Chlorpromazine HCl

Chlorpromazine HCl is an orally effective, blood-brain-permeable phenothiazine antipsychotic that can effectively antagonize D2 dopamine receptors and 5-HT_2A and has a strong sedative effect^{[1, 2]}. Chlorpromazine HCl has anticancer activities, including anti-proliferation, induction of cell autophagy and cell cycle arrest, inhibition of cytochrome c oxidase, inhibition of tumor growth and metastasis, and inhibition of tumor immune escape^[3]. Chlorpromazine HCl can block hNa_v1.7 channels and hERG potassium channels^{[4, 5]}.

In vitro, treatment of U-87MG cells with Chlorpromazine HCl (10-40μM) for 24h and 48h reduced cell viability, cell proliferation, and intracellular cyclin A and cyclin B1 levels in a dose- and time-dependent manner^[6]. Chlorpromazine HCl (10μM) treatment of mouse bone marrow cells for 1h significantly inhibited the internalization of small extracellular vesicles (sEVs) and significantly reduced the number of myeloid-derived suppressor cells (MDSCs)^[7].

In vivo, Chlorpromazine HCl (20mg/kg) was intraperitoneally injected into U-87MG glioma cell xenograft mice for 24 days and significantly inhibited tumor growth, with a tumor growth inhibition rate of 43.5% on day 24^[6].

References:
[1] Asano T, Tanaka K, Tada A, et al. Ameliorative effect of chlorpromazine hydrochloride on visceral hypersensitivity in rats: possible involvement of 5‐HT2A receptor[J]. British Journal of Pharmacology, 2017, 174(19): 3370-3381.
[2] Suzuki H, Gen K, Inoue Y. Comparison of the anti-dopamine D2 and anti-serotonin 5-HT2A activities of chlorpromazine, bromperidol, haloperidol and second-generation antipsychotics parent compounds and metabolites thereof[J]. Journal of Psychopharmacology, 2013, 27(4): 396-400.
[3] Kamgar-Dayhoff P, Brelidze T I. Multifaceted effect of chlorpromazine in cancer: Implications for cancer treatment[J]. Oncotarget, 2021, 12(14): 1406.
[4] Lee S J, Kim D H, Hahn S J, et al. Mechanism of inhibition by chlorpromazine of the human pain threshold sodium channel, Nav1. 7[J]. Neuroscience Letters, 2017, 639: 1-7.
[5] Thomas D, Wu K, Kathöfer S, et al. The antipsychotic drug chlorpromazine inhibits HERG potassium channels[J]. British journal of pharmacology, 2003, 139(3): 567-574.
[6] Shin S Y, Lee K S, Choi Y K, et al. The antipsychotic agent chlorpromazine induces autophagic cell death by inhibiting the Akt/mTOR pathway in human U-87MG glioma cells[J]. Carcinogenesis, 2013, 34(9): 2080-2089.
[7] Yang Z, Huo Y, Zhou S, et al. Cancer cell-intrinsic XBP1 drives immunosuppressive reprogramming of intratumoral myeloid cells by promoting cholesterol production[J]. Cell Metabolism, 2022, 34(12): 2018-2035. e8.

Chlorpromazine HCl是一种口服有效的、可透过血脑屏障的吩噻嗪类抗精神病药，能够有效抑制D2多巴胺受体和5-HT_2A，具有很强的镇静作用^{[1, 2]}。Chlorpromazine HCl具有抗癌活性，包括抗增殖、诱导细胞自噬和周期停滞、抑制细胞色素c氧化酶、抑制肿瘤生长和转移以及抑制肿瘤免疫逃逸等^[3]。Chlorpromazine HCl能够阻断hNa_v1.7通道和hERG钾通道^{[4, 5]}。

在体外，Chlorpromazine HCl（10-40μM）处理U-87MG细胞24h和48h，以剂量和时间依赖性方式降低了细胞活力，减少了细胞增殖， 降低了细胞内细胞周期蛋白A和细胞周期蛋白B1的水平^[6]。Chlorpromazine HCl（10μM）处理小鼠骨髓细胞1h，显著抑制了小细胞外囊泡（sEV）内化，显著减少了骨髓源性抑制细胞（MDSC）数量^[7]。

在体内，Chlorpromazine HCl（20mg/kg）通过腹腔注射治疗U-87MG胶质瘤细胞异种移植小鼠24天，显著抑制了肿瘤的生长，第24天的肿瘤生长抑制率为 43.5%^[6]。