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
IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata
View Archive Info| Field | Value | |
| Title |
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
|
|
| Creator |
Ganguly, Agneyo
Das, Benubrata Roy, Amit Sen, Nilkantha Dasgupta, Somdeb Bose Mukhopadhayay, Sibabrata Majumder, Hemanta K |
|
| Subject |
Infectious Diseases and Immunology
|
|
| Description |
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–DNAcleavable complexes by an indirect process of reactive oxygen species (ROS) generation and subsequent oxidative DNAdamage. In this study, we show that betulinic acid, a catalytic inhibitor of topoisomerases, inhibits the formation of apoptotic topoisomerase I–DNAclea vable complexes in prostate cancer cells induced by drugs like camptothecin, staurosporine, and etoposide. Although events like ROS generation, oxidative DNA damage, and DNAfragmentation were observed after betulinic acid treatment, there is no topoisomerase I–DNAclea vable 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–DNAcomplexes and prevents the cellular topoisomerase I
from directly participating in the apoptotic process
|
|
| Date |
2007
|
|
| Type |
Article
PeerReviewed |
|
| Format |
application/pdf
|
|
| Identifier |
http://www.eprints.iicb.res.in/209/1/CANCER_RESEARCH%2C_67(24)%2C_11848%2D11858%2C2007_[5].pdf
Ganguly, Agneyo and Das, Benubrata and Roy, Amit and Sen, Nilkantha and Dasgupta, Somdeb Bose and Mukhopadhayay, Sibabrata and Majumder, Hemanta K (2007) 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. Cancer Research, 67. pp. 11848-11858. |
|
| Relation |
http://dx.doi.org/10.1158/0008-5472.CAN-07-1615
http://www.eprints.iicb.res.in/209/ |
|