Zoledronic Acid Restores Doxorubicin Chemosensitivity and Immunogenic Cell Death in Multidrug-Resistant Human Cancer Cells

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 MDR2 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 chemotherapyinduced
cytotoxicity and escape immunogenic cell death.