Characterization of 2-chloro-N10-substituted phenoxazines for reversing multidrug resistance in cancer cells

Kuntebommanahalli N. Thimmaiah, Bellur S. Jayashree, Glen S. Germain, Peter J. Houghton, Julie K. Horton

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Twenty-one 2-chloro-N10-substituted phenoxazines have been synthesized and characterized as potential modulators of multidrug resistance (MDR). Many of the compounds, at a concentration of 100 μM, enhanced accumulation of vinblastine (VLB) in drug-resistant KB8-5. cells to a greater extent than the same concentration of verapamil (VRP). However, the effects on VLB accumulation were specific, because these derivatives had little activity in the parental drug-sensitive line KB3-1. The compounds slowed the efflux of VLB from KB8-5 cells, suggesting that the chlorophenoxazines, like VRP, can inhibit P-glycoprotein (P-gp)-mediated efflux of VLB from this cell line. Two of the chlorophenoxazine derivatives, and also VRP, were able to stimulate the vanadate-sensitive ATPase activity attributable to P-gp in membranes isolated from MDR1 baculovirus-infected Sf9 cells. This result suggests that these modulators exert their effect by directly interacting with P-gp. Apart from the parent unsubstituted molecule, 2-chlorophenoxazine, there was a good correlation between log10P and the ability of the compounds to enhance VLB accumulation in KB8-5. This suggests that lipophilicity of a modulator is important, but is not the sole determinant of potency. Within this series of compounds, the optimal structural features for MDR modulation include a hydrophobic phenoxazine ring with a -Cl atom in the C-2 position and a tertiary amine group four carbons from the tricyclic ring. Many of the agents at the IC10 concentration completely reversed the 37-fold VLB resistance in KB8-5 cells. The most active agents in KB8-5 were able to partially reverse VLB resistance in an MDR colon carcinoma cell line GC3/cI and completely reversed the 86-fold VLB resistance in the MDR1-overexpressing breast carcinoma cell line BC19/3. These same agents could only partially sensitize BC19/3 cells to taxol and doxorubicin, suggesting that the chlorophenoxazine derivatives show some specificity for modulating VLB resistance.

Original languageEnglish
Pages (from-to)29-41
Number of pages13
JournalOncology Research
Volume10
Issue number1
Publication statusPublished - 01-12-1998

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Multiple Drug Resistance
P-Glycoprotein
Verapamil
Cell Line
Neoplasms
Sf9 Cells
Vinblastine
Baculoviridae
Paclitaxel
Pharmaceutical Preparations
Doxorubicin
Amines
Colon
Carbon
Breast Neoplasms
Carcinoma
Membranes
phenoxazine

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Thimmaiah, Kuntebommanahalli N. ; Jayashree, Bellur S. ; Germain, Glen S. ; Houghton, Peter J. ; Horton, Julie K. / Characterization of 2-chloro-N10-substituted phenoxazines for reversing multidrug resistance in cancer cells. In: Oncology Research. 1998 ; Vol. 10, No. 1. pp. 29-41.
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Characterization of 2-chloro-N10-substituted phenoxazines for reversing multidrug resistance in cancer cells. / Thimmaiah, Kuntebommanahalli N.; Jayashree, Bellur S.; Germain, Glen S.; Houghton, Peter J.; Horton, Julie K.

In: Oncology Research, Vol. 10, No. 1, 01.12.1998, p. 29-41.

Research output: Contribution to journalArticle

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T1 - Characterization of 2-chloro-N10-substituted phenoxazines for reversing multidrug resistance in cancer cells

AU - Thimmaiah, Kuntebommanahalli N.

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AB - Twenty-one 2-chloro-N10-substituted phenoxazines have been synthesized and characterized as potential modulators of multidrug resistance (MDR). Many of the compounds, at a concentration of 100 μM, enhanced accumulation of vinblastine (VLB) in drug-resistant KB8-5. cells to a greater extent than the same concentration of verapamil (VRP). However, the effects on VLB accumulation were specific, because these derivatives had little activity in the parental drug-sensitive line KB3-1. The compounds slowed the efflux of VLB from KB8-5 cells, suggesting that the chlorophenoxazines, like VRP, can inhibit P-glycoprotein (P-gp)-mediated efflux of VLB from this cell line. Two of the chlorophenoxazine derivatives, and also VRP, were able to stimulate the vanadate-sensitive ATPase activity attributable to P-gp in membranes isolated from MDR1 baculovirus-infected Sf9 cells. This result suggests that these modulators exert their effect by directly interacting with P-gp. Apart from the parent unsubstituted molecule, 2-chlorophenoxazine, there was a good correlation between log10P and the ability of the compounds to enhance VLB accumulation in KB8-5. This suggests that lipophilicity of a modulator is important, but is not the sole determinant of potency. Within this series of compounds, the optimal structural features for MDR modulation include a hydrophobic phenoxazine ring with a -Cl atom in the C-2 position and a tertiary amine group four carbons from the tricyclic ring. Many of the agents at the IC10 concentration completely reversed the 37-fold VLB resistance in KB8-5 cells. The most active agents in KB8-5 were able to partially reverse VLB resistance in an MDR colon carcinoma cell line GC3/cI and completely reversed the 86-fold VLB resistance in the MDR1-overexpressing breast carcinoma cell line BC19/3. These same agents could only partially sensitize BC19/3 cells to taxol and doxorubicin, suggesting that the chlorophenoxazine derivatives show some specificity for modulating VLB resistance.

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