In cancer, all roads lead to NADPH

Rather, Gulam Mohmad; Pramono, Alvinsyah Adhityo; Székely, Zoltán; Bertino, Joseph R.; Tedeschi, Philip M.

doi:10.1016/j.pharmthera.2021.107864

Cited by 51 publications

(39 citation statements)

References 71 publications

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“…[23][24] This novel mechanism of drug action (MOA) can provide selectivity towards cancer cells over normal cells as Tedeschi et al, recently reported the significant upregulation of NAD(P)H concentration in cancer cells. [31] Important to note that NAD(P)H depletion by photoactive Ir(III) complexes in cancer cells may also provide a MOA to combat against tumor hypoxia-related drug resistance. [32,33] In this newly emerging area of photo-catalytic cancer drug development research, one of the main challenges is to achieve photo-catalysis with longer wavelength light.…”

Section: Introductionmentioning

confidence: 99%

Highly Efficient Ir(III)‐Coumarin Photo‐Redox Catalyst for Synergetic Multi‐Mode Cancer Photo‐Therapy

Huang

Fan

Xie

et al. 2021

Chemistry A European J

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Four photo‐catalysts of the general formula [Ir(CO6/ppy)2(L)]Cl where CO6=coumarin 6 (Ir1–Ir3), ppy=2‐phenylpyridine (Ir4), L=4′‐(3,5‐di‐tert‐butylphenyl)‐2,2′ : 6′,2′′‐terpyridine (Ir1), 4′‐(3,5‐bis(trifluoromethyl)phenyl)‐2,2′ : 6′,2′′‐terpyridine (Ir2 and Ir4), and 4‐([2,2′ : 6′,2′′‐terpyridin]‐4′‐yl)‐N,N‐dimethylaniline (Ir3) were synthesized and characterized. These photostable photo‐catalysts (Ir1–Ir3) showed strong visible light absorption between 400–550 nm. Upon light irradiation (465 and 525 nm), Ir1–Ir3 generated singlet oxygen and induced rapidly photo‐catalytic oxidation of cellular coenzymes NAD(P)H. Ir1–Ir3 showed time‐dependent cellular uptake with excellent intracellular retention efficiency. Upon green light irradiation (525 nm), Ir2 provided a much higher photo‐index (PI=793) than the clinically used photosensitizer, 5‐aminolevulinicacid (5‐ALA, PI>30) against HeLa cancer cells. The observed necro‐apoptotic anticancer activity of Ir2 was due to the Ir2 triggered photo‐induced intracellular redox imbalance (by NAD(P)H oxidation and ROS generation) and change in the mitochondrial membrane potential. Remarkably, Ir2 showed in vivo photo‐induced catalytic anticancer activity in mouse models.

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Section: Introductionmentioning

confidence: 99%

Highly Efficient Ir(III)‐Coumarin Photo‐Redox Catalyst for Synergetic Multi‐Mode Cancer Photo‐Therapy

Huang

Fan

Xie

et al. 2021

Chemistry A European J

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“…Interestingly, increased flux through the kynurenine pathways will lead to elevated nicotinic acid. NADH and NADPH [112] have recently been reported as being overexpressed in tumor cells with mutant p53 [113].…”

Section: Kynureninementioning

confidence: 99%

Metabolic Rewiring and the Characterization of Oncometabolites

Beyoğlu

Idle

2021

Cancers

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The study of low-molecular-weight metabolites that exist in cells and organisms is known as metabolomics and is often conducted using mass spectrometry laboratory platforms. Definition of oncometabolites in the context of the metabolic phenotype of cancer cells has been accomplished through metabolomics. Oncometabolites result from mutations in cancer cell genes or from hypoxia-driven enzyme promiscuity. As a result, normal metabolites accumulate in cancer cells to unusually high concentrations or, alternatively, unusual metabolites are produced. The typical oncometabolites fumarate, succinate, (2R)-hydroxyglutarate and (2S)-hydroxyglutarate inhibit 2-oxoglutarate-dependent dioxygenases, such as histone demethylases and HIF prolyl-4-hydroxylases, together with DNA cytosine demethylases. As a result of the cancer cell acquiring this new metabolic phenotype, major changes in gene transcription occur and the modification of the epigenetic landscape of the cell promotes proliferation and progression of cancers. Stabilization of HIF1α through inhibition of HIF prolyl-4-hydroxylases by oncometabolites such as fumarate and succinate leads to a pseudohypoxic state that promotes inflammation, angiogenesis and metastasis. Metabolomics has additionally been employed to define the metabolic phenotype of cancer cells and patient biofluids in the search for cancer biomarkers. These efforts have led to the uncovering of the putative oncometabolites sarcosine, glycine, lactate, kynurenine, methylglyoxal, hypotaurine and (2R,3S)-dihydroxybutanoate, for which further research is required.

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“…Cancer cells have the ability to scavenge ROS formation by activating antioxidant mechanisms, but usually these require high NADPH levels ( Ju et al, 2020 ). There are several mechanisms orchestrated by NADPH balance, including antioxidant reactions that lead to reduced glutathione, necessary for hydrogen peroxide reduction and fatty acids, amino acids and nucleotides synthesis able to promote tumour growth ( Ju et al, 2020 ; Rather et al, 2021 ). Moreover, NADPH works as an essential electron donor and cofactor maintaining reduction potential in anabolic reactions.…”

Section: Nadph Synthesis As a Targetmentioning

confidence: 99%

“…In conclusion, targeting mutated IDH in CRC seems to be appealing for IBD-CRCs, while in sporadic CRC wild-type IDH seems to be more plausible. Several mutant IDH1 inhibitors have entered clinical trials for hematologic malignancies ( Rather et al, 2021 ), while only ivosidenib has been proposed as wild-type inhibitor in myeloid neoplasms (NCT03564821). The only clinical trial proposing IDH1 inhibitor for CRC is NCT04584008, aiming to use DNA sequencing in order to enrich patient populations with selected genotypes.…”

Section: Nadph Synthesis As a Targetmentioning

confidence: 99%

“…Several reviews have addressed the advantage of targeting NAD/NADPH homeostasis and consuming enzymes in cancer ( Audrito et al, 2019 ; Galli et al, 2020 ; Ju et al, 2020 ; Rather et al, 2021 ); thus, an extensive description is beyond the purpose of this manuscript, and we refer to other excellent reviews on the subject, including the ones that describe the entire NADome ( Chiarugi et al, 2012 ). In the present review, we have searched on MEDLINE/PubMed the names more than of 400 NAD and NADPH-dependent enzymes followed by the term “colorectal cancer” and have chosen the most relevant, and less reviewed, targets in the context of CRC.…”

Section: Introductionmentioning

confidence: 99%

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Insight Into Nicotinamide Adenine Dinucleotide Homeostasis as a Targetable Metabolic Pathway in Colorectal Cancer

et al. 2021

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Tumour cells modify their cellular metabolism with the aim to sustain uncontrolled proliferation. Cancer cells necessitate adequate amounts of NAD and NADPH to support several enzymes that are usually overexpressed and/or overactivated. Nicotinamide adenine dinucleotide (NAD) is an essential cofactor and substrate of several NAD-consuming enzymes, such as PARPs and sirtuins, while NADPH is important in the regulation of the redox status in cells. The present review explores the rationale for targeting the key enzymes that maintain the cellular NAD/NADPH pool in colorectal cancer and the enzymes that consume or use NADP(H).

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In cancer, all roads lead to NADPH

Cited by 51 publications

References 71 publications

Highly Efficient Ir(III)‐Coumarin Photo‐Redox Catalyst for Synergetic Multi‐Mode Cancer Photo‐Therapy

Highly Efficient Ir(III)‐Coumarin Photo‐Redox Catalyst for Synergetic Multi‐Mode Cancer Photo‐Therapy

Metabolic Rewiring and the Characterization of Oncometabolites

Insight Into Nicotinamide Adenine Dinucleotide Homeostasis as a Targetable Metabolic Pathway in Colorectal Cancer

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