Oxythiamine and dehydroepiandrosterone inhibit the nonoxidative synthesis of ribose and tumor cell proliferation

Laszlo G. Boros, Joaquim Puigjaner, Marta Cascante, Wai Nang Paul Lee, James L. Brandes, Sara Bassilian, Fouza I. Yusuf, Robert D. Williams, Peter Muscarella, W. Scott Melvin, William J. Schirmer

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Abstract

This study investigates the significance of the glucose-6-phosphate dehydrogenase (G6PD) catalyzed oxidative and the transketolase (TK) catalyzed nonoxidative pentose cycle (PC) reactions in the tumor proliferation process by characterizing tumor growth patterns and synthesis of the RNA ribose moiety in the presence of respective inhibitors of G6PD and TK. Mass spectra analysis of 13C-labeled carbons revealed that these PC reactions contribute to over 85% of de novo ribose synthesis in RNA from [1,2-13C]glucose in cultured Mia pancreatic adenocarcinoma cells, with the fraction synthesized through the TK pathway predominating (85%). Five days of treatment with the TK inhibitor oxythiamine (OT) and the G6PD inhibitor dehydroepiandrosterone- sulfate (0.5 μM each) exerted a 39 and a 23% maximum inhibitory effect on cell proliferation in culture, which was increased to 60% when the two drugs were administered in combination. In vivo testing of 400 mg/kg OT or dehydroepiandrosterone-sulfate in C57BL/6 mice hosting Ehrlich's ascitic tumor cells revealed a 90.4 and a 46% decrease in the final tumor mass after 3 days of treatment. RNA ribose fractional synthesis through the TK reaction using metabolites directly from glycolysis declined by 9.1 and 23.9% after OT or the combined treatment, respectively. Nonoxidative PC reactions play a central regulating role in the carbon-recruiting process toward de novo nucleic acid ribose synthesis and cell proliferation in vitro and in vivo. Therefore, enzymes or substrates regulating the nonoxidative synthesis of ribose could also be the sites to preferentially target tumor cell proliferation by new anticancer drugs.

Original languageEnglish (US)
Pages (from-to)4242-4248
Number of pages7
JournalCancer Research
Volume57
Issue number19
StatePublished - Oct 1 1997
Externally publishedYes

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Oxythiamine
Transketolase
Ribose
Dehydroepiandrosterone
Pentoses
Cell Proliferation
Glucosephosphate Dehydrogenase
Dehydroepiandrosterone Sulfate
RNA
Neoplasms
Carbon
Glycolysis
Inbred C57BL Mouse
Pharmaceutical Preparations
Nucleic Acids
Mass Spectrometry
Adenocarcinoma
Glucose
Enzymes
Growth

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Boros, L. G., Puigjaner, J., Cascante, M., Lee, W. N. P., Brandes, J. L., Bassilian, S., ... Schirmer, W. J. (1997). Oxythiamine and dehydroepiandrosterone inhibit the nonoxidative synthesis of ribose and tumor cell proliferation. Cancer Research, 57(19), 4242-4248.

Oxythiamine and dehydroepiandrosterone inhibit the nonoxidative synthesis of ribose and tumor cell proliferation. / Boros, Laszlo G.; Puigjaner, Joaquim; Cascante, Marta; Lee, Wai Nang Paul; Brandes, James L.; Bassilian, Sara; Yusuf, Fouza I.; Williams, Robert D.; Muscarella, Peter; Melvin, W. Scott; Schirmer, William J.

In: Cancer Research, Vol. 57, No. 19, 01.10.1997, p. 4242-4248.

Research output: Contribution to journalArticle

Boros, LG, Puigjaner, J, Cascante, M, Lee, WNP, Brandes, JL, Bassilian, S, Yusuf, FI, Williams, RD, Muscarella, P, Melvin, WS & Schirmer, WJ 1997, 'Oxythiamine and dehydroepiandrosterone inhibit the nonoxidative synthesis of ribose and tumor cell proliferation', Cancer Research, vol. 57, no. 19, pp. 4242-4248.
Boros LG, Puigjaner J, Cascante M, Lee WNP, Brandes JL, Bassilian S et al. Oxythiamine and dehydroepiandrosterone inhibit the nonoxidative synthesis of ribose and tumor cell proliferation. Cancer Research. 1997 Oct 1;57(19):4242-4248.
Boros, Laszlo G. ; Puigjaner, Joaquim ; Cascante, Marta ; Lee, Wai Nang Paul ; Brandes, James L. ; Bassilian, Sara ; Yusuf, Fouza I. ; Williams, Robert D. ; Muscarella, Peter ; Melvin, W. Scott ; Schirmer, William J. / Oxythiamine and dehydroepiandrosterone inhibit the nonoxidative synthesis of ribose and tumor cell proliferation. In: Cancer Research. 1997 ; Vol. 57, No. 19. pp. 4242-4248.
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abstract = "This study investigates the significance of the glucose-6-phosphate dehydrogenase (G6PD) catalyzed oxidative and the transketolase (TK) catalyzed nonoxidative pentose cycle (PC) reactions in the tumor proliferation process by characterizing tumor growth patterns and synthesis of the RNA ribose moiety in the presence of respective inhibitors of G6PD and TK. Mass spectra analysis of 13C-labeled carbons revealed that these PC reactions contribute to over 85{\%} of de novo ribose synthesis in RNA from [1,2-13C]glucose in cultured Mia pancreatic adenocarcinoma cells, with the fraction synthesized through the TK pathway predominating (85{\%}). Five days of treatment with the TK inhibitor oxythiamine (OT) and the G6PD inhibitor dehydroepiandrosterone- sulfate (0.5 μM each) exerted a 39 and a 23{\%} maximum inhibitory effect on cell proliferation in culture, which was increased to 60{\%} when the two drugs were administered in combination. In vivo testing of 400 mg/kg OT or dehydroepiandrosterone-sulfate in C57BL/6 mice hosting Ehrlich's ascitic tumor cells revealed a 90.4 and a 46{\%} decrease in the final tumor mass after 3 days of treatment. RNA ribose fractional synthesis through the TK reaction using metabolites directly from glycolysis declined by 9.1 and 23.9{\%} after OT or the combined treatment, respectively. Nonoxidative PC reactions play a central regulating role in the carbon-recruiting process toward de novo nucleic acid ribose synthesis and cell proliferation in vitro and in vivo. Therefore, enzymes or substrates regulating the nonoxidative synthesis of ribose could also be the sites to preferentially target tumor cell proliferation by new anticancer drugs.",
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