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Existence of a distinct concentration window governing daunorubicin-induced mammalian liver mitotoxicity--implication for determining therapeutic window.

Abstract：

:Daunorubicin (DNR) is a well known anticancer drug believed to act mainly by topoisomerase II inhibition and mitochondria-mediated free radical generation. Though several studies were dedicated to elucidate the mechanism of action of DNR, however the mechanism still remains illusive. DNR is reported to affect mitochondrial respiration. However, there are contradictory reports regarding DNR effect on oxygen consumption. Interestingly, DNR at low concentration (<10 microM) dose-dependently augments respiration but at higher concentration inhibits respiration. To investigate, if a concentration window exists in which the effect of DNR on mitochondria is optimum, dose-dependent effect of DNR on mitochondria was studied. DNR inhibited electron transfer and generates reactive oxygen species (ROS) at complex I and III but not at complex II. DNR-induced ROS generation was found instrumental in mitochondrial membrane potential collapse and mitochondrial permeability transition (MPT) opening. MPT closure reduced the observed respiratory burst. Thus, at lower DNR concentration, MPT opening leads to a sudden burst of respiration while at higher concentration electron transfer gets inhibited, therefore respiration gets repressed. We for the first time, provide a possible explanation for the reports regarding the differential regulation of respiration by DNR. Thus, further establishing the concept of concentration window and justifying the need for dose optimization for maximal therapeutic effect.

journal_name

Biochem Pharmacol

journal_title

Biochemical pharmacology

authors

Paul MK,Patkari M,Mukhopadhayay AK

doi

10.1016/j.bcp.2007.06.009

subject

Has Abstract

pub_date

2007-09-15 00:00:00

pages

821-30

issue

6

eissn

0006-2952

issn

1873-2968

pii

S0006-2952(07)00370-X

journal_volume

74

pub_type

杂志文章

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