Abstract
Benzamide riboside (BR) after anabolism to an analogue of NAD, was shown to inhibit the activity of NAD-dependent enzymes such as inosine 5-monophosphate dehydrogenase (IMPDH), the rate limiting enzyme in de novo guanylate biosynthesis, and malate dehydrogenase which is involved in the citric cycle and respiratory chain. BR exhibits strong anti-carcinogenic effects due to growth retardation and due to induction of apoptosis and necrosis. Apoptosis is ascribed to the inhibition of IMPDH because cell death can be blocked by restoring intracellular guanylate metabolism by the addition of guanosine. It is shown here, however, that also survival-relevant genes such as cdc25A, akt, bcl-2 and transferrin receptor become repressed by BR, whereas the expression level of the apoptosis enforcing gene c-myc persists. Even though BRmediated growth retardation still allows BR to induce apoptosis, rapamycin-mediated cell cycle block and cell contact inhibition prevent cell death, it strongly suggests that BR induces a type of c-Myc-dependent apoptosis. At high concentrations BR induces DNA double strand breaks by yet to be determined mechanisms that occur hours before necrosis can be detected. This is accompanied by a dramatic decrease of intracellular ATP. The artificial restoration of ATP by addition of adenosine or sufficient provision of an energy source such as glucose prevents BR-promoted necrosis and favors apoptosis. This observation may be of clinical relevance.
Keywords: antitumor activity, benzamide riboside, staurosporine, cytarabine, cisplatin, combination therapy, apoptosis
Current Medicinal Chemistry
Title: Potential Mechanisms of Benzamide Riboside Mediated Cell Death
Volume: 9 Issue: 7
Author(s): Doris Polgar, Susanne Gfatter, Maria Uhl, Fekadu Kassie, Christina Leisser, Georg Krupitza and Michael Grusch
Affiliation:
Keywords: antitumor activity, benzamide riboside, staurosporine, cytarabine, cisplatin, combination therapy, apoptosis
Abstract: Benzamide riboside (BR) after anabolism to an analogue of NAD, was shown to inhibit the activity of NAD-dependent enzymes such as inosine 5-monophosphate dehydrogenase (IMPDH), the rate limiting enzyme in de novo guanylate biosynthesis, and malate dehydrogenase which is involved in the citric cycle and respiratory chain. BR exhibits strong anti-carcinogenic effects due to growth retardation and due to induction of apoptosis and necrosis. Apoptosis is ascribed to the inhibition of IMPDH because cell death can be blocked by restoring intracellular guanylate metabolism by the addition of guanosine. It is shown here, however, that also survival-relevant genes such as cdc25A, akt, bcl-2 and transferrin receptor become repressed by BR, whereas the expression level of the apoptosis enforcing gene c-myc persists. Even though BRmediated growth retardation still allows BR to induce apoptosis, rapamycin-mediated cell cycle block and cell contact inhibition prevent cell death, it strongly suggests that BR induces a type of c-Myc-dependent apoptosis. At high concentrations BR induces DNA double strand breaks by yet to be determined mechanisms that occur hours before necrosis can be detected. This is accompanied by a dramatic decrease of intracellular ATP. The artificial restoration of ATP by addition of adenosine or sufficient provision of an energy source such as glucose prevents BR-promoted necrosis and favors apoptosis. This observation may be of clinical relevance.
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Cite this article as:
Polgar Doris, Gfatter Susanne, Uhl Maria, Kassie Fekadu, Leisser Christina, Krupitza Georg and Grusch Michael, Potential Mechanisms of Benzamide Riboside Mediated Cell Death, Current Medicinal Chemistry 2002; 9 (7) . https://dx.doi.org/10.2174/0929867024606849
DOI https://dx.doi.org/10.2174/0929867024606849 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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