Inhibition of intracellular Ca2+ signalling, cytotoxicity and antitumor activity of the herbicide oryzalin and its analogues

Garth Powis, Alfred Gallegos, Robert T. Abraham, Curtis L. Ashendel, Leon H. Zalkow, Robert T Dorr, Katerina Dvorakova, Sydney Salmon, Steadman Harrison, John Worzalla

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8 Scopus citations

Abstract

Purpose: Studies were conducted on oryzalin (3,5-dinitro-N,N-di(n- propyl)sulfanilamide), a widely used dinitroaniline sulfonamide herbicide, which was identified from plant extracts as an inhibitor of mitogen-and growth factor-mediated intracellular free Ca2+ ([Ca2+](i)) signalling in mammalian cells. Methods and Results: Oryzalin inhibited vasopressin, bradykinin and platelet-derived growth factor [Ca2+](i) signalling in Swiss 3T3 fibroblasts with IC50 values of 14, 16 and 18 μM, respectively 45Ca2+ uptake into nonmitochondrial stores of saponin-permeabilized Swiss 3T3 cells was inhibited by oryzalin with an IC50 of 34 μM. Oryzalin inhibited colony formation of HT-29 colon carcinoma cells with an IC50 of 8 μM and inhibited the growth of a number of other cancer cell lines and primary human tumors in vitro with IC50 values in the range 3 to 22 μM A number of oryzalin analogues were studied and an association was found between the ability to inhibit [Ca2+](i) signalling and inhibition of the growth of HT-29 human colon cancer cells (P = 0001) and of CCRF-CEM human leukemia cells (P = 0016). Oryzalin at doses up to 600 mg/kg administered orally or subcutaneously daily to mice for 3 to 10 days beginning a day after tumor inoculation inhibited the growth of murine B16 melanoma by 63% but showed no appreciable activity when administered subcutaneously or intraperitoneally to mice beginning a number of days after tumor inoculation against a variety of human tumor xenografts. The peak plasma concentration of oryzalin following repeated subcutaneous administration of oryzalin at 600 mg/kg per day to mice was 37 μM and of its major metabolite N-depropyl oryzalin was 53 μM. Conclusion: It is unlikely that the absence of significant antitumor activity of oryzalin is a result of the inability to achieve adequate plasma concentrations.

Original languageEnglish (US)
Pages (from-to)22-28
Number of pages7
JournalCancer Chemotherapy and Pharmacology
Volume41
Issue number1
DOIs
Publication statusPublished - 1997

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Keywords

  • Cell proliferation
  • Intracellular Ca
  • Oryzalin

ASJC Scopus subject areas

  • Cancer Research
  • Pharmacology
  • Oncology

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