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

• Published in: Breast cancer research and treatment Vol. 126; no. 3; pp. 577 - 587
• Main Authors: Díaz Bessone, María Ines, Berardi, Damian E., Campodónico, Paola B., Todaro, Laura B., Lothstein, Leonard, Bal de Kier Joffé, Elisa D., Urtreger, Alejandro J.
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01.04.2011; Springer; Springer Nature B.V
• Subjects: Animals; Anthracyclines; Antibiotics; Antibiotics, Antineoplastic - pharmacology; Apoptosis; Biological and medical sciences; Breast cancer; Cancer; Cancer research; Cancer therapies; Cell Line, Tumor; Cell Survival; DNA; DNA Topoisomerases, Type II - chemistry; Doxorubicin - analogs & derivatives; Doxorubicin - pharmacology; Drug resistance; Drug Resistance, Neoplasm; Female; Gene Expression Profiling; Gynecology. Andrology. Obstetrics; Health aspects; Mammary gland diseases; Mammary Neoplasms, Animal - metabolism; Medical sciences; Medicine; Medicine & Public Health; Mice; NF-kappa B - metabolism; Oncology; Preclinical Study; Protein Kinase C-delta - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Subcellular Fractions; Tumors; PKCδ; AD 198; Cell death resistance; AD 288; Antineoplastic agent; DNA topoisomerase (ATP-hydrolysing); Protein kinase C; Enzyme; Transferases; Enzyme inhibitor; Topoisomerase II inhibitor; Protein kinase Cδ; Doxorubicin; Resistance; Isomerases; Cell death; Analog; Anthracyclins; Apoptosis
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1007/s10549-010-0956-2

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.