The enhanced antitumour response of pimozide combined with the IDO inhibitor L‑MT in melanoma

Abstract

Melanoma is one of the most fatal and therapy-resistant types of cancer; therefore, identifying novel therapeutic candidates to improve patient survival is an ongoing effort. Previous studies have revealed that pimozide is not sufficient to treat melanoma; therefore, enhancing the treatment is necessary. Indoleamine 2, 3-dioxygenase (IDO) is an immunosuppressive, intracellular rate-limiting enzyme, which contributes to immune tolerance in various tumours, including melanoma, and inhibition of IDO may be considered a novel therapeutic strategy when combined with pimozide. The present study aimed to assess the antitumour activities of pimozide in vitro, and to investigate the effects of pimozide combined with L-methyl-tryptophan (L-MT) in vivo. For in vitro analyses, the B16 melanoma cell line was used. Cell cytotoxicity assay, cell viability assay, wound-healing assay and western blotting were conducted to analyse the effects of pimozide on B16 cells. Furthermore, B16 cell-bearing mice were established as the animal model. Haematoxylin and eosin staining, immunohistochemistry, terminal deoxynucleotidyl transferase dUTP nick end-labelling staining, western blotting and flow cytometry were performed to determine the effects of monotherapy and pimozide and L-MT cotreatment on melanoma. The results demonstrated that pimozide exhibited potent antitumour activity via the regulation of proliferation, apoptosis and migration. Furthermore, the antitumour effects of pimozide were enhanced when combined with L-MT, not only via regulation of proliferation, apoptosis and migration, but also via immune modulation. Notably, pimozide may regulate tumour immunity through inhibiting the activities of signal transducer and activator of transcription (Stat)3 and Stat5. In conclusion, the present study proposed the use of pimozide in combination with the IDO inhibitor, L-MT, as a potential novel therapeutic strategy for the treatment of melanoma.

Inhibition of cancer stem cells promoted by Pimozide

“…Additionally, Pimozide has showed an anticancer effect on other types of cancer: melanoma, CNS tumours, osteosarcoma, neuroblastoma, myeloproliferative neoplasms, breast, lung, prostate, ovarian, colorectal, pancreatic and hepatocellular carcinoma . Although, patients with mental disorders such as schizophrenia are less likely to develop cancer than the general population, there are yet no reports about the cancer incidence specifically in Pimozide users.…”

“…Additionally, Krummel, Neifeld and Taub investigated the effects of this drug in murine melanomas and observed inhibition of 50% of the C‐leucine and H‐TdR incorporation without loss in cell viability or cell counting, which indicates proliferative activity in melanoma cells decreased. Jia et al observed antitumour activity of Pimozide in vitro using B16 melanoma cell line, and investigated its effect combined with L‐methyl‐tryptophan (L‐MT) in vivo . The author's results demonstrated that Pimozide is able to regulate the proliferation, apoptosis and migration.…”

“…The author's results demonstrated that Pimozide is able to regulate the proliferation, apoptosis and migration. Furthermore, regulation of tumour immunity was observed when combined with L‐MT …”

“…The Wnt/β-catenin signalling pathway has been reported for leading to EMT in many cancers. 56 TA B L E 1 Studies that evaluated Pimozide as a possible therapeutic target against cancer Taub and Baker (1979) 8 Melanoma Krummel, Neifeld and Taub (1982) 9 Neifeld et al (1983) 10 Jia et al (2018) 11 Strobl et al (1990) 12 Breast carcinoma…”

“…Pimozide, an orally active antipsychotic agent used to treat Tourette's syndrome, chronic psychosis, resistant phonic, and motor tics, has been widely indicated as a potential anticancer agent . All studies that used Pimozide as an anti‐tumour drug showed positive results, mainly against CSC, which are responsible for chemoresistance …”