Oleandrin, a cardiac glycoside, induces immunogenic cell death via the PERK/elF2α/ATF4/CHOP pathway in breast cancer

Abstract

Chemotherapeutic agents have been linked to immunogenic cell death (ICD) induction that is capable of augmenting anti-tumor immune surveillance. The cardiac glycoside oleandrin, which inhibits Na+/K+-ATPase pump (NKP), has been shown to suppress breast cancer growth via inducing apoptosis. In the present study, we showed that oleandrin treatment triggered breast cancer cell ICD by inducing calreticulin (CRT) exposure on cell surface and the release of high-mobility group protein B1 (HMGB1), heat shock protein 70/90 (HSP70/90), and adenosine triphosphate (ATP). The maturation and activation of dendritic cells (DCs) were increased by co-culturing with the oleandrin-treated cancer cells, which subsequently enhanced CD8+ T cell cytotoxicity. Murine breast cancer cell line EMT6 was engrafted into BALB/c mice, and tumor-bearing mice were administered with oleandrin intraperitoneally every day. Oleandrin inhibited tumor growth and increased tumor infiltrating lymphocytes including DCs and T cells. Furthermore, the differential mRNA expression incurred by oleandrin was investigated by mRNA sequencing and subsequently confirmed by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. Mechanistically, oleandrin induced endoplasmic reticulum (ER) stress-associated, caspase-independent ICD mainly through PERK/elF2α/ATF4/CHOP pathway. Pharmacological and genetic inhibition of protein kinase R-like ER kinase (PERK) suppressed oleandrin-triggered ICD. Taken together, our findings showed that oleandrin triggered ER stress and induced ICD-mediated immune destruction of breast cancer cells. Oleandrin combined with immune checkpoint inhibitors might improve the efficacy of immunotherapy.

The Botanical Drug PBI-05204, a Supercritical CO2 Extract of Nerium Oleander, Is Synergistic With Radiotherapy in Models of Human Glioblastoma

“…Both PBI-05204 and its active principal ingredient, oleandrin, have been tested in GBM models ( Colapietro et al, 2020a ) and, in addition, have also been shown to be active against a wide number of human tumor cell types such as melanoma ( Lin et al, 2008 ), prostate ( Smith et al, 2001 ), pancreas ( Pan et al, 2015 ), and breast ( Li et al, 2021 ) cancers as well as certain hematologic malignancies. The botanical drug PBI-05204 has gone through both Phase I and II clinical trials in cancer patients and has been shown to be safe as an oral drug for daily administration ( Hong et al, 2014 ; Roth et al, 2020 ).…”

Targeting HMGB1: An available Therapeutic Strategy for Breast Cancer Therapy

“…More importantly, HMGB1 participates in the regulation of chemo- and radiotherapy resistance in breast cancer 9 , 16 , 17 . Due to the complexity of HMGB1 functions in breast cancer progression, new therapeutic strategies targeting HMGB1 are constantly being developed, such as the identification of potential ICD inducers and the combination therapies with immune checkpoint blockade 18 - 20 .…”

Immunogenic ferroptosis and where to find it?

“… 55 Also, CRT expression at the membrane was observed after an hour of necroptosis induction. In strong contrast, in apoptotic MCF7 cells, ATP and HMGB1 release peaked only after 12 and 48 hours, respectively, 56 and membrane CRT expression was observed only after 10 hours. Despite these differences, both cell death modalities have been shown to be immunogenic in nature.…”