Clinically Evaluated Cancer Drugs Inhibiting Redox Signaling

Kirkpatrick, David; Powis, Garth

doi:10.1089/ars.2016.6633

Cited by 49 publications

(37 citation statements)

References 105 publications

(85 reference statements)

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“…Conversely, we found that REDD1-deficient tumors are highly sensitive to glutathione depletion with BSO. Clinical trials using this agent have not yielded responses in a large proportion of tumors, yet our findings suggest the possibility that targeting a metabolically defined tumor subset, such as that discovered here, may be more successful (Kirkpatrick and Powis 2017). Finally, CD36 itself is an attractive potential therapeutic target whose inhibition has proven relatively nontoxic in preclinical models (Pascual et al 2017).…”

Section: Discussionmentioning

confidence: 76%

REDD1 loss reprograms lipid metabolism to drive progression of RAS mutant tumors

et al. 2020

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Human cancers with activating RAS mutations are typically highly aggressive and treatment-refractory, yet RAS mutation itself is insufficient for tumorigenesis, due in part to profound metabolic stress induced by RAS activation. Here we show that loss of REDD1, a stress-induced metabolic regulator, is sufficient to reprogram lipid metabolism and drive progression of RAS mutant cancers. Redd1 deletion in genetically engineered mouse models (GEMMs) of KRAS-dependent pancreatic and lung adenocarcinomas converts preneoplastic lesions into invasive and metastatic carcinomas. Metabolic profiling reveals that REDD1-deficient/RAS mutant cells exhibit enhanced uptake of lysophospholipids and lipid storage, coupled to augmented fatty acid oxidation that sustains both ATP levels and ROSdetoxifying NADPH. Mechanistically, REDD1 loss triggers HIF-dependent activation of a lipid storage pathway involving PPARγ and the prometastatic factor CD36. Correspondingly, decreased REDD1 expression and a signature of REDD1 loss predict poor outcomes selectively in RAS mutant but not RAS wild-type human lung and pancreas carcinomas. Collectively, our findings reveal the REDD1-mediated stress response as a novel tumor suppressor whose loss defines a RAS mutant tumor subset characterized by reprogramming of lipid metabolism, invasive and metastatic progression, and poor prognosis. This work thus provides new mechanistic and clinically relevant insights into the phenotypic heterogeneity and metabolic rewiring that underlies these common cancers.

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Section: Discussionmentioning

confidence: 76%

REDD1 loss reprograms lipid metabolism to drive progression of RAS mutant tumors

et al. 2020

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“…Here we have shown that Tat induced mitochondrial ROS. New generation of antioxidants specifically targeting mitochondria is currently being developed [114] , [115] , [116] . Their use may allow for further advances in understanding the processed involved in HIV-induced oncogenesis.…”

Section: Discussionmentioning

confidence: 99%

HIV-1 Tat protein induces DNA damage in human peripheral blood B-lymphocytes via mitochondrial ROS production

El-Amine¹,

Germini

Zakharova³

et al. 2018

Redox Biology

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Human immunodeficiency virus (HIV) infection is associated with B-cell malignancies in patients though HIV-1 is not able to infect B-cells. The rate of B-cell lymphomas in HIV-infected individuals remains high even under the combined antiretroviral therapy (cART) that reconstitutes the immune function. Thus, the contribution of HIV-1 to B-cell oncogenesis remains enigmatic. HIV-1 induces oxidative stress and DNA damage in infected cells via multiple mechanisms, including viral Tat protein. We have detected elevated levels of reactive oxygen species (ROS) and DNA damage in B-cells of HIV-infected individuals. As Tat is present in blood of infected individuals and is able to transduce cells, we hypothesized that it could induce oxidative DNA damage in B-cells promoting genetic instability and malignant transformation. Indeed, incubation of B-cells isolated from healthy donors with purified Tat protein led to oxidative stress, a decrease in the glutathione (GSH) levels, DNA damage and appearance of chromosomal aberrations. The effects of Tat relied on its transcriptional activity and were mediated by NF-κB activation. Tat stimulated oxidative stress in B-cells mostly via mitochondrial ROS production which depended on the reverse electron flow in Complex I of respiratory chain. We propose that Tat-induced oxidative stress, DNA damage and chromosomal aberrations are novel oncogenic factors favoring B-cell lymphomas in HIV-1 infected individuals.

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“…Those results support the idea that cancer cells might evolve resistance mechanisms in other antioxidant pathways in order to counteract oxidative stress, thus being able to survive. In a clinical context, BSO was shown to be a chemosensitizer but with no clinical advantages due to the severe adverse effects, thus clinical trials are no longer being developed [ 63 ].…”

Section: Gsh Antagonists In Ovarian Cancermentioning

confidence: 99%

“…Telcyta (TLK286) is a GSH analogue that, when metabolized by GSTP1-1, releases a reactive tetrakis (chloroethyl) phosphorodiamidate fragment and a glutathione analogue vinyl sulphone that, following activation, triggers the stress response pathway, leading to cellular apoptosis induction [ 69 ]. Telcyta has been tested in Phase II and III clinical trials for ovarian cancer treatment, as a monotherapy regime or in combination with other chemotherapeutic agents [ 63 ]. However, a Phase III (NCT00350948) randomized study of Telcyta and doxorubicin in platinum refractory ovarian cancer patients (ASSIST-5) showed that Telcyta led to poorer outcomes than standard strategies [ 63 ].…”

Section: Gsh Antagonists In Ovarian Cancermentioning

confidence: 99%

Glutathione in Ovarian Cancer: A Double-Edged Sword

Nunes

Serpa

2018

IJMS

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Glutathione (GSH) has several roles in a cell, such as a reactive oxygen species (ROS) scavenger, an intervenient in xenobiotics metabolism and a reservoir of cysteine. All of these activities are important in the maintenance of normal cells homeostasis but can also constitute an advantage for cancer cells, allowing disease progression and resistance to therapy. Ovarian cancer is the major cause of death from gynaecologic disease and the second most common gynaecologic malignancy worldwide. In over 50 years, the overall survival of patients diagnosed with epithelial ovarian cancer has not changed, regardless of the efforts concerning early detection, radical surgery and new therapeutic approaches. Late diagnosis and resistance to therapy are the main causes of this outcome, and GSH is profoundly associated with chemoresistance to platinum salts, which, together with taxane-based chemotherapy and surgery, are the main therapy strategies in ovarian cancer treatment. Herein, we present some insights into the role of GSH in the poor prognosis of ovarian cancer, and also point out how some strategies underlying the dependence of ovarian cancer cells on GSH can be further used to improve the effectiveness of therapy.

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Clinically Evaluated Cancer Drugs Inhibiting Redox Signaling

Cited by 49 publications

References 105 publications

REDD1 loss reprograms lipid metabolism to drive progression of RAS mutant tumors

REDD1 loss reprograms lipid metabolism to drive progression of RAS mutant tumors

HIV-1 Tat protein induces DNA damage in human peripheral blood B-lymphocytes via mitochondrial ROS production

Glutathione in Ovarian Cancer: A Double-Edged Sword

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