chlorpromazine

P2/3, N=30, Recruiting, M.D. Anderson Cancer Center | Active, not recruiting --> Recruiting | N=11 --> 30

P1, N=32, Recruiting, Capital Medical University | Not yet recruiting --> Recruiting

We verify the structure using mutagenesis and confirm that the conformation corresponds to the active state of the receptor. Subsequent study of TrkB interaction with the antidepressant drug fluoxetine, and the antipsychotic drug chlorpromazine, provides a clear self-consistent model, describing the mechanism by which fluoxetine activates the receptor by binding to its transmembrane domain.

P1, N=32, Not yet recruiting, Capital Medical University

Previous studies have shown that chlorpromazine (CPZ) can inhibit YAP1 expression...Collectively, our findings indicate that FOXP3 competitively binds TEAD4 to regulate YAP1 localization in the nucleus and cytoplasm to suppress NPC progression. Consequently, FOXP3 may be a prognostic indicator for HNSCC.

P=N/A, N=338, Suspended, The Affiliated Hospital of Shandong Second Medical University; The Affiliated Hospital of Shandong Second Medical University | Not yet recruiting --> Suspended

P=N/A, N=1000, Not yet recruiting, Peking University Sixth Hospital; Peking University Sixth Hospital

P=N/A, N=200, Completed, Central South University | Recruiting --> Completed

Chlorpromazine potentiates the cytotoxic effects of the alkylating agent temozolomide through a mechanism involving downregulation of Cx43 expression and disruption of the cell cycle arrest essential for DNA repair processes. This finding suggests that chlorpromazine may be a potential therapeutic strategy to overcome TMZ resistance in GBM cells by inhibiting their DNA repair mechanisms.

P3, N=0, Withdrawn, Centre Hospitalier St Anne | N=40 --> 0 | Unknown status --> Withdrawn

P2/3, N=11, Active, not recruiting, M.D. Anderson Cancer Center | Enrolling by invitation --> Active, not recruiting | N=150 --> 11

These findings provide a foundation for the potential clinical application of CNS drugs in GBM treatment. Additionally, this work offers critical insights into the mechanisms and determinants of cytotoxicity for drugs currently undergoing clinical trials as repurposing agents for various cancers, including Fluoxetine, Sertraline, Thioridazine, Chlorpromazine, and Fluphenazine.

Taurine and COQ-10 alone notably improved the antioxidant/anti-inflammatory status relative to controls. Among other mechanisms, taurine and COQ-10 abated CPZ-induced hematological deficiencies, via decreased serum levels of oxidative stress, and pro-inflammatory cytokines release, with increased antioxidants and anti-inflammation function.

Based on our findings, a mechanism of cell death was not able to be established due to lack of cleaved caspase-3 expression. Capable of bypassing many aspects of the lengthy, costly, and difficult cancer drug approval process, chlorpromazine and prazosin deserve further investigation for use in conjunction with traditional chemotherapeutics.

Endocytosis inhibitors identified that Monensin and Chlorpromazine hydrochloride significantly reduced MM-ZC internalization...Overall, the current study provides valuable insights into the cellular uptake and intracellular trafficking of MM-ZC in myeloma cells. Identifying these mechanisms and molecular players involved in MM-ZC uptake contributes to a better understanding of the delivery and potential applications of cell-specific Zip-Codes in gene delivery and drug targeting in cancer research.

In this phase II clinical trial, we evaluated the addition of chlorpromazine to temozolomide in the adjuvant phase of the standard first-line therapeutic protocol in patients with unmethylated MGMT gene promoter. These findings provide proof-of-concept for the potential of adding CPZ to standard TMZ treatment in GBM patients with unmethylated MGMT gene promoter. https://clinicaltrials.gov/study/NCT04224441, identifier NCT04224441.

P1, N=70, Completed, Whanin Pharmaceutical Company | .

6,9). The addition of Chlorpromazine to temozolomide was well tolerated in newly diagnosed Glioblastoma unmethylated patients, with promising impact on outcome measures.

The combined treatment of C + P plays a crucial role in stroke therapy by inhibiting ER stress-mediated autophagy, thereby leading to reduced apoptosis and increased neuroprotection. Our findings highlight the PERK-eIF2α pathway as a central mechanism through which C + P exerts its beneficial effects. The results from this study may pave the way for the development of more targeted and effective treatments for stroke patients.

P2/3, N=70, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Jun 2023 --> Jun 2025

P1, N=15, Recruiting, Mohammed Milhem | Trial completion date: Jun 2025 --> Jul 2024 | Trial primary completion date: Jun 2023 --> Jul 2024

Despite current treatment options such as surgery, radiotherapy, and the use of temozolomide and bevacizumab, it is considered incurable...Typical antipsychotics include chlorpromazine, trifluoperazine, and pimozide...Olanzapine and Quetiapine are examples of atypical antipsychotics, a category that was created later...These include NF-B suppression, cyclin deregulation, and -catenin phosphorylation, among others. This review will delve deeper into the polypharmacological, the multiple effects of antipsychotics in the treatment of GBM, and an outlook for the field's future progression.

In this study, the antipsychotic drug chlorpromazine was characterized as an LSD1 inhibitor (IC = 5.135 μM), and a series of chlorpromazine derivatives were synthesized...An in vivo study confirmed that compound 3s can inhibit MFC cell proliferation without significant toxicity in immunocompetent mice. Taken together, our findings indicated that the novel LSD1 inhibitor 3s tethering a phenothiazine scaffold may serve as a lead compound for further development to activate T-cell immunity in gastric cancer.

CPZ is administered orally at a dose of 50 mg/day – GG 1-28 – of every cycle of the adjuvant treatment with TMZ. At present, 53 patients out of 60 patients planned have been enrolled, without relevant toxicity.

When utilized in combination with trametinib (a MEK inhibitor), dabrafenib (an RAF inhibitor), and everolimus (an mTOR inhibitor), CPZ suppressed the growth of PC9ZD cells cooperatively with everolimus but not with trametinib or dabrafenib. However, after CPZ treatment, EGFR was unevenly distributed in the cells, and colocalization with the early endosome marker Rab5 and EEA1 became more apparent, indicating that CPZ disrupted the intracellular transport of EGFR. These results suggest that CPZ has therapeutic potential for NSCLC with mutated EGFR by a novel mechanism different from conventional TKIs alone or in combination with other agents.

CPZ is administered orally at a dose of 50 mg/day – GG 1-28 – of every cycle of the adjuvant treatment with TMZ. At present, 38 patients out of 41 patients planned have been enrolled.

These findings indicated that repurposing CPZ is a novel treatment strategy for CRC patients.

Relative to wildtype MCF10A cells, CDH1 MCF10A cells showed significantly greater sensitivity to several drugs targeting these processes, including the autophagy inhibitor chloroquine, the endocytosis inhibitors chlorpromazine and PP1, and the sphingosine kinase 1 inhibitor PF-543. Synthetic lethality was confirmed in both gastric and mammary organoid models of CDH1 loss, derived from CD44-Cre/Cdh1/tdTomato mice. Collectively, these results suggest that both sphingolipid metabolism and vesicle trafficking represent previously unrecognised druggable vulnerabilities in CDH1-null cells and may lead to the development of new therapies for HDGC.

CPZ is administered orally at a dose of 50 mg/day – GG 1-28 – of every cycle of the adjuvant treatment with TMZ. At present, 28 patients out of 41 patients planned have been enrolled, without relevant toxicity.

This discrepancy could be central in explaining the lethal effects of the drug on GBM cells and the relatively scarce cytotoxicity toward normal tissues attributed to this compound. The data presented here offer support to the multicenter phase II clinical trial we have undertaken, which consists of the addition of CPZ to first-line treatment of GBM patients carrying a hypo- or un-methylated MGMT gene, i.e. those characterized by intrinsic resistance to temozolomide.

There was a similar increase in protein levels of P21, P27 and SIPR2 in OCI-LY3 and TMD8 cells after 24 hours of treatment (P<0.05) . Chlorpromazine hydrochloride at a specific concentration may inhibit the proliferation of ABC diffuse large B lymphoma cells by promoting the expression of S1PR2, and promote cell apoptosis and G1 phase cell cycle arrest.

Moreover, the colocalization of LC3 with lysosomal-associated membrane protein 1 (LAMP1), a lysosome marker, was also suppressed after TFP treatment, suggesting that TFP might block the fusion of autophagosomes with lysosomes, which led to autophagosome accumulation. Taken together, our data highlight the potential of repurposing TFP as a new adjuvant drug for treating melanoma patients with brain, lung, and bone metastases.

Mechanistically, CPZ reduces CALM protein at post transcriptional level and perturbs the intracellular localization of MT-RTKs, thereby blocking their signaling. Our study presents a therapeutic strategy for AML with MT-RTKs by altering the intracellular localization of MT-RTKs using CPZ.

In vitro, human islets and βTC3 cells were stimulated with cytokines in the presence or absence of chlorpromazine (CPZ), a drug that disrupts clathrin-mediated endocytosis... Our results suggest that AAT is internalized by β cells through clathrin-mediated endocytosis that leads to the suppression of caspase 9 activation. This process is required for the protective function of AAT in islets when challenged with proinflammatory cytokines or after islet transplantation.

This study showed an inhibitory effect of C+P on brain inflammation, which may be partially dependent on drug-induced hibernation, as well as other mechanisms of action by these drugs. These findings further suggest the great potential of C+P in the clinical treatment of ischemic stroke.

Cells devoid of MARCKS function showed incomplete ABCB1 internalization, leading to higher ABCB1 activity enhancing chemoresistance. Vice versa our data suggest the prevention of MARCKS inhibition by reversing hyperphosphorylation or genomic restoration after deletion as two promising approaches to overcome tumor cell resistance towards chemotherapeutic ABCB1 substrates.

It was also implied that chlorpromazine (CPZ) can inhibit the malignant traits of GC and downregulate the expression of PELP1. In a word, PELP1 is an oncogene in gastric cancer and c-Src-PI3K-ERK pathway activation may be responsible for its tumorigenesis, PELP1 may be a potential therapeutic target of chlorpromazine in GC.