Betulinic acid, a catalytic inhibitor of topoisomerase I, inhibits reactive oxygen species-mediated apoptotic topoisomerase I-DNA cleavable complex formation in prostate cancer cells but does not affect the process of cell death

Agneyo Ganguly, Benubrata Das, Amit Roy, Nilkantha Sen, Somdeb Bose Dasgupta, Sibabrata Mukhopadhayay, Hemanta K. Majumder

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

The ubiquitious enzyme topoisomerase I can be targeted by drugs which turn these enzymes into cellular poisons and subsequently induce cell death. Drugs like staurosporine, which do not target topoisomerase I directly, can also lead to stabilization of topoisomerase I-DNA cleavable complexes by an indirect process of reactive oxygen species (ROS) generation and subsequent oxidative DNA damage. In this study, we show that betulinic acid, a catalytic inhibitor of topoisomerases, inhibits the formation of apoptotic topoisomerase I-DNA cleavable complexes in prostate cancer cells induced by drugs like camptothecin, staurosporine, and etoposide. Although events like ROS generation, oxidative DNA damage, and DNA fragmentation were observed after betulinic acid treatment, there is no topoisomerase I-DNA cleavable complex formation, which is a key step in ROS-induced apoptotic processes. We have shown that betulinic acid interacts with cellular topoisomerase I and prohibits its interaction with the oxidatively damaged DNA. Using oligonucleotide containing 8-oxoguanosine modification, we have shown that betulinic acid inhibits its cleavage by topoisomerase I in vitro. Whereas silencing of topoisomerase I gene by small interfering RNAreduces cell death in the case of staurosporine and camptothecin, it cannot substantially reduce betulinic acid-induced cell death. Thus, our study provides evidence that betulinic acid inhibits formation of apoptotic topoisomerase I-DNA complexes and prevents the cellular topoisomerase I from directly participating in the apoptotic process.

Original languageEnglish (US)
Pages (from-to)11848-11858
Number of pages11
JournalCancer Research
Volume67
Issue number24
DOIs
StatePublished - Dec 15 2007

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Topoisomerase I Inhibitors
Type I DNA Topoisomerase
Reactive Oxygen Species
Prostatic Neoplasms
Cell Death
Staurosporine
Camptothecin
DNA Damage
Topoisomerase Inhibitors
betulinic acid
Pharmaceutical Preparations
Poisons
DNA Fragmentation
Etoposide
Enzymes
Oligonucleotides

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Betulinic acid, a catalytic inhibitor of topoisomerase I, inhibits reactive oxygen species-mediated apoptotic topoisomerase I-DNA cleavable complex formation in prostate cancer cells but does not affect the process of cell death. / Ganguly, Agneyo; Das, Benubrata; Roy, Amit; Sen, Nilkantha; Dasgupta, Somdeb Bose; Mukhopadhayay, Sibabrata; Majumder, Hemanta K.

In: Cancer Research, Vol. 67, No. 24, 15.12.2007, p. 11848-11858.

Research output: Contribution to journalArticle

Ganguly, Agneyo ; Das, Benubrata ; Roy, Amit ; Sen, Nilkantha ; Dasgupta, Somdeb Bose ; Mukhopadhayay, Sibabrata ; Majumder, Hemanta K. / Betulinic acid, a catalytic inhibitor of topoisomerase I, inhibits reactive oxygen species-mediated apoptotic topoisomerase I-DNA cleavable complex formation in prostate cancer cells but does not affect the process of cell death. In: Cancer Research. 2007 ; Vol. 67, No. 24. pp. 11848-11858.
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