Pimozide augments bromocriptine lethality in prolactinoma cells and in a xenograft model via the STAT5/cyclin D1 and STAT5/Bcl‑xL signaling pathways

Abstract

As hyperprolactinemia is observed in patients with bromocriptine-resistant prolactinoma, prolactin (PRL) has been implicated in the development of bromocriptine resistance. Since PRL primarily mediates cell survival and drug resistance via the Janus kinase-2 (JAK2)/signal transducer and activator of transcription 5A (STAT5) signaling pathway, the STAT5 inhibitor, pimozide, may inhibit cell proliferation and reverse bromocriptine resistance in prolactinoma cells. In the present study, compared with bromocriptine or pimozide alone, the combination of pimozide and bromocriptine exerted enhanced reduction in cell growth and proliferation, and increased apoptosis and cell cycle arrest in bromocriptine-resistant prolactinoma cells. A reduction in phospho-STAT5, cyclin d1 and B-cell lymphoma extra-large (Bcl-xL) expression levels were observed in cells treated with the combination of drugs. In addition, pimozide suppressed spheroid formation of human pituitary adenoma stem-like cells, and reduced the protein expression of the cancer stem cell markers, cd133 and nestin. Pimozide did not exert any additional antitumor activity in STAT5-knockdown primary culture cells of human bromocriptine-resistant prolactinomas. Furthermore, Pimozide combined with bromocriptine treatment significantly reduced human prolactinoma xenograft growth. Western blot and immunohistochemical analyses also demonstrated significant inhibition of cell proliferation and stem cell marker proteins in vivo. collectively, these data indicated that pimozide treatment reduced prolactinoma growth by targeting both proliferating cells and stem cells, at least in part, by inhibiting the STAT5/Bcl-xL and STAT5/cyclin d1 signaling pathways.

The JAK/STAT signaling pathway: from bench to clinic

“…504 Pimozide treatment reduced prolactinoma growth and increased apoptosis and cell cycle arrest in bromocriptine-resistant prolactinoma via the inhibition of the STAT5/Bcl-xL and STAT5/cyclin D1 pathway. 505 There are several other molecules that inhibit STAT5 or STAT6, such as chromone-derived nicotinylhydrazone, BP-1108, BP-1075, leflunomide, and niflumic acid.…”

STAT5a Confers Doxorubicin Resistance to Breast Cancer by Regulating ABCB1

“…In breast cancer, pimozide has also been proven to promote apoptosis by inhibiting RAN GTPase and AKT and to inhibit epithelial-mesenchymal transition and cell migration (45). Pimozide also acts as a STAT5 inhibitor (46) or STAT3 inhibitor (47) to kill breast cancer cells or sensitize cancer cells to other drugs (48). Additionally, pimozide was found to inhibit ABCB1 in drug-resistant KBV20C oral cancer cells, but the authors did not explain the mechanism (49).…”

Repurposing Antipsychotics for Cancer Treatment

“…Additionally, pimozide has been found to inhibit the in vitro phosphorylation of STAT5 in BCR-ABL positive and pSTAT5 overexpressing K562 chronic lymphocytic leukemia (CLL) cell lines [ 64 , 65 ], as well as in mice models with acute myeloid leukemia that contain the FLT3 internal tandem duplication (ITD) mutation [ 66 ]. A similar anti-cancer effect mediated by the inhibition of STAT5 phosphorylation was observed in Rat prolactinoma MMQ cells through inhibition of the STAT5/Bcl-xL and STAT5/cyclin D1 signaling pathways, in peripheral T-lymphoma through induction of the TRAIL/DR4-dependent apoptosis [ 67 ], and in osteosarcoma cells through inhibition of the proliferation of osteosarcoma stem cells [ 68 ]. Finally, Fako et al found that haloperidol inhibits the in vitro growth of hepatocellular carcinoma Hep3B and HepG2 cell lines through impairment of the Wnt/β-catenin signaling pathway and its downstream molecules, including EpCAM, which is involved in cancer cell stemness [ 69 ].…”