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

María Ines Dìaz Bessone, Damian E. Berardi, Paola B. Campodónico, Laura B. Todaro, Leonard Lothstein, Elisa D. Bal De Kier Joffe, Alejandro J. Urtreger

Research output: Contribution to journalArticle

16 Citations (Scopus)

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 over-expression 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.

Original languageEnglish (US)
Pages (from-to)577-587
Number of pages11
JournalBreast Cancer Research and Treatment
Volume126
Issue number3
DOIs
StatePublished - Apr 1 2011

Fingerprint

Protein Kinase C-delta
Doxorubicin
Type II DNA Topoisomerase
Apoptosis
Cell Death
Somatostatin-Secreting Cells
delta protein
Isoenzymes
DNA Damage
Neoplasms
Cell Survival
Protein Isoforms
Cell Count
Anti-Bacterial Agents
Survival
N-benzyladriamycin-14-valerate

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Bessone, M. I. D., Berardi, D. E., Campodónico, P. B., Todaro, L. B., Lothstein, L., Bal De Kier Joffe, E. D., & Urtreger, A. J. (2011). Involvement of PKC delta (PKCδ) in the resistance against different doxorubicin analogs. Breast Cancer Research and Treatment, 126(3), 577-587. https://doi.org/10.1007/s10549-010-0956-2

Involvement of PKC delta (PKCδ) in the resistance against different doxorubicin analogs. / Bessone, María Ines Dìaz; Berardi, Damian E.; Campodónico, Paola B.; Todaro, Laura B.; Lothstein, Leonard; Bal De Kier Joffe, Elisa D.; Urtreger, Alejandro J.

In: Breast Cancer Research and Treatment, Vol. 126, No. 3, 01.04.2011, p. 577-587.

Research output: Contribution to journalArticle

Bessone, MID, Berardi, DE, Campodónico, PB, Todaro, LB, Lothstein, L, Bal De Kier Joffe, ED & Urtreger, AJ 2011, 'Involvement of PKC delta (PKCδ) in the resistance against different doxorubicin analogs', Breast Cancer Research and Treatment, vol. 126, no. 3, pp. 577-587. https://doi.org/10.1007/s10549-010-0956-2
Bessone, María Ines Dìaz ; Berardi, Damian E. ; Campodónico, Paola B. ; Todaro, Laura B. ; Lothstein, Leonard ; Bal De Kier Joffe, Elisa D. ; Urtreger, Alejandro J. / Involvement of PKC delta (PKCδ) in the resistance against different doxorubicin analogs. In: Breast Cancer Research and Treatment. 2011 ; Vol. 126, No. 3. pp. 577-587.
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