Anticancer agent CHS-828 inhibits cellular synthesis of NAD

U.H. Olesen; M.K. Christensen; F. Bjorkling; M. Jaattela; P.B. Jensen; M. Sehested; S.J. Nielsen

Anticancer agent CHS-828 inhibits cellular synthesis of NAD

U.H. Olesen, M.K. Christensen, F. Bjorkling, M. Jaattela, P.B. Jensen, M. Sehested, S.J. Nielsen

89 Citations (Scopus)

Abstract

Malignant cells display increased demands for energy production and DNA repair. Nicotinamide adenine dinucleotide (NAD) is required for both processes and is also continuously degraded by cellular enzymes. Nicotinamide phosphoribosyltransferase (Nampt) is a crucial factor in the resynthesis of NAD, and thus in cancer cell survival. Here, we establish the cytotoxic mechanism of action of the small molecule inhibitor CHS-828 to result from impaired synthesis of NAD. Initially, we detected cross-resistance in cells between CHS-828 and a known inhibitor of Nampt, FK866, a compound of a structurally different class. We then showed that nicotinamide protects against CHS-828-mediated cytotoxicity. Finally, we observed that treatment with CHS-828 depletes cellular NAD levels in sensitive cancer cells. In conclusion, these results strongly suggest that, like FK866, CHS-828 kills cancer cells by depleting NAD
Udgivelsesdato: 2008/3/21

Original language	English
Journal	Biochemical and Biophysical Research Communications
Volume	367
Issue number	4
Pages (from-to)	799-804
Number of pages	5
ISSN	0006-291X
Publication status	Published - 2008

Cite this

@article{1d3713b0f38d11ddbf70000ea68e967b,

title = "Anticancer agent CHS-828 inhibits cellular synthesis of NAD",

abstract = "Malignant cells display increased demands for energy production and DNA repair. Nicotinamide adenine dinucleotide (NAD) is required for both processes and is also continuously degraded by cellular enzymes. Nicotinamide phosphoribosyltransferase (Nampt) is a crucial factor in the resynthesis of NAD, and thus in cancer cell survival. Here, we establish the cytotoxic mechanism of action of the small molecule inhibitor CHS-828 to result from impaired synthesis of NAD. Initially, we detected cross-resistance in cells between CHS-828 and a known inhibitor of Nampt, FK866, a compound of a structurally different class. We then showed that nicotinamide protects against CHS-828-mediated cytotoxicity. Finally, we observed that treatment with CHS-828 depletes cellular NAD levels in sensitive cancer cells. In conclusion, these results strongly suggest that, like FK866, CHS-828 kills cancer cells by depleting NAD Udgivelsesdato: 2008/3/21",

author = "U.H. Olesen and M.K. Christensen and F. Bjorkling and M. Jaattela and P.B. Jensen and M. Sehested and S.J. Nielsen",

year = "2008",

language = "English",

volume = "367",

pages = "799--804",

journal = "Biochemical and Biophysical Research Communications",

issn = "0006-291X",

publisher = "Elsevier",

number = "4",

}

TY - JOUR

T1 - Anticancer agent CHS-828 inhibits cellular synthesis of NAD

AU - Olesen, U.H.

AU - Christensen, M.K.

AU - Bjorkling, F.

AU - Jaattela, M.

AU - Jensen, P.B.

AU - Sehested, M.

AU - Nielsen, S.J.

PY - 2008

Y1 - 2008

N2 - Malignant cells display increased demands for energy production and DNA repair. Nicotinamide adenine dinucleotide (NAD) is required for both processes and is also continuously degraded by cellular enzymes. Nicotinamide phosphoribosyltransferase (Nampt) is a crucial factor in the resynthesis of NAD, and thus in cancer cell survival. Here, we establish the cytotoxic mechanism of action of the small molecule inhibitor CHS-828 to result from impaired synthesis of NAD. Initially, we detected cross-resistance in cells between CHS-828 and a known inhibitor of Nampt, FK866, a compound of a structurally different class. We then showed that nicotinamide protects against CHS-828-mediated cytotoxicity. Finally, we observed that treatment with CHS-828 depletes cellular NAD levels in sensitive cancer cells. In conclusion, these results strongly suggest that, like FK866, CHS-828 kills cancer cells by depleting NAD Udgivelsesdato: 2008/3/21

AB - Malignant cells display increased demands for energy production and DNA repair. Nicotinamide adenine dinucleotide (NAD) is required for both processes and is also continuously degraded by cellular enzymes. Nicotinamide phosphoribosyltransferase (Nampt) is a crucial factor in the resynthesis of NAD, and thus in cancer cell survival. Here, we establish the cytotoxic mechanism of action of the small molecule inhibitor CHS-828 to result from impaired synthesis of NAD. Initially, we detected cross-resistance in cells between CHS-828 and a known inhibitor of Nampt, FK866, a compound of a structurally different class. We then showed that nicotinamide protects against CHS-828-mediated cytotoxicity. Finally, we observed that treatment with CHS-828 depletes cellular NAD levels in sensitive cancer cells. In conclusion, these results strongly suggest that, like FK866, CHS-828 kills cancer cells by depleting NAD Udgivelsesdato: 2008/3/21

M3 - Journal article

SN - 0006-291X

VL - 367

SP - 799

EP - 804

JO - Biochemical and Biophysical Research Communications

JF - Biochemical and Biophysical Research Communications

IS - 4

ER -