Two pyridine analogues with more effective ability to reverse multidrug resistance and with lower calcium channel blocking activity than their dihydropyridine counterparts

Norimasa Shudo, Tetsuro Mizoguchi, Akihiko Yoshimura, Makoto Arita, Akihiko Yoshimura, Kiyotomo Seto, Ryozo Sakoda, Shin Ichi Akiyama

Research output: Contribution to journalArticle

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Abstract

Four pyridine analogues and their dihydropyridine counterparts were examined for their ability to reverse drug resistance in a multidrug-resistant human carcinoma cell line, KB-C2. Two pyridine analogues were more able to reverse drug resistance than their dihydropyridine counterparts. The other two pyridine analogues had an effect on drug resistance similar to their dihydropyridine counterparts. The calcium channel-blocking activity of all the pyridine analogues was considerably lower than that of the dihydropyridine analogues. Of the pyridine analogues, 2-[4-(diphenylmethyl)-1-piperazinyl]ethyl 5-(trans-4,6-dimethyl-1,3,2-dioxaphosphorinan-2-yl)-2,6-dimethyl-4-(3- nitrophenyl)-3-pyridinecarboxylate P-oxide (PAK-104P) was the most effective in reversing multidrug resistance. PAK-104P (1 and 5 μM) completely reversed the drug resistance in KB-8-5 and KB-C2 cells, respectively. The reversing effect of PAK-104P was greater than that of other multidrug resistance-reversing agents, cepharanthine, verapamil, nimodipine, and nicardipine. PAK-104P at 1 μM increased about 10-fold the accumulation of vinblastine in KB-C2 cells, whereas verapamil at the same concentration increased the accumulation about 2-fold. The inhibition of [3H]azidopine photolabeling of P-glycoprotein by the pyridine and dihydropyridine analogues except 2-[methyl(phenyl-methyl)amino]ethyl 4-(2-chlorophenyl)-5-(4-methyl-1,3,2-dioxaphosphorinan-2-yl)-1,4-dihydro-2,6- dimethyl-3-pyridinecarboxylate P-oxide correlated with the reversing of drug resistance by the analogues. Some newly synthesized pyridine analogues seemed to have lower calcium channel-blocking activity and more potent resistance-reversing ability than verapamil and other calcium channel blockers.

Original languageEnglish
Pages (from-to)3055-3061
Number of pages7
JournalCancer Research
Volume50
Issue number10
Publication statusPublished - 1990 May 15
Externally publishedYes

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Multiple Drug Resistance
Calcium Channels
Drug Resistance
Verapamil
KB Cells
Nicardipine
Nimodipine
Vinblastine
Calcium Channel Blockers
P-Glycoprotein
1,4-dihydropyridine
pyridine
Oxides
PAK 104P
Carcinoma
Cell Line

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Two pyridine analogues with more effective ability to reverse multidrug resistance and with lower calcium channel blocking activity than their dihydropyridine counterparts. / Shudo, Norimasa; Mizoguchi, Tetsuro; Yoshimura, Akihiko; Arita, Makoto; Yoshimura, Akihiko; Seto, Kiyotomo; Sakoda, Ryozo; Akiyama, Shin Ichi.

In: Cancer Research, Vol. 50, No. 10, 15.05.1990, p. 3055-3061.

Research output: Contribution to journalArticle

Shudo, Norimasa ; Mizoguchi, Tetsuro ; Yoshimura, Akihiko ; Arita, Makoto ; Yoshimura, Akihiko ; Seto, Kiyotomo ; Sakoda, Ryozo ; Akiyama, Shin Ichi. / Two pyridine analogues with more effective ability to reverse multidrug resistance and with lower calcium channel blocking activity than their dihydropyridine counterparts. In: Cancer Research. 1990 ; Vol. 50, No. 10. pp. 3055-3061.
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AU - Arita, Makoto

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AU - Seto, Kiyotomo

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