mTOR inhibitors sensitize thyroid cancer cells to cytotoxic effect of vemurafenib

Hanly, Elyse K.; Bednarczyk, Robert B.; Tuli, Neha; Moscatello, Augustine; Halicka, H. Dorota; Li, Jiangwei; Geliebter, Jan; Darzynkiewicz, Zbigniew; Tiwari, Raj K.

doi:10.18632/oncotarget.4052

Cited by 31 publications

(24 citation statements)

References 49 publications

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“…The growth inhibition in these cells was associated with inhibition of the ERK signaling pathway (Chen et al 2015). In a similar study, the combination of metformin with vemurafenib (a BRAFV600E inhibitor) resulted in an increased loss of cell viability and apoptosis in ATC and PTC cells in comparison to treatment with either metformin or vemurafenib alone (Hanly et al 2015).…”

Section: Preclinical Evidencementioning

confidence: 84%

The role of an anti-diabetic drug metformin in the treatment of endocrine tumors

Thakur

Daley

Kłubo-Gwieździńska

2019

Journal of Molecular Endocrinology

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Incidence of endocrine cancers is rising every year. Over the last decade, evidence has accumulated that demonstrates the anti-cancer effects of an anti-diabetic drug, metformin, in endocrine malignancies. We performed a literature review utilizing the PubMed, Medline and clinicaltrials.gov databases using the keyword ‘metformin’ plus the following terms: ‘thyroid cancer’, ‘thyroid nodules’, ‘parathyroid’, ‘hyperparathyroidism’, ‘adrenal adenoma’, ‘Cushing syndrome’, ‘hyperaldosteronism’, ‘adrenocortical cancer’, ‘neuroendocrine tumor (NET)’, ‘pancreatic NET (pNET)’, ‘carcinoid’, ‘pituitary adenoma’, ‘pituitary neuroendocrine tumor (PitNET)’, ‘prolactinoma’, ‘pheochromocytoma/paraganglioma’. We found 37 studies describing the preclinical and clinical role of metformin in endocrine tumors. The available epidemiological data show an association between exposure of metformin and lower incidence of thyroid cancer and pNETs in diabetic patients. Metformin treatment has been associated with better response to cancer therapy in thyroid cancer and pNETs. Preclinical evidence suggests that the primary direct mechanisms of metformin action include inhibition of mitochondrial oxidative phosphorylation via inhibition of both mitochondrial complex I and mitochondrial glycerophosphate dehydrogenase, leading to metabolic stress. Decreased ATP production leads to an activation of a cellular energy sensor, AMPK, and subsequent downregulation of mTOR signaling pathway, which is associated with decreased cellular proliferation. We also describe several AMPK-independent mechanisms of metformin action, as well as the indirect mechanisms targeting insulin resistance. Overall, repositioning of metformin has emerged as a promising strategy for adjuvant therapy of endocrine tumors. The mechanisms of synergy between metformin and other anti-cancer agents need to be elucidated further to guide well-designed prospective trials on combination therapies in endocrine malignancies.

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Section: Preclinical Evidencementioning

confidence: 84%

The role of an anti-diabetic drug metformin in the treatment of endocrine tumors

Thakur

Daley

Kłubo-Gwieździńska

2019

Journal of Molecular Endocrinology

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“…Metformin in combination with dexamethasone has been demonstrated to repress the expression of myeloid cell leukemia-1 and activate caspase 3, as well as increasing the number of cells in the G1 phase of the cell cycle (23). A previous study reported that metformin combined with vemurafenib may induce apoptosis and result in the synergistic inhibition of the growth of cancer cells, suggesting that metformin reverses the resistance of cancer cells to vemurafenib by altering the cellular energy balance (24). Metformin and salicylate may synergistically reduce the survival of cancer cells in vitro by inhibiting de novo lipogenesis and targeting pro-apoptotic and Bcl-2 family members (25,26).…”

Section: Discussionmentioning

confidence: 99%

Metformin synergizes with rapamycin to inhibit the growth of pancreatic cancer inï¿½vitro and inï¿½vivo

2017

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Abstract. Previous studies have suggested that metformin may improve the survival rate of patients with pancreatic cancer (PC) by regulating the adenosine monophosphate-activated protein kinase/mammalian target of rapamycin (mTOR) signaling pathway. Rapamycin specifically targets mTOR. In the present study, the efficacy of metformin and rapamycin in isolation and combination were investigated for the treatment of PC. The efficacy of metformin and rapamycin in reducing the proliferation of PC cell line SW1990 in vitro and in vivo was evaluated. It was revealed that metformin (10 mmol/l) + rapamycin (2 ng/ml), metformin (15 mmol/l) + rapamycin (20 ng/ml) and metformin (20 mmol/l) + rapamycin (200 ng/ml) significantly inhibited the viability of PC cells compared with untreated cells. Additionally, metformin (20 mmol/l) + rapamycin (200 ng/ml) significantly suppressed the expression of phosphorylated mTOR compared with metformin or rapamycin alone. Using a xenograft tumor model, it was revealed that combination treatment significantly inhibited the growth of PC cells compared with monotherapy. The present study revealed that a combination of metformin and rapamycin synergistically inhibited the growth of PC in vitro and in vivo and may be a potential treatment option for patients with PC.

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“…6,44 mTOR pathway could be involved in this process since it is inhibited in low serum conditions and mTOR inhibitors like rapamycin sensitize cancer cells to anticancer drugs. 45,46 Then, it could be on purpose to test the potentiating effect of the co-treatment rapamycin/D2-TGZ on breast cancer cells. Moreover, the starvation-based method was named the differential stress resistance since it potentiated the action of the chemotherapeutic agent toward cancer cells while being less deleterious for normal cells.…”

Section: Discussionmentioning

confidence: 99%

Δ2-Troglitazone promotes cytostatic rather than pro-apoptotic effects in breast cancer cells cultured in high serum conditions

et al. 2016

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We have previously shown that D2-Troglitazone (D2-TGZ) displayed anticancer effects on breast cancer cell lines grown in low serum conditions (1% fetal calf serum (FCS)). The present study was performed in order to characterize the effects of D2-TGZ in high serum containing medium and to determine if starvation could influence the response of breast cancer cells to this compound, keeping in mind the potential interest for breast cancer therapy. We observed that in high serum conditions (10% FCS), a 48 h treatment with D2-TGZ induced a decrease in cell numbers in MDA-MB-231 and MCF-7 breast cancer cell lines. The IC 50 values were higher than in low serum conditions. Furthermore, in contrast to our previous results obtained in 1% FCS conditions, we observed that in 10% FCS-containing medium, MCF-7 cells were more sensitive to D2-TGZ than MDA-MB-231 cells. D2-TGZ also induced endoplasmic reticulum (ER) stress mainly in MDA-MB-231 cells. Besides, in high serum conditions, D2-TGZ induced a G 0 /G 1 cell cycle arrest, an inhibition of BrdU incorporation and a reduced level of cyclin D1. We observed a limited cleavage of PARP and a limited proportion of cells in sub-G 1 phase. Thus, in high serum conditions, D2-TGZ displayed cytostatic effects rather than apoptosis as previously reported in 1% FCS-containing medium. Our results are in accordance with studies suggesting that serum starvation could potentiate the action of diverse anti-cancer agents.

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mTOR inhibitors sensitize thyroid cancer cells to cytotoxic effect of vemurafenib

Abstract: ABSTRACT

Cited by 31 publications

References 49 publications

The role of an anti-diabetic drug metformin in the treatment of endocrine tumors

The role of an anti-diabetic drug metformin in the treatment of endocrine tumors

Metformin synergizes with rapamycin to inhibit the growth of pancreatic cancer inï¿½vitro and inï¿½vivo

Δ2-Troglitazone promotes cytostatic rather than pro-apoptotic effects in breast cancer cells cultured in high serum conditions

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