Phenformin as an Anticancer Agent: Challenges and Prospects

Rubiño, Ma Eugenia García; Carrillo, Esmeralda; Alcalá, Gloria Ruiz; Domínguez‐Martín, Alicia; Marchal, Juan Antonio; Boulaiz, Houría

doi:10.3390/ijms20133316

Cited by 74 publications

(31 citation statements)

References 80 publications

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“…Remarkably, when combined with 2-DG, or dichloroacetate the lactic acidosis incidence was reduced [169]. While there are several proposed mechanisms of action, the main mechanism of action of biguanides is inhibiting complex I of the mitochondrial respiratory chain which causes an increase in the AMP/ATP ratio, hence activating AMPK [149,170,171]. In turn, AMPK is an invaluable energy sensor for cells that is activated in conditions of low ATP.…”

Section: Biguandes (Metformin and Phenformin)mentioning

confidence: 99%

Redox Homeostasis and Metabolism in Cancer: A Complex Mechanism and Potential Targeted Therapeutics

Ghoneum

Abdulfattah

Warren

et al. 2020

IJMS

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Reactive Oxygen Species or “ROS” encompass several molecules derived from oxygen that can oxidize other molecules and subsequently transition rapidly between species. The key roles of ROS in biological processes are cell signaling, biosynthetic processes, and host defense. In cancer cells, increased ROS production and oxidative stress are instigated by carcinogens, oncogenic mutations, and importantly, metabolic reprograming of the rapidly proliferating cancer cells. Increased ROS production activates myriad downstream survival pathways that further cancer progression and metastasis. In this review, we highlight the relation between ROS, the metabolic programing of cancer, and stromal and immune cells with emphasis on and the transcription machinery involved in redox homeostasis, metabolic programing and malignant phenotype. We also shed light on the therapeutic targeting of metabolic pathways generating ROS as we investigate: Orlistat, Biguandes, AICAR, 2 Deoxyglucose, CPI-613, and Etomoxir.

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Section: Biguandes (Metformin and Phenformin)mentioning

confidence: 99%

Redox Homeostasis and Metabolism in Cancer: A Complex Mechanism and Potential Targeted Therapeutics

Ghoneum

Abdulfattah

Warren

et al. 2020

IJMS

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“…For instance, several studies have revealed that orlistat, as an antitumor drug, inhibits tumor growth in a variety of cancers, including prostate cancer, by inhibiting fatty acid synthase [ 37 ]. Biguanides (metformin and metformin) increase the AMP/ATP ratio mainly by inhibiting mitochondrial respiratory chain complex I, thus activating AMPK, further inducing catabolism process, increasing ATP level, reducing protein and lipid synthesis, and ultimately inhibiting tumor growth [ 38 , 39 ]. This would provide new insights into metabolic therapy as an alternative therapy.…”

Section: Discussionmentioning

confidence: 99%

Exploration of Redox‐Related Molecular Patterns and the Redox Score for Prostate Cancer

Zhang

Feng

et al. 2021

Oxidative Medicine and Cellular Longevity

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Redox homeostasis is the key to cell survival, and its imbalance can promote the occurrence and progression of tumors. However, it remains unclear whether these redox-related genes (RRGs) have potential roles in the tumor microenvironment, immunotherapy, and drug sensitivity. Here, we performed a systematic and comprehensive analysis of 489 prostate cancer (PC) samples from The Cancer Genome Atlas database and 214 PC samples from 8 datasets in the Gene Expression Omnibus database to determine redox modification patterns and the redox scoring system for PC. We identified two modification patterns (Redox_A and Redox_B) in PC using unsupervised consensus clustering based on 1410 differential expression RRGs. We then compared the prognostic value, tumor microenvironment characteristics, immune cell infiltration, and molecular characteristics of the two patterns. The Redox_A pattern was significantly enriched in the carcinogenic activation signaling pathways and had a poor prognosis, while the Redox_B pattern was mainly enriched in a variety of metabolic and redox pathways and had a good prognosis. Next, redox-related characteristic genes were extracted from these two patterns, and a scoring system (Redox_score) was constructed to evaluate PC patients. Further analysis indicated that lower Redox_score patients had a better prognosis, while higher Redox_score patients had a higher tumor mutation burden, driver gene mutation rate, and immune checkpoint inhibitor gene expression. We also found that higher Redox_score patients were more responsive to anti-PD-1 immunotherapy. Moreover, Redox_score was determined to be significantly correlated with anticancer drug sensitivity and resistance. Our study provides a comprehensive analysis of redox modifications in PC and reveals new patterns of PC based on RRGs, which will provide insights into the complex mechanisms of PC and develop more effective individualized therapeutic strategies.

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“…While aerobic glycolysis is a known feature of cancer cells, targeting this pathway for therapy has proven challenging due to the cytotoxicity of many anti-glycolytic agents [25]. Biguanides, such as metformin and phenformin, are common therapeutics for the treatment of type 2 diabetes, and have recently been reported to exhibit anticancer activity in vitro and in vivo [26][27][28]. Specifically, both agents have an inhibitory effect on glycolysis and oxidative metabolism.…”

Section: Discussionmentioning

confidence: 99%

Loss of Rb1 Enhances Glycolytic Metabolism in Kras-Driven Lung Tumors In Vivo

Conroy

Dougherty

Kruer

et al. 2020

Cancers

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Dysregulated metabolism is a hallmark of cancer cells and is driven in part by specific genetic alterations in various oncogenes or tumor suppressors. The retinoblastoma protein (pRb) is a tumor suppressor that canonically regulates cell cycle progression; however, recent studies have highlighted a functional role for pRb in controlling cellular metabolism. Here, we report that loss of the gene encoding pRb (Rb1) in a transgenic mutant Kras-driven model of lung cancer results in metabolic reprogramming. Our tracer studies using bolus dosing of [U-13C]-glucose revealed an increase in glucose carbon incorporation into select glycolytic intermediates. Consistent with this result, Rb1-depleted tumors exhibited increased expression of key glycolytic enzymes. Interestingly, loss of Rb1 did not alter mitochondrial pyruvate oxidation compared to lung tumors with intact Rb1. Additional tracer studies using [U-13C,15N]-glutamine and [U-13C]-lactate demonstrated that loss of Rb1 did not alter glutaminolysis or utilization of circulating lactate within the tricarboxylic acid cycle (TCA) in vivo. Taken together, these data suggest that the loss of Rb1 promotes a glycolytic phenotype, while not altering pyruvate oxidative metabolism or glutamine anaplerosis in Kras-driven lung tumors.

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Phenformin as an Anticancer Agent: Challenges and Prospects

Cited by 74 publications

References 80 publications

Redox Homeostasis and Metabolism in Cancer: A Complex Mechanism and Potential Targeted Therapeutics

Redox Homeostasis and Metabolism in Cancer: A Complex Mechanism and Potential Targeted Therapeutics

Exploration of Redox‐Related Molecular Patterns and the Redox Score for Prostate Cancer

Loss of Rb1 Enhances Glycolytic Metabolism in Kras-Driven Lung Tumors In Vivo

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