HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

A newly synthesized bifunctional inhibitor, W-77, enhances adriamycin activity against human ovarian carcinoma cells.

Abstract
A newly synthesized calmodulin antagonist, (S)-P-(2-aminoethyloxy)-N-[2-(4-benzyloxy-carbonylpiperazinyl++ +)-1-(P-methoxybenzyl)ethyl]-N-methylbenzenesulfonamide dihydrochloride (W-77), acts as a calcium-independent uncompetitive antagonist which binds to glutathione-S-transferase (GST). We purified GST from human placenta using drug affinity chromatography on a column of W-77 coupled with Sepharose 6B and demonstrated that W-77 bound to GST. A spectrophotometric assay also showed that W-77 inhibited GST activity. We prepared Adriamycin-resistant and -sensitive cells from human ovarian serous cystadenocarcinomas. Immunoblot analysis revealed that GST expression was increased in the Adriamycin-resistant cells. We also purified GST from Adriamycin-resistant cells and found that W-77 bound to the GST obtained from these ovarian carcinoma cells. Adriamycin resistance was partially overcome by the addition of W-77 (10 microM) to the cultured cells. In addition, we investigated the effect of W-77 on P-glycoprotein. Northern blot analysis revealed MDR1 gene expression in Adriamycin-resistant cells. Although W-77 was less potent in increasing the intracellular Adriamycin content than verapamil, it was more effective in overcoming Adriamycin resistance. These results suggest that W-77 enhances the antitumor activity of Adriamycin by inhibiting both GST and P-glycoprotein.
AuthorsO Maeda, M Terasawa, T Ishikawa, H Oguchi, K Mizuno, M Kawai, F Kikkawa, Y Tumoda, H Hidaka
JournalCancer research (Cancer Res) Vol. 53 Issue 9 Pg. 2051-6 (May 01 1993) ISSN: 0008-5472 [Print] United States
PMID8097673 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Calmodulin
  • DNA, Neoplasm
  • Membrane Glycoproteins
  • Piperazines
  • RNA, Messenger
  • Sulfonamides
  • W 77
  • Doxorubicin
  • Glutathione Transferase
  • Ethacrynic Acid
Topics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Calmodulin (antagonists & inhibitors)
  • Cell Survival (drug effects)
  • Cystadenocarcinoma (drug therapy)
  • DNA, Neoplasm (genetics)
  • Doxorubicin (administration & dosage)
  • Drug Resistance
  • Drug Synergism
  • Ethacrynic Acid (pharmacology)
  • Female
  • Gene Expression
  • Glutathione Transferase (genetics)
  • Humans
  • In Vitro Techniques
  • Membrane Glycoproteins (genetics)
  • Ovarian Neoplasms (drug therapy)
  • Piperazines (pharmacology, toxicity)
  • RNA, Messenger (genetics)
  • Sulfonamides (pharmacology, toxicity)
  • Tumor Cells, Cultured (drug effects)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: