Anticancer Derivative of Butyric Acid (Pivalyloxymethyl Butyrate) Specifically Potentiates the Cytotoxicity of Doxorubicin and Daunorubicin through the Suppression of Microsomal Glycosidic Activity

  1. Nozomi Niitsu1,2,
  2. Takashi Kasukabe1,
  3. Akihiro Yokoyama1,
  4. Junko Okabe-Kado1,
  5. Yuri Yamamoto-Yamaguchi1,
  6. Masanori Umeda2 and
  7. Yoshio Honma1
  1. 1Saitama Cancer Center Research Institute, Saitama, Japan (N.N., T.K., A.Y., J.O.-K., Y.Y.-Y., Y.H.) and 2The 1st Department of Internal Medicine, Toho University School of Medicine, Tokyo, Japan (N.N., M.U.)

    Abstract

    Pivalyloxymethyl butyrate (AN9) is an anticancer derivative of butyric acid. In this study, doxorubicin (DXR) and AN9 synergistically inhibited the growth of lymphoma and lung carcinoma cells, whereas there was no synergy between AN9 and antimetabolites. AN9 did not affect the intracellular uptake of DXR. Among anthracyclines and their derivatives, the synergistic effect was prominent in compounds with a daunosamine moiety, suggesting that AN9 may affect the catabolism of these compounds. The degradation of DXR in the extract from AN9-treated cells was much less than that in extract from untreated cells. AN9 did not directly inhibit the enzyme activity but rather suppressed expression of the enzyme. With respect to the expression of drug resistance-related genes, there was no significant difference between untreated and AN9-treated cells. However, AN9 significantly down-regulated the levels NADPH-cytochrome P450 reductase and DT-diaphorase mRNA in the presence of DXR but not the level of xanthine oxidase mRNA. The enhancement of the sensitivity to anthracyclines was closely associated with the suppression of the mRNA expression.

    Footnotes

    • Yoshio Honma, Saitama Cancer Center Research Institute, 818 Komuro, Ina, Saitama 362-0806, Japan. E-mail:honma{at}cancer-c.pref.saitama.jp

    • This work was supported by grants for Cancer Research from the Ministry of Education, Science, Sports and Culture of Japan and the Ministry of Health and Welfare of Japan.

    • Abbreviations:
      DXR
      doxorubicin
      AN9
      pivalyloxymethyl butyrate
      DNR
      daunorubicin
      MTT
      3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
      RT
      reverse transcription
      PCR
      polymerase chain reaction
      • Received November 10, 1999.
      • Accepted March 13, 2000.
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    1. Molecular Pharmacology July 1, 2000 vol. 58 no. 1 27-36
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