Zoledronic acid restores doxorubicin chemosensitivity and immunogenic cell death in multidrug-resistant human cancer cells.

Abstract

Durable tumor cell eradication by chemotherapy is challenged by the development of multidrug-resistance (MDR) and the failure to induce immunogenic cell death. The aim of this work was to investigate whether MDR and immunogenic cell death share a common biochemical pathway eventually amenable to therapeutic intervention. We found that mevalonate pathway activity, Ras and RhoA protein isoprenylation, Ras- and RhoA-downstream signalling pathway activities, Hypoxia Inducible Factor-1alpha activation were significantly higher in MDR+ compared with MDR- human cancer cells, leading to increased P-glycoprotein expression, and protection from doxorubicin-induced cytotoxicity and immunogenic cell death. Zoledronic acid, a potent aminobisphosphonate targeting the mevalonate pathway, interrupted Ras- and RhoA-dependent downstream signalling pathways, abrogated the Hypoxia Inducible Factor-1alpha-driven P-glycoprotein expression, and restored doxorubicin-induced cytotoxicity and immunogenic cell death in MDR+ cells. Immunogenic cell death recovery was documented by the ability of dendritic cells to phagocytise MDR+ cells treated with zoledronic acid plus doxorubicin, and to recruit anti-tumor cytotoxic CD8+ T lymphocytes. These data indicate that MDR+ cells have an hyper-active mevalonate pathway which is targetable with zoledronic acid to antagonize their ability to withstand chemotherapy-induced cytotoxicity and escape immunogenic cell death.

• Authors: Chiara Riganti, Barbara Castella, Joanna Kopecka, Ivana Campia, Marta Coscia, Gianpiero Pescarmona, Amalia Bosia, Dario Ghigo, Massimo Massaia
• Journal: PloS one (PLoS One) Vol. 8 Issue 4 Pg. e60975 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23593363 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Retracted Publication)

Chemical References

• ABCB1 protein, human
• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Diphosphonates
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Imidazoles
• Protein Kinase Inhibitors
• Terpenes
• Zoledronic Acid
• Doxorubicin
• Cholesterol
• rho-Associated Kinases
• Extracellular Signal-Regulated MAP Kinases
• ras Proteins
• Mevalonic Acid

Topics

• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily B, Member 1 (metabolism)
• CD8-Positive T-Lymphocytes (drug effects, metabolism)
• Cell Death (drug effects, immunology)
• Cell Line, Tumor
• Cholesterol (biosynthesis)
• Dendritic Cells (drug effects, metabolism)
• Diphosphonates (pharmacology)
• Down-Regulation (drug effects)
• Doxorubicin (pharmacology)
• Drug Resistance, Multiple (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Drug Screening Assays, Antitumor
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Imidazoles (pharmacology)
• Mevalonic Acid (metabolism)
• Models, Biological
• Phagocytosis (drug effects)
• Prenylation (drug effects)
• Protein Kinase Inhibitors (pharmacology)
• Signal Transduction (drug effects)
• Terpenes (metabolism)
• Zoledronic Acid
• ras Proteins (metabolism)
• rho-Associated Kinases (metabolism)