The Orexin-A/OX1R System Induces Cell Death in Pancreatic Cancer Cells Resistant to Gemcitabine and Nab-Paclitaxel Treatment

Abstract

Pancreatic ductal adenocarcinoma (PDAC) represents the fourth cause of cancer-associated death in the West. This type of cancer has a very poor prognosis notably due to the development of chemoresistance when treatments including gemcitabine and Abraxane (Nab-paclitaxel) were prescribed. The identification of new treatment circumventing this chemoresistance represents a key challenge. Previous studies demonstrated that the activation of orexin receptor type 1 (OX1R), which was ectopically expressed in PDAC, by its natural ligand named orexin-A (OxA), led to anti-tumoral effect resulting in the activation of mitochondrial pro-apoptotic mechanism. Here, we demonstrated that OxA inhibited the pancreatic cancer cell (AsPC-1) growth and inhibited the tumor volume in preclinical models as effectively as gemcitabine and Nab-paclitaxel. Moreover, the combination therapy including OxA plus gemcitabine or OxA plus Nab-paclitaxel was additive on the inhibition of cancer cell growth and tumor development. More importantly, the treatment by OxA of chemoresistant tumors to gemcitabine or Nab-paclitaxel obtained by successive xenografts in mice revealed that OxA was able to induce a strong inhibition of tumor development, whereas no OxA resistance was identified in tumors. The OX1R/OxA system might be an innovative and powerful alternative treatment of chemoresistant PDAC.

Imaging flow cytometry of tumoroids: A new method for studying GPCR expression

“…A total of 5.10 4 cells/well in 24-well plates were treated with or without OxA or OxA-rhodamine B (OxA-rho) at different concentrations between 10 À9 and 10 À6 M as previously described [20]. After 48 h of treatment, cells were dissociated and cells excluding trypan blue were counted as described [20]. The results are expressed as the percentage of untreated cells.…”

“…This expression appeared in the continuum of tumor development ranging from precancerous lesions to invasive tumors and metastasis [11]. In contrast, OX1R was not present in normal epithelium adjacent to cancer [20]. In digestive cancer cells, OX1R activation by orexins induced a mitochondrial apoptosis mediated by the recruitment of the tyrosine phosphatase SHP2 [11].…”

“…In digestive cancer cells, OX1R activation by orexins induced a mitochondrial apoptosis mediated by the recruitment of the tyrosine phosphatase SHP2 [11]. This pro‐apoptotic properties of orexins in cancer cells were induced in a preclinical mouse model where cancer cells from colon or pancreas tumor cells were subcutaneously xenografted in mice, causing strong tumor regression [17, 20, 21]. These observations indicated that the orexins/OX1R system could represent a putative target in the treatment of digestive cancers [11].…”

The Orexin receptors: Structural and anti-tumoral properties

“…The OxA-dependent tumor volume reduction resulted of cell apoptosis in tumor as confirmed by histological analysis. It should be noted that OxA induced also anti-tumoral actions in xenografted tumors resistant to gemcitabine or NAB-paclitaxel which represent the “gold-standard” treatment of PDAC ( 86 ). As previously mentioned above, a lot of OX1R and OX2R antagonist were developed to treat insomnia, surprisingly, DORA compounds as almorexant and suvorexant were able to induce cell apoptosis in AsPC-1 cell line although these compounds antagonized the Ca 2+ release triggered by OxA ( 85 ).…”

Orexin‐A mediates glioblastoma proliferation inhibition by increasing ferroptosis triggered by unstable iron pools and GPX4 depletion

“…Orexin‐A exerts its effects by binding to orexin‐A receptor and activates a variety of downstream signalling pathways involved in anti‐inflammatory, neuroprotective and immune regulation 14–17 . Interestingly, a series of researches focused on the interaction of orexin‐A with tumours in recent years discovered that orexin‐A shows an exciting potential in the treatment of certain types of cancer 15,18–20 . Orexin‐A has been reported to play an antitumor role by inducing tumour cell apoptosis and enhancing antitumour immunity, and is considered as a promising antitumor drug 21 .…”