Targeting DRD2 by the antipsychotic drug, penfluridol, retards growth of renal cell carcinoma via inducing stemness inhibition and autophagy-mediated apoptosis

Abstract

Renal cell carcinoma (RCC) is one of the most lethal genitourinary malignancies with poor prognoses, since it is largely resistant to chemotherapy, radiotherapy, and targeted therapy. The persistence of cancer stem cells (CSCs) is the major cause of treatment failure with RCC. Recent evidence showed that dopamine receptor D2 (DRD2)-targeting antipsychotic drugs such as penfluridol exert oncostatic effects on several cancer types, but the effect of penfluridol on RCC remains unknown. Here, we uncovered penfluridol suppressed in vitro cell growth and in vivo tumorigenicity of various RCC cell lines (Caki-1, 786-O, A498, and ACHN) and enhanced the Sutent (sunitinib)-triggered growth inhibition on clear cell (cc)RCC cell lines. Mechanistically, upregulation of endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) was critical for autophagy-mediated apoptosis induced by penfluridol. Transcriptional inhibition of OCT4 and Nanog via inhibiting GLI1 was important for penfluridol-induced stemness and proliferation inhibition. The anticancer activities of penfluridol on ccRCC partially occurred through DRD2. In clinical ccRCC specimens, positive correlations of DRD2 with GLI1, OCT4, and Nanog were observed and their expressions were correlated with worse prognoses. Summarizing, DRD2 antagonists such as penfluridol induce UPR signaling and suppress the GLI1/OCT4/Nanog axis in ccRCC cells to reduce their growth through inducing autophagy-mediated apoptosis and stemness inhibition. These drugs can be repurposed as potential agents to treat ccRCC patients.

De novodrug design by iterative multiobjective deep reinforcement learning with graph-based molecular quality assessment

“…DRD2 (dopamine receptor type 2). DRD2 is an essential antipsychotic therapeutic target to treat schizophrenia, Parkinson’s disease, and psychotic disorders ( Beaulieu and Gainetdinov, 2011 ; Howes et al, 2012 ; Wang et al, 2018 ), and proved to exert oncostatic effects on several cancers ( Bakadlag et al, 2019 ; Tung et al, 2022 ). In this study, the DRD2 binding affinity of a molecule is estimated by a binary classification model which is trained to classify DRD2 binding molecules from non-binding molecules by fine-tuning the molecular QA model with binding affinity data of DRD2.…”

Drug Repurposing of Generic Drugs: Challenges and the Potential Role for Government

“…While generic drugs may be used to merely validate further screening for new chemical entities, they themselves may also be proposed for new therapeutic uses based on the screening. Examples of the therapeutic breadth of some of these proposals is shown in Table 1 [ 3 – 30 ]. However, nearly all of the proposals remain untested in the clinic, many for the reasons outlined in this article.…”

Dissecting the novel abilities of aripiprazole: The generation of anti-colorectal cancer effects by targeting Gαq via HTR2B

“…In recent years, antipsychotics that modulate dopamine D2 receptor (D2R) and 5-HTRs have potential anticancer activities 13 , 14 , 15 , and several epidemiological studies have shown lower rates of prostate and colorectal cancer in patients with schizophrenia who receive antipsychotics medications 16 , 17 . At present, first-generation antipsychotics, such as pentafluridol and thioridazine, exhibit surprising anticancer effects on malignant tumors, and it is suggested that the D2R might be the key target for antipsychotics against cancer 18 , 19 , 20 . Aripiprazole (Ari) is a representative drug of third-generation antipsychotics with remarkable regulatory ability to modulate the 5-HTR.…”