Antiproliferative effects of metformin in cellular models of pheochromocytoma

Meireles, Cinthia Gabriel; Lima, Caroline Lourenço de; Oliveira, Marcela Martins de Paula; Miranda, Rafael Abe da Rocha; Romano, Lisa E.L.; Brashaw, Teisha Yo-Stella; Guerra, Eliete Neves Silva; Neves, Francisco de Assis Rocha; Chapple, J. Paul; Simeoni, Luiz Alberto; Lofrano‐Porto, Adriana

doi:10.1016/j.mce.2021.111484

Cited by 5 publications

(4 citation statements)

References 40 publications

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“…Moreover, the authors found a downregulation of Cyclin-A2 (Ccna2) and Ccnb2 expression, which plays an important role in the regulation of cell cycle progression [ 12 ]. Analogous results on the inhibition of cell proliferation are also described in other two studies conducted on immortalized head and neck PGL cell cultures and again on PC12 cell line [ 13 , 36 ]. According with the aforementioned results, in this study we showed that, after metformin treatment, MTT cells undergo a decrease in proliferation and downregulate cyclin D1.…”

Section: Discussionsupporting

confidence: 79%

“…After metformin treatment, ATP concentrations were significantly decreased in all the cell types, suggesting the well-known inhibition of the mitochondrial complex I by this drug (for recent reviews see [46,47]). Moreover, while Meireles and colleagues [13] demonstrated a reduction in oxygen consumption and ATP production only when cells were treated at high dose of metformin (20 mM), in our experimental conditions this effect was obtained with a 5-fold lower dose. It is also well-known that the metformin-induced metabolic shift toward aerobic glycolysis induces an increase in lactate production [48].…”

Section: Discussioncontrasting

confidence: 48%

“…We next investigated which pathways were regulated by metformin in the two MTT populations and in the fibroblasts. It is well known that metformin induces AMPK phosphorylation [ 13 ]. Western blot analyses showed that after 4 mM metformin, both MTT and fibroblasts significantly increased phosphorylation of AMPK at the Thr172 site, as compared to their untreated counterparts ( Figure 7 A).…”

Section: Resultsmentioning

confidence: 99%

“…Recently, metformin has been proposed as a potential antitumoral drug due to its inhibitory effect on growth and survival of different cell lines, including neuroblastoma [9], glioblastoma cells [10,11], and rat PPGL cells [12]. Its anticarcinogenic activity was also supported by evidence obtained from epidemiological studies and clinical trials on endometrial [13], colorectal [14], prostate [15], breast [16], adrenocortical [17], and head and neck cancers [18]. However, whether metformin plays a role in inhibiting the migration of PPGL cells has yet to be explored.…”

Section: Introductionmentioning

confidence: 94%

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Metformin Treatment Induces Different Response in Pheochromocytoma/Paraganglioma Tumour Cells and in Primary Fibroblasts

Martinelli

Amore

Mello

et al. 2022

Cancers

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Pheochromocytoma/paragangliomas (PPGLs) are neuroendocrine tumours, often non-metastatic, but without available effective treatment for their metastatic form. Recent studies have shown that metformin exhibits antiproliferative activity in many human cancers, including PPGLs. Nevertheless, no data are available on the role of metformin on PPGL cells (two-dimension, 2D) and spheroids (three-dimension, 3D) migration/invasion. In this study, we observed that metformin exerts an antiproliferative effect on 2D and 3D cultures of pheochromocytoma mouse tumour tissue (MTT), either silenced or not for the SDHB subunit. However, metformin did not affect MTT migration. On the other hand, metformin did not have a short-term effect on the proliferation of mouse primary fibroblasts, but significantly decreased their ability to migrate. Although the metabolic changes induced by metformin were similar between MTT and fibroblasts (i.e., an overall decrease of ATP production and an increase in intracellular lactate concentration) the activated signalling pathways were different. Indeed, after metformin administration, MTT showed a reduced phosphorylation of Akt and Erk1/2, while fibroblasts exhibited a downregulation of N-Cadherin and an upregulation of E-Cadherin. Herein, we demonstrated that metformin has different effects on cell growth and spread depending on the cell type nature, underlining the importance of the tumour microenvironment in dictating the drug response.

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Section: Discussionsupporting

confidence: 79%

Section: Discussioncontrasting

confidence: 48%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

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Metformin Treatment Induces Different Response in Pheochromocytoma/Paraganglioma Tumour Cells and in Primary Fibroblasts

Martinelli

Amore

Mello

et al. 2022

Cancers

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Formononetin ameliorates the LPS-induced inflammatory response and apoptosis of neuronal cells via NF-κB/NLRP3 signaling pathway

Zhou,

Zhang

2023

Funct Integr Genomics

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The Immune Landscape of Pheochromocytoma and Paraganglioma: Current Advances and Perspectives

Uher,

Hadrava Vanova,

Taïeb

et al. 2024

Endocrine Reviews

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Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors derived from neural crest cells from adrenal medullary chromaffin tissues or extra-adrenal paraganglia, respectively. Although the current treatment for PPGLs is surgery, optimal treatment options for advanced and metastatic cases have been limited. Hence, understanding the role of the immune system in PPGL tumorigenesis can provide essential knowledge for the development of better therapeutic and tumor management strategies, especially for those with advanced and metastatic PPGLs. The first part of this review outlines the fundamental principles of the immune system and tumor microenvironment, and their role in cancer immunoediting, particularly emphasizing on PPGLs. We focus on how the unique pathophysiology of PPGLs, such as their high molecular, biochemical, and imaging heterogeneity and production of several oncometabolites, creates a tumor-specific microenvironment and immunologically “cold” tumors. Thereafter, we discuss recently published studies related to the reclustering of PPGLs based on their immune signature. The second part of this review discusses future perspectives in PPGL management, including immunodiagnostic and promising immunotherapeutic approaches for converting “cold” tumors into immunologically active or “hot” tumors known for their better immunotherapy response and patient outcomes. Special emphasis is placed on potent immune-related imaging strategies and immune signatures that could be used for the reclassification, prognostication, and management of these tumors to improve patient care and prognosis. Furthermore, we introduce currently available immunotherapies and their possible combinations with other available therapies as an emerging treatment for PPGLs that targets hostile tumor environments.

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Antiproliferative effects of metformin in cellular models of pheochromocytoma

Cited by 5 publications

References 40 publications

Metformin Treatment Induces Different Response in Pheochromocytoma/Paraganglioma Tumour Cells and in Primary Fibroblasts

Metformin Treatment Induces Different Response in Pheochromocytoma/Paraganglioma Tumour Cells and in Primary Fibroblasts

Formononetin ameliorates the LPS-induced inflammatory response and apoptosis of neuronal cells via NF-κB/NLRP3 signaling pathway

The Immune Landscape of Pheochromocytoma and Paraganglioma: Current Advances and Perspectives

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