Involvement of PKC delta (PKCd) in the resistance against different doxorubicin analogs
- نوع فایل : کتاب
- زبان : انگلیسی
- مؤلف : Marı´a Ines Dı´az Bessone Damian E. Berardi Paola B. Campodo´nico Laura B. Todaro Leonard Lothstein Elisa D. Bal de Kier Joffe´ Alejandro J.
- چاپ و سال / کشور: 2010
Description
Doxorubicin is an anti-tumor antibiotic widely used in the management of cancer patients. Its main mechanism of action involves the generation of DNA damage and the inhibition of topoisomerase II, promoting apoptosis. AD 198 is a novel doxorubicin analog devoid of DNA binding and topoisomerase II inhibitory capacities. It has been proposed that AD 198 induces apoptosis by activating protein kinase C delta (PKCd); a PKC isoform described as growth inhibitory in a large number of cell types. We have previously demonstrated that PKCd overexpression in NMuMG cells induced the opposite effect, promoting proliferation and cell survival. In this study, we found that PKCd overexpression confers an enhanced cell death resistance against AD 198 cytotoxic effect and against AD 288, another doxorubicin analog that preserves its mechanism of action. These resistances involve PKCdmediated activation of two well-known survival pathways: Akt and NF-jB. While the resistance against AD 198 could be abrogated upon the inhibition of either Akt or NF-jB pathways, only NF-jB inhibition could revert the resistance to AD 288. Altogether, our results indicate that PKCd increases cell death resistance against different apoptosis inductors, independently of their mechanism of action, through a differential modulation of Akt and NF-jB pathways. Our study contributes to a better understanding of the mechanisms involved in PKCd-induced resistance and may greatly impact in the rationale design of isozymespecific PKC modulators as therapeutic agents.
Breast Cancer Res Treat (2011) 126:577–587 Received: 6 March 2010 / Accepted: 14 May 2010 / Published online: 30 May 2010 Springer Science+Business Media, LLC. 2010
