Anti-tumor Effects of Penfluridol through Dysregulation of Cholesterol Homeostasis

Wu, Lu; Liu, Yanyang; Li, Zhixi; Zhao, Qian; Wang, Xia; Yu, Yang; Wang, Yuyi; Wang, Yiqin; Luo, Feng

doi:10.7314/apjcp.2014.15.1.489

Cited by 30 publications

(21 citation statements)

References 24 publications

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“…al. , did not observe any statistically significant 4T1 tumor growth suppression with an oral dose of 0.06–0.12 mg/week/mouse (3–6 mg/kg/week) PF in mice (21). Interestingly, our results showed significant tumor growth suppression in all the three in vivo models by 10mg/kg PF administration every day by oral gavage.…”

Section: Discussionmentioning

confidence: 87%

“…al. recently have the shown the anti-cancer effects of PF by modulating cholesterol homeostasis (21). The study showed that IC 50 of PF was between 2–4µM after 48h treatment in B16/F10, LL/2, 4T1 and CT26 cells.…”

Section: Discussionmentioning

confidence: 99%

“…Penfluridol (PF) is an oral anti-psychotic drug available since 1970 for the treatment of schizophrenia (20). Limited studies indicate that PF exhibits anti-cancer activity however, mechanism of the anti-cancer effect of PF is not known (21). …”

Section: Introductionmentioning

confidence: 99%

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Penfluridol: An Antipsychotic Agent Suppresses Metastatic Tumor Growth in Triple-Negative Breast Cancer by Inhibiting Integrin Signaling Axis

2016

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Metastasis of breast cancer, especially to the brain, is the major cause of mortality. The inability of anti-cancer agents to cross the blood-brain-barrier represents a critical challenge for successful treatment. In the current study, we investigated the anti-metastatic potential of penfluridol (PF), an antipsychotic drug frequently prescribed for schizophrenia with anti-cancer activity. We show that PF induced apoptosis and reduced the survival of several metastatic triple negative breast cancer (TNBC) cell lines. Additionally, PF treatment significantly reduced the expression of integrinα6, integrin β4, Fak, Paxillin, Rac1/2/3, and ROCK1 in vitro. We further evaluated the efficacy of PF in three different in vivo tumor models. We demonstrate that PF administration to an orthotopic model of breast cancer suppressed tumor growth by 49%. On the other hand, PF treatment inhibited the growth of metastatic brain tumors introduced by intracardiac or intracranial injection of breast cancer cells by 90% and 72%, respectively. PF-treated tumors from all three models exhibited reduced integrinβ4 and increased apoptosis. Moreover, chronic administration of PF failed to elicit significant toxic or behavioral side effects in mice. Taken together, our result indicate that PF effectively reduces the growth of primary TNBC tumors and especially metastatic growth in the brain by inhibiting integrin signaling, and prompt further preclinical investigation into repurposing PF for the treatment of metastatic TNBC.

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

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Penfluridol: An Antipsychotic Agent Suppresses Metastatic Tumor Growth in Triple-Negative Breast Cancer by Inhibiting Integrin Signaling Axis

2016

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“…23 According to an in vitro study conducted at University of New South Wales, pimozide inhibits lung, breast, and brain cancer. In our previous study, we have established the anti-cancer effects of penfluridol against breast cancer and its metastasis to brain through inhibition of integrin signaling, whereas Wu et al 24 observed dysregulation of cholesterol homeostasis by penfluridol in breast cancer. 17 ER plays critical role in synthesis and secretion of transmembrane and secretary proteins.…”

Section: Discussionmentioning

confidence: 99%

Penfluridol induces endoplasmic reticulum stress leading to autophagy in pancreatic cancer

et al. 2017

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Pancreatic cancer is one of the most aggressive and difficult to treat cancers. Experimental and clinical evidence suggests that high basal state autophagy in pancreatic tumors could induce resistance to chemotherapy. Recently, we have demonstrated that penfluridol suppresses pancreatic tumor growth by autophagy-mediated apoptosis both in vitro and in vivo; however, the mechanism of autophagy induction by penfluridol was not clear. Several studies have established that endoplasmic reticulum stress could lead to autophagy and inhibit tumor progression. In this study, we demonstrated that penfluridol induced endoplasmic reticulum stress in BxPC-3, AsPC-1, and Panc-1 pancreatic cancer cell lines as indicated by upregulation of endoplasmic reticulum stress markers such as binding protein (BIP), C/EBP homologous protein (CHOP) and inositol requiring 1α (IRE1α) after treatment with penfluridol in a concentration-dependent manner. Inhibiting endoplasmic reticulum stress by pretreatment with pharmacological inhibitors such as sodium phenylbutyrate and mithramycin or by silencing CHOP using CHOP small interfering RNA, blocked penfluridol-induced autophagy. These results clearly indicate that penfluridol-induced endoplasmic reticulum stress lead to autophagy in our model. Western blot analysis of subcutaneously implanted AsPC-1 and BxPC-3 tumors as well as orthotopically implanted Panc-1 tumors demonstrated upregulation of BIP, CHOP, and IRE1α expression in the tumor lysates from penfluridol-treated mice as compared to tumors from control mice. Altogether, our study establishes that penfluridol-induced endoplasmic reticulum stress leads to autophagy resulting in reduced pancreatic tumor growth. Our study opens a new therapeutic target for advanced chemotherapies against pancreatic cancer.

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“…The Rhizophara apiculata extract can inhibit the lung metastasis and tumor masses of B16F10 melanoma cells in C57BL/6 mice (Prabhu and Guruvayoorappan, 2013). Besides, the Penfluridol (C28H27CIF5NO) also can inhibit growth of B16F10 melanoma cells through dysregulation of cholesterol homeostasis in vitro and in vivo (Wu et al, 2014). But the inhibition effect and mechanism of polysaccharide substance on cancer has not been investigated clearly and there are two reports about the inhibition mechanism of Barbigerone (Yang et al, 2014) and Hepatocellular Carcinoma Vaccine (Su et al, 2013).…”

Section: Different Immunology Mechanisms Of Phellinus Igniarius In Inmentioning

confidence: 99%

Different Immunology Mechanisms of Phellinus igniarius in Inhibiting Growth of Liver Cancer and Melanoma Cells

Zhou

Jiang²,

Wang³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Anti-tumor Effects of Penfluridol through Dysregulation of Cholesterol Homeostasis

Cited by 30 publications

References 24 publications

Penfluridol: An Antipsychotic Agent Suppresses Metastatic Tumor Growth in Triple-Negative Breast Cancer by Inhibiting Integrin Signaling Axis

Penfluridol: An Antipsychotic Agent Suppresses Metastatic Tumor Growth in Triple-Negative Breast Cancer by Inhibiting Integrin Signaling Axis

Penfluridol induces endoplasmic reticulum stress leading to autophagy in pancreatic cancer

Different Immunology Mechanisms of Phellinus igniarius in Inhibiting Growth of Liver Cancer and Melanoma Cells

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