Depletion of nicotinamide adenine dinucleotide in normal and xeroderma pigmentosum fibroblast cells by the antitumor drug CC-1065

Jacobson, Myron K.; Twehous, Debra; Hurley, Laurence H.

doi:10.1021/bi00368a014

Cited by 14 publications

(8 citation statements)

References 18 publications

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“…In support of this notion, NAD ϩ biosynthesis pathway has recently become a target for innovative therapy. 41,42 Indeed a chemical inhibitor of Nampt induces cell death in several types of human cancers. Importantly, the consequences of Nampt inhibition in healthy PBMCs as well as in CD34 ϩ hematopoietic progenitors 26 are less deleterious, indicating a favorable therapeutic window.…”

Section: Discussionmentioning

confidence: 99%

Targeting NAD+ salvage pathway induces autophagy in multiple myeloma cells via mTORC1 and extracellular signal-regulated kinase (ERK1/2) inhibition

Cea

Cagnetta

Fulciniti

et al. 2012

Blood

126

144

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Malignant cells have a higher nicotinamide adenine dinucleotide (NAD ؉) IntroductionMultiple myeloma (MM) is a clonal B-cell malignancy characterized by excessive bone marrow plasma cells in association with monoclonal protein. 1 The therapeutics currently available improve patients' survival and quality of life, but resistance to therapy and disease progression remain unsolved issues. Therefore, the definition of new aspects of MM biology that can be targeted and exploited from a therapeutic perspective remains a major basic and clinical research goal.Autophagy is a conserved process of normal cell turnover by regulating degradation of its components, which is characterized by the formation of autophagosomes, double-membrane cytoplasmic vesicles engulfing intracellular material including protein, lipids, as well as organelles, such as mitochondria and endoplasmic reticulum. Subsequently autophagosomes fuse with lysosomes, and their contents are degradated by lysosomal enzymes. 2 This selfcannibalization event is a highly conserved response to metabolic stress, in which cellular components are degraded for the maintenance of homeostasis. 3 Intriguingly, the waste removal function of autophagy appears as to be a double-edged sword, because it can either lead to cell survival or death. 4 A series of molecular mechanisms coordinate the autophagy machinery. Specifically, the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) is the major intracellular hub for integrating autophagy-related signals. 5 Upstream of mTORC1 is the cellular energy-sensing pathway. 6 Regulation of autophagy also occurs through the transcription factors EB (TFEB) and forkhead box (FOXO), whose activation leads to transcription of Atg genes. 7,8 Although apoptosis induction has been the major focus of research in novel MM therapies, a recent study documented a pivotal role for autophagy as a prosurvival mechanism in MM cells, suggesting its potential as an additional target for novel therapeutics. 9,10 Intracellular nicotinamide adenine nucleotide (NAD ϩ ) plays a major role in the regulation of several cellular processes. 11,12 In mammals, NAD ϩ is replenished from nicotinamide (Nam), tryptophan or nicotinic acid (NA), with Nam as the most important and widely available precursor. 13 Nicotinamide phosphoribosyltransferase (NAMPT), pre-B colony enhancing factor, is the ratelimiting enzyme in NAD ϩ synthesis from Nam. 14 The expression of this enzyme is up-regulated in activated immune cells, 15 in differentiated myeloid cells, 16 during the circadian clock, 17 in glucose-restriction impaired skeletal myoblast differentiation, 18 and during cytokine production in immune cells. 19 Importantly, Nampt is also overexpressed in cancer cells, which exhibit a significant dependence on NAD ϩ to support their rapid cell proliferation. 20 Importantly, a specific chemical inhibitor of Nampt FK866, also called APO866 or WK175, exhibits a broad antitumor activity both in vitro and in vivo against cell lines derived from several tumors, with a favorabl...

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Section: Discussionmentioning

confidence: 99%

Targeting NAD+ salvage pathway induces autophagy in multiple myeloma cells via mTORC1 and extracellular signal-regulated kinase (ERK1/2) inhibition

Cea

Cagnetta

Fulciniti

et al. 2012

Blood

126

144

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“…Interestingly, Jacobson et al (1986) recently found that Xeroderma pigmentosum cells, which are deficient in repair of UV-induced and polycyclic carbon induced DNA damage (Hanawalt et al, 1987), show normal nicotinamide adenine dinucleotide depletion as normal human cells after CC-1065 treatment. These results indicate that in human cells there are different repair pathways for repairing UVand CC-1065-induced DNA damage.…”

Section: Discussionmentioning

confidence: 99%

Recognition and repair of the CC-1065-(N3-adenine)-DNA adduct by the UVRABC nucleases

Tang¹,

Lee²,

Doisy³

et al. 1988

Biochemistry

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The recognition and repair of the helix-stabilizing and relatively nondistortive CC-1065-(N3-adenine)-DNA adduct by UVRABC nuclease has been investigated both in vivo with phi X174 RFI DNA by a transfection assay and in vitro by a site-directed adduct in a 117 base pair fragment from M13mp1. CC-1065 is a potent antitumor antibiotic produced by Streptomyces zelensis which binds within the minor groove of DNA through N3 of adenine. In contrast to the helix-destabilizing and distortive modifications of DNA caused by ultraviolet light or N-acetoxy-2-(acetylamino)fluorene, CC-1065 increases the melting point of DNA and decreases the S1 nuclease activity. Using a viral DNA-Escherichia coli transfection system, we have found that the uvrA, uvrB, and uvrC genes, which code for the major excision repair proteins for UV- and NAAAF-induced DNA damage, are also involved in the repair of CC-1065-DNA adducts. In contrast, the uvrD gene product, which has been found to be involved in the repair of UV damage, has no effect in repairing CC-1065-DNA adducts. Purified UVRA, UVRB, and UVRC proteins must work in concert to incise the drug-modified phi X174 RFI DNA. Using a site-directed and multiple CC-1065 modified (MspI-BstNI) 117 base pair fragment from M13mp1, we have found that UVRABC nuclease incises at the eighth phosphodiester bond on the 5' side of the CC-1065-DNA adduct on the drug-modified strand.(ABSTRACT TRUNCATED AT 250 WORDS)

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“…Novel approaches to circumvent tumor cell resistance mechanisms are therefore required and, in this context, several anticancer agents have recently been described that induce cell death by manipulating cellular energy stores. Indeed, intracellular depletion of nicotinamide adenine dinucleotide (NAD) and adenosine triphosphate (ATP) exerts strong cytolytic effects, [1][2][3][4][5][6][7][8] and the antitumor agent APO866 (previously called FK866 or WK175) is reported to induce cell death by reducing intracellular NAD content. 9,10 NAD plays a crucial role as a cofactor/substrate in numerous biochemical and biologic processes, including those catalyzed by poly(ADP-ribose) polymerase 1 (PARP1), sirtuins, and ADP-ribosyl cyclase 1-6.…”

Section: Introductionmentioning

confidence: 99%

The NAD biosynthesis inhibitor APO866 has potent antitumor activity against hematologic malignancies

Nahimana

Attinger²,

Aubry

et al. 2009

Blood

170

188

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Depletion of nicotinamide adenine dinucleotide in normal and xeroderma pigmentosum fibroblast cells by the antitumor drug CC-1065

Cited by 14 publications

References 18 publications

Targeting NAD+ salvage pathway induces autophagy in multiple myeloma cells via mTORC1 and extracellular signal-regulated kinase (ERK1/2) inhibition

Targeting NAD+ salvage pathway induces autophagy in multiple myeloma cells via mTORC1 and extracellular signal-regulated kinase (ERK1/2) inhibition

Recognition and repair of the CC-1065-(N3-adenine)-DNA adduct by the UVRABC nucleases

The NAD biosynthesis inhibitor APO866 has potent antitumor activity against hematologic malignancies

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