. Obesity is a risk factor for several different types of cancer, significantly promoting cancer incidence, progression, poor prognosis and resistance to anti-cancer therapies. The study of this resistance is critical as development of chemoresistance is a serious drawback for the successful and effective drug-based treatments of cancer. There is increasing evidence that augmented adiposity can impact on chemotherapeutic treatment of cancer and the development of resistance to these treatments, particularly through one of its signature mediators, the adipokine leptin. Leptin is a pro-inflammatory, pro-angiogenic and pro-tumorigenic adipokine that has been implicated in many cancers promoting processes such as angiogenesis, metastasis, tumorigenesis and survival/resistance to apoptosis. Several possible mechanisms that could potentially be developed by cancer cells to elicit drug resistance have been suggested in the literature. Here, we summarize and discuss the current state of the literature on the role of obesity and leptin on chemoresistance, particularly as it relates to breast and pancreatic cancers. We focus on the role of leptin and its significance in possibly driving these proposed chemoresistance mechanisms, and examine its effects on cancer cell survival signals and expansion of the cancer stem cell sub-populations.

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Section: Pancreatic Cancer Stem Cellsmentioning

confidence: 96%

Leptin signaling and cancer chemoresistance: Perspectives

Candelaria¹,

Rampoldi²,

Harbuzariu³

et al. 2017

WJCO

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“…Several studies have suggested that patients taking MET for the treatment of diabetes also have a decreased incidence of pancreatic cancer [24,25]. MET has also been implicated in its ability to increase sensitivity of pancreatic cancer cells to GEM [24]. Other studies have concluded, however, that there is no association between MET use and cancer risk or prognosis [26,27].…”

Section: Introductionmentioning

confidence: 93%

“…MET is the primary drug used for the treatment of type 2 diabetes mellitus, and has become a drug of interest for the treatment of pancreatic cancer [19][20][21][22][23]. Several studies have suggested that patients taking MET for the treatment of diabetes also have a decreased incidence of pancreatic cancer [24,25]. MET has also been implicated in its ability to increase sensitivity of pancreatic cancer cells to GEM [24].…”

Section: Introductionmentioning

confidence: 99%

Combined treatment of gemcitabine with indole-3-carbinol or metformin on drug efficacy in pancreatic cancer cell lines: The role of human equilibrative nucleoside transporters

Joseph¹,

Word²,

Lyn‐Cook³

2018

J Cancer Res Ther.

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Pancreatic cancer is one of the most lethal carcinomas in the United States. In accord with the American Cancer Society pancreatic cancer is anticipated to move from the third to the second leading cause of deaths in the United States by 2020. Although the standard treatment for advanced pancreatic cancer is gemcitabine (GEM), the response rate is less than 20%. Chemoresistance is a hallmark of this cancer, and modulation of drug transporters expression has been shown to increase cancer drug efficacy. Studies have shown that human equilibrative nucleoside transporters (hENTs) expression patterns may predict GEM treatment efficacy. This study investigated whether or not GEM in combination with metformin (MET) or indole-3-carbinol (I3C) increases cytotoxicity and modulates hENT1 and hENT4. Pancreatic cancer cells from males and females were treated for 24 or 72h with GEM and/or MET or I3C. Cell viability, drug interactions, and protein and mRNA expression levels of hENTs were assessed. Treatment with GEM and/or MET or I3C showed cell line specific reductions in pancreatic cancer cell proliferation, and modulation of hENT1 and hENT4 expression. Response to GEM and MET/I3C may be dependent upon the genetic profile of the tumor and the level of expression of a specific transporter. The sensitivity of GEM could depend on the method of treatment, whether cells were pre-treated with MET or I3C, which studies, including our own, have showed that pre-treatment with I3C increased upregulation of hENT1 expression in pancreatic cancer cell lines.Keywords: pancreatic cancer; gemcitabine; indole-3-carbinol; metformin; human equilibrative nucleoside transporters

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“…It enhanced the effect of denosumab, an antibody against RANKL (receptor activator of NFκB ligand, a cytokine), in inhibiting breast CSC spheroids [98]. It enhanced the sensitivity of pancreatic CSCs to gemcitabine in vivo, significantly reducing the tumor volume in murine xenografts [99]. When given in combination, metformin and doxorubicin showed the advantage of targeting both breast CSCs and non-stem cancer cells, by reducing the overall tumor growth and tumor remission in nude mice [100].…”

Section: Metforminmentioning

confidence: 99%

Targeting cancer stem cells with dietary phytochemical - Repositioned drug combinations

2018

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The tumor microenvironment is complex with the cancer stem cell (CSC) as a member within its community. This population possesses the capacity to self-renew and to cause cellular heterogeneity of the tumor. CSCs are resistant to conventional anti-proliferative drugs. In order to be curative, it is imperative that CSCs must be eliminated by cancer therapy. A variety of dietary phytochemicals and repositioned drugs can act synergistically with conventional anti-cancer agents. In this review, we advocate the development of a novel approach, namely combination therapy by incorporating both phytochemicals and repositioned drugs to target CSCs. We cover select dietary phytochemicals (curcumin, resveratrol, EGCG, genistein) and repurposed drugs (metformin, niclosamide, thioridazine, chloroquine). Five of the eight (curcumin, resveratrol, EGCG, genistein, metformin) are listed in "The Halifax Project", that explores "the concept of a low-toxicity 'broad-spectrum' therapeutic approach that could simultaneously target many key pathways and mechanisms" [1]. For these compounds, we discuss their mechanisms of action, in which models their anti-CSC activities were identified, as well as advantages, challenges and potentials of combination therapy.

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Metformin Increases Sensitivity of Pancreatic Cancer Cells to Gemcitabine by Reducing CD133+ Cell Populations and Suppressing ERK/P70S6K Signaling

Cited by 63 publications

References 52 publications

Leptin signaling and cancer chemoresistance: Perspectives

Leptin signaling and cancer chemoresistance: Perspectives

Combined treatment of gemcitabine with indole-3-carbinol or metformin on drug efficacy in pancreatic cancer cell lines: The role of human equilibrative nucleoside transporters

Targeting cancer stem cells with dietary phytochemical - Repositioned drug combinations

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