Gene Expression Signature of Human Cancer Cell Lines Treated with the Ras Inhibitor Salirasib (<i>S</i>-Farnesylthiosalicylic Acid)

Blum, Roy; Elkon, Ran; Yaari, Shira; Zundelevich, Adi; Jacob‐Hirsch, Jasmine; Rechavi, Gideon; Shamir, Ron; Kloog, Yoel

doi:10.1158/0008-5472.can-06-4287

Cited by 51 publications

(48 citation statements)

References 47 publications

(88 reference statements)

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“…Under conditions of glucose limitation, in fact, transformed cells continue to consume more glucose but are unable to upregulate mitochondrial activity. It has been shown that removal of glucose causes preferential cytotoxicity to human cancer cells compared to normal cells (Lee et al, 1998a;Spitz et al, 2000;Blum et al, 2005). This response has been connected to the production of ROS such as superoxide and hydrogen peroxide during glucose deprivation, that is, to a metabolic oxidative stress (Blackburn et al, 1999;Ahmad et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Ras-dependent carbon metabolism and transformation in mouse fibroblasts

et al. 2006

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Mutational activation of ras genes is required for the onset and maintenance of different malignancies. Here we show, using a combination of molecular physiology, nutritional perturbations and transcriptional profiling, that full penetrance of phenotypes related to oncogenic Ras activation, including the shift of carbon metabolism towards fermentation and upregulation of key cell cycle regulators, is dependent upon glucose availability. These responses are induced by Ras activation, being specifically reverted by downregulation of the Ras pathway obtained through the expression of a dominant-negative Rasspecific guanine nucleotide exchange protein. Our data allow to link directly to ras activation the alteration in energy metabolism of cancer cells, their fragility towards glucose shortage and ensuing apoptotic death.

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Section: Discussionmentioning

confidence: 99%

Ras-dependent carbon metabolism and transformation in mouse fibroblasts

et al. 2006

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“…The important role of Ras in promoting glycolysis was recently demonstrated in a study, in which transformation of cells by hTERT, SV-40T/t, and H-ras caused an increase in glycolysis dependency, and as the cells progressed toward a more tumorigenic state, they became more sensitive to the glycolytic inhibitor 2-DG (Ramanathan et al, 2005). Interestingly, inhibition of H-ras by trans-farnesylthiosalicylic acid resulted in inhibition of glycolysis and cell death in human glioblastoma U87 cells, with concomitant decrease in HIF-1a and glycolytic enzymes (Blum et al, 2005).…”

Section: Hypoxiamentioning

confidence: 98%

Glycolysis inhibition for anticancer treatment

et al. 2006

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Most cancer cells exhibit increased glycolysis and use this metabolic pathway for generation of ATP as a main source of their energy supply. This phenomenon is known as the Warburg effect and is considered as one of the most fundamental metabolic alterations during malignant transformation. In recent years, there are significant progresses in our understanding of the underlying mechanisms and the potential therapeutic implications. Biochemical and molecular studies suggest several possible mechanisms by which this metabolic alteration may evolve during cancer development. These mechanisms include mitochondrial defects and malfunction, adaptation to hypoxic tumor microenvironment, oncogenic signaling, and abnormal expression of metabolic enzymes. Importantly, the increased dependence of cancer cells on glycolytic pathway for ATP generation provides a biochemical basis for the design of therapeutic strategies to preferentially kill cancer cells by pharmacological inhibition of glycolysis. Several small molecules have emerged that exhibit promising anticancer activity in vitro and in vivo, as single agent or in combination with other therapeutic modalities. The glycolytic inhibitors are particularly effective against cancer cells with mitochondrial defects or under hypoxic conditions, which are frequently associated with cellular resistance to conventional anticancer drugs and radiation therapy. Because increased aerobic glycolysis is commonly seen in a wide spectrum of human cancers and hypoxia is present in most tumor microenvironment, development of novel glycolytic inhibitors as a new class of anticancer agents is likely to have broad therapeutic applications.

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“…These effects of FTS are manifested by a decrease in the amount of cellular Ras accompanied by interruption of the Ras-dependent Raf-1/ERK signaling cascade (45). FTS plays an antitumoral role in several non-hepatic cancer cell lines (46), and a phase I clinical trial of gemcitabine and FTS has demonstrated that FTS is well tolerated in patients with solid non-liver tumors (47). As its expression is well tolerated, salirasib may become a drug of choice for the treatment of HCC by targeting Ras and mammalian target of rapamycin (mTOR) protein kinase (48).…”

Section: Targeting Rasmentioning

confidence: 99%

Targeting the Ras/Raf/MEK/ERK pathway in hepatocellular carcinoma

2017

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Abstract. Although the biological basis of hepatocellular carcinoma (HCC) remains unclear, effective treatments and improvement of the survival rate remain worthwhile research goals. Abnormal protein signaling pathways contributing to uncontrolled cell proliferation, differentiation, survival and apoptosis are biomarkers of the carcinogenic process. Certain mutated components or overexpression of the rat sarcoma virus (Ras)/rapidly accelerated fibrosarcoma (Raf)/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway are increasingly being studied in HCC carcinogenesis. The present review addresses the effect of the Ras/Raf/MEK/ERK signaling pathway on the pathogenesis of HCC, and provides an update on the preclinical and clinical development of various inhibitors targeting this core signaling pathway, which include various Ras inhibitors, Raf inhibitors and MEK inhibitors for HCC.

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Gene Expression Signature of Human Cancer Cell Lines Treated with the Ras Inhibitor Salirasib (S-Farnesylthiosalicylic Acid)

Abstract: Deregulation of Ras pathways results in complex abnormalities of multiple signaling cascades that contribute to human malignancies. Ras is therefore considered an appropriate target for cancer therapy.

Cited by 51 publications

References 47 publications

Ras-dependent carbon metabolism and transformation in mouse fibroblasts

Ras-dependent carbon metabolism and transformation in mouse fibroblasts

Glycolysis inhibition for anticancer treatment

Targeting the Ras/Raf/MEK/ERK pathway in hepatocellular carcinoma

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