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 Dorr, Katerina Dvorakova, Sydney Salmon, Steadman Harrison, John Worzalla

Research output: Contribution to journalArticle

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
StatePublished - Dec 1 1997

Keywords

  • Cell proliferation
  • Intracellular Ca
  • Oryzalin

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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    Powis, G., Gallegos, A., Abraham, R. T., Ashendel, C. L., Zalkow, L. H., Dorr, R., Dvorakova, K., Salmon, S., Harrison, S., & Worzalla, J. (1997). Inhibition of intracellular Ca2+ signalling, cytotoxicity and antitumor activity of the herbicide oryzalin and its analogues. Cancer Chemotherapy And Pharmacology, 41(1), 22-28. https://doi.org/10.1007/s002800050703