Drug resistance reversal, anti-mutagenicity and antiretroviral effect of phthalimido- and chloroethyl-phenothiazines

Noboru Motohashi, Teruo Kurihara, Masami Kawase, Anikó Hevér, Masaru Tanaka, Diana Szabo, János Nacsa, Wataru Yamanaka, Ablikim Kerim, Joseph Molnár

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24 Citations (Scopus)

Abstract

The effect of substituted phenothiazines was studied in three different systems; bacteria and cancer cells and reverse transcriptase enzyme of Moloney leukemia virus. F'lac and hemolysin plasmids were eliminated by some substituted phenothiazines from E. coli at a very low frequency. The same phenothiazine derivatives also were synergistic with tetracycline in bacteria and shown antimutagenic effect in Ames test. No mutagenic effects were observed in TA 98 strain of Salmonella typhimunium. Chloroethyl-substituted phenothiazines showed antimutagenic equivalent to the parent compounds; however, phthalimido-substituted phenothiazines had higher antimutagenicity of 50%. P-glycoprotein responsible for multidrug resistance was also inhibited in tumor cells. The accumulation of the flourescent rhodamine 123 in the phenothiazine treated multi-drug resistant tumor cells was measured by flow cytometry. Some of the substituted phenothiazines were effective P-glycoprotein blockers, while some compounds had moderate activity, but others were without effect as compared to 5 μM verapamil. On the basis of computer analysis there are some correlations between the biological activities and the dipole moments, and entropy of the studied molecules. Our results suggest that the inhibition of Hly+ plasmid replication and P-glycoprotein function may depend partly on similar electronic properties of the studied phenothiazine derivatives. The activity of Moloney leukemia virus reverse transcriptase was inhibited by the substituted phenothiazines, however, no basic differences were found in the activities of phthalimido- and chloroethyl substituted phenothiazines.

Original languageEnglish
Pages (from-to)3537-3543
Number of pages7
JournalAnticancer research
Volume17
Issue number5 A
Publication statusPublished - Sep 1 1997

Keywords

  • Anti-mutagenicity
  • Bacteria antiplasmid
  • Mutagenicity
  • Reversal of multidrug resistance
  • Reverse transcriptase inhibition
  • Ring substituted chlorpromazines
  • Synergism
  • Tumor cells

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Motohashi, N., Kurihara, T., Kawase, M., Hevér, A., Tanaka, M., Szabo, D., Nacsa, J., Yamanaka, W., Kerim, A., & Molnár, J. (1997). Drug resistance reversal, anti-mutagenicity and antiretroviral effect of phthalimido- and chloroethyl-phenothiazines. Anticancer research, 17(5 A), 3537-3543.