Breast Cancer Research and Treatment

, Volume 126, Issue 3, pp 577–587 | Cite as

Involvement of PKC delta (PKCδ) in the resistance against different doxorubicin analogs

  • María Ines Díaz Bessone
  • Damian E. Berardi
  • Paola B. Campodónico
  • Laura B. Todaro
  • Leonard Lothstein
  • Elisa D. Bal de Kier Joffé
  • Alejandro J. Urtreger
Preclinical study

Abstract

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 (PKCδ); a PKC isoform described as growth inhibitory in a large number of cell types. We have previously demonstrated that PKCδ overexpression in NMuMG cells induced the opposite effect, promoting proliferation and cell survival. In this study, we found that PKCδ 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 PKCδ-mediated activation of two well-known survival pathways: Akt and NF-κB. While the resistance against AD 198 could be abrogated upon the inhibition of either Akt or NF-κB pathways, only NF-κB inhibition could revert the resistance to AD 288. Altogether, our results indicate that PKCδ increases cell death resistance against different apoptosis inductors, independently of their mechanism of action, through a differential modulation of Akt and NF-κB pathways. Our study contributes to a better understanding of the mechanisms involved in PKCδ-induced resistance and may greatly impact in the rationale design of isozyme-specific PKC modulators as therapeutic agents.

Keywords

PKCδ AD 198 AD 288 Cell death resistance 

Abbreviations

AD 198

N-benzyladriamycin-14-valerate

AD 288

N-benzyladriamycin

DAG

Diacylglycerol

Dox

Doxorubicin

FCS

Fetal calf serum

MEM

Minimum essential medium

Nuclear factor-κB

NF-κB

PAGE

Polyacrylamide gel electrophoresis

PBS

Phosphate-buffered saline

PKC

Protein kinase C

PMA

Phorbol 12-myristate 13-acetate

Rott

Rottlerin

SDS

Sodium dodecyl sulfate

Topo II

Topoisomerase II

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Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • María Ines Díaz Bessone
    • 1
  • Damian E. Berardi
    • 1
  • Paola B. Campodónico
    • 1
  • Laura B. Todaro
    • 1
  • Leonard Lothstein
    • 2
  • Elisa D. Bal de Kier Joffé
    • 1
  • Alejandro J. Urtreger
    • 1
  1. 1.Research Area, Institute of Oncology “Angel H. Roffo”University of Buenos AiresBuenos AiresArgentina
  2. 2.The University of Tennessee Health Science Center and Center for Cancer ResearchMemphisUSA

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