Insights into P-Glycoprotein Inhibitors: New Inducers of Immunogenic Cell Death.

Abstract

Doxorubicin is a strong inducer of immunogenic cell death (ICD), but it is ineffective in P-glycoprotein (Pgp)-expressing cells. Indeed, Pgp effluxes doxorubicin and impairs the immunesensitizing functions of calreticulin (CRT), an "eat-me" signal mediating ICD. It is unknown if classical Pgp inhibitors, designed to reverse chemoresistance, may restore ICD. We addressed this question by using Pgp-expressing cancer cells, treated with Tariquidar, a clinically approved Pgp inhibitor, and R-3 compound, a N,N-bis(alkanol)amine aryl ester derivative with the same potency of Tariquidar as Pgp inhibitor. In Pgp-expressing/doxorubicin-resistant cells, Tariquidar and R-3 increased doxorubicin accumulation and toxicity, reduced Pgp activity, and increased CRT translocation and ATP and HMGB1 release. Unexpectedly, only R-3 promoted phagocytosis by dendritic cells and activation of antitumor CD8+T-lymphocytes. Although Tariquidar did not alter the amount of Pgp present on cell surface, R-3 promoted Pgp internalization and ubiquitination, disrupting its interaction with CRT. Pgp knock-out restores doxorubicin-induced ICD in MDA-MB-231/DX cells that recapitulated the phenotype of R-3-treated cells. Our work demonstrates that plasma membrane-associated Pgp prevents a complete ICD notwithstanding the release of ATP and HMGB1, and the exposure of CRT. Pharmacological compounds reducing Pgp activity and amount may act as promising chemo- and immunesensitizing agents.

• Authors: Joanna Kopecka, Martina Godel, Silvia Dei, Roberta Giampietro, Dimas Carolina Belisario, Muhlis Akman, Marialessandra Contino, Elisabetta Teodori, Chiara Riganti
• Journal: Cells (Cells) Vol. 9 Issue 4 (04 22 2020) ISSN: 2073-4409 [Electronic] Switzerland
• PMID: 32331368 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Calreticulin
• Esters
• Quinolines
• Doxorubicin
• tariquidar

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (antagonists & inhibitors, metabolism)
• Apoptosis (drug effects)
• Calreticulin (metabolism)
• Cell Line, Tumor
• Doxorubicin (pharmacology)
• Drug Resistance, Neoplasm (drug effects)
• Endocytosis (drug effects)
• Esters (pharmacology)
• Humans
• Immunogenic Cell Death (drug effects)
• Kinetics
• Proteolysis (drug effects)
• Quinolines (pharmacology)
• Ubiquitination (drug effects)