Penfluridol Represses Integrin Expression in Breast Cancer through Induction of Reactive Oxygen Species and Downregulation of Sp Transcription Factors

Hedrick, Erik; Li, Xi; Safe, Stephen

doi:10.1158/1535-7163.mct-16-0451

Cited by 52 publications

(43 citation statements)

References 44 publications

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“…Repression of integrins with penfluridol treatment in breast cancer was also shown through reactive oxygen species and Sp transcription factors in a very recent study [16]. It has been reported by several published studies that GLI1 regulates integrins in different cancer models [17, 18].…”

Section: Discussionmentioning

confidence: 91%

Penfluridol suppresses glioblastoma tumor growth by Akt-mediated inhibition of GLI1

Ranjan

Srivastava

2017

Oncotarget

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Glioblastoma (GBM) is the most common brain tumor with poor survival rate. Our results show that penfluridol, an antipsychotic drug significantly reduced the survival of ten adult and pediatric glioblastoma cell lines with IC50 ranging 2–5 μM after 72 hours of treatment and induced apoptosis. Penfluridol treatment suppressed the phosphorylation of Akt at Ser473 and reduced the expression of GLI1, OCT4, Nanog and Sox2 in several glioblastoma cell lines in a concentration-dependent manner. Inhibiting Akt with LY294002 and siRNA, or inhibiting GLI1 using GANT61, cyclopamine, siRNA and CRISPR/Cas9 resulted in enhanced cell growth suppressive effects of penfluridol. On the other hand, overexpression of GLI1 significantly attenuated the effects of penfluridol. Our results further demonstrated that penfluridol treatment inhibited the growth of U87MG tumors by 65% and 72% in subcutaneous and intracranial in vivo glioblastoma tumor models respectively. Immunohistochemical and western blot analysis of tumors revealed reduced pAkt (Ser 473), GLI1, OCT4 and increase in caspase-3 cleavage and TUNEL staining, confirming in vitro findings. Taken together, our results indicate that overall glioblastoma tumor growth suppression by penfluridol was associated with Akt-mediated inhibition of GLI1.

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Section: Discussionmentioning

confidence: 91%

Penfluridol suppresses glioblastoma tumor growth by Akt-mediated inhibition of GLI1

Ranjan

Srivastava

2017

Oncotarget

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“…Penfluridol is a long acting oral antipsychotic agent for schizophrenia treatment, widely used in the clinic since 1970 [46]. It has been recently demonstrated to have potent anti-cancer activity for breast cancer [27,30,47], pancreatic cancer [28,48] and glioblastoma [29,49]. A series of characteristics of this drug, such as its in vivo stability, allowing weekly administration to schizophrenia patients, the high potency to cross the blood-brain-barrier, and the anticancer activity, highlight the potential for repurposing this drug for cancer treatment.…”

Section: Discussionmentioning

confidence: 99%

“…Penfluridol is a potent, long-acting oral antipsychotic drug long used for schizophrenia, acute psychosis, and Tourette syndrome [23][24][25][26]. Our previous studies have shown the anti-cancer efficacy of penfluridol against breast, brain, and pancreatic carcinoma [27][28][29][30]. However, there is no study on the effect of penfluridol on the tumor vascular microenvironment, especially in clinically relevant doses prescribed for schizophrenia and other psychotic disorders.…”

Section: Introductionmentioning

confidence: 99%

Low Dose of Penfluridol Inhibits VEGF-Induced Angiogenesis

Srivastava

Zahra

Gupta

et al. 2020

IJMS

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Metastasis is considered a major burden in cancer, being responsible for more than 90% of cancer-related deaths. Tumor angiogenesis is one of the main processes that lead to tumor metastasis. Penfluridol is a classic and commonly used antipsychotic drug, which has a great ability to cross the blood–brain barrier. Recent studies have revealed that penfluridol has significant anti-cancer activity in diverse tumors, such as metastatic breast cancer and glioblastoma. Here, we aim to identify the effect of low doses of penfluridol on tumor microenvironment and compare it with its effect on tumor cells. Although low concentration of penfluridol was not toxic for endothelial cells, it blocked angiogenesis in vitro and in vivo. In vitro, penfluridol inhibited VEGF-induced primary endothelial cell migration and tube formation, and in vivo, it blocked VEGF- and FGF-induced angiogenesis in the matrigel plug assay. VEGF-induced VEGFR2 phosphorylation and the downstream p38 and ERK signaling pathways were not affected in endothelial cells, although VEGF-induced Src and Akt activation were abrogated by penfluridol treatment. When cancer cells were treated with the same low concentration of penfluridol, basal Src activation levels were mildly impaired, thus impacting their cell migration and wound healing efficiency. The potential of cancer-induced paracrine effect on endothelial cells was explored, although that did not seem to be a player for angiogenesis. Overall, our data demonstrates that low penfluridol levels, similar to the ones clinically used for anti-psychotic conditions, suppress angiogenic efficiency in the tumor microenvironment.

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“…Interaction between the long non-coding RNA ZFAS1 and miR-150-5p suppresses the expression of Sp1 in epithelial OC cells [95]. An antipsychotic drug, penfluridol, is currently used as an anti-cancer drug since it can downregulate the TFs like Sp1, Sp3, and Sp4 [96]. It was found that penfluridol inhibits cancer cell growth by suppressing expressions of α6and β4-integrins, primarily regulated by the Sp1 along with orphan nuclear receptor 4A1 (NR4A1) [97].…”

Section: Sp1 As a Therapeutic Target In Ocmentioning

confidence: 99%

Understanding the Role of the Transcription Factor Sp1 in Ovarian Cancer: from Theory to Practice

Vellingiri

Iyer

Subramaniam

et al. 2020

IJMS

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Ovarian cancer (OC) is one of the deadliest cancers among women contributing to high risk of mortality, mainly owing to delayed detection. There is no specific biomarker for its detection in early stages. However, recent findings show that over-expression of specificity protein 1 (Sp1) is involved in many OC cases. The ubiquitous transcription of Sp1 apparently mediates the maintenance of normal and cancerous biological processes such as cell growth, differentiation, angiogenesis, apoptosis, cellular reprogramming and tumorigenesis. Sp1 exerts its effects on cellular genes containing putative GC-rich Sp1-binding site in their promoters. A better understanding of the mechanisms underlying Sp1 transcription factor (TF) regulation and functions in OC tumorigenesis could help identify novel prognostic markers, to target cancer stem cells (CSCs) by following cellular reprogramming and enable the development of novel therapies for future generations. In this review, we address the structure, function, and biology of Sp1 in normal and cancer cells, underpinning the involvement of Sp1 in OC tumorigenesis. In addition, we have highlighted the influence of Sp1 TF in cellular reprogramming of iPSCs and how it plays a role in controlling CSCs. This review highlights the drugs targeting Sp1 and their action on cancer cells. In conclusion, we predict that research in this direction will be highly beneficial for OC treatment, and chemotherapeutic drugs targeting Sp1 will emerge as a promising therapy for OC. common reproductive cancer among women in India [2]. Although OC is a single disease, its clinical pathway is mostly intercalated by other tumor types having different prognosis stages, morphologies, and molecular and epigenetic backgrounds [3]. Presently, there are no early-stage treatment options for OC since the early symptoms cannot be comprehended. Due to high prevalence and the continuously rising incidence, OC poses a major threat to personal health as well as the health care system [1]. Despite ongoing efforts to detect OC, specific diagnostic biomarkers are yet to be identified [4]. It is evident that transcription factors (TFs) play a pivotal role in the regulation of cellular functions, including cell activation, repression, and alteration of gene expression. Any dysfunctional activation or inactivation of TFs may result in cellular induction of tumorigenesis [4]. Mutations in cancer is caused due to changes in various proteins functions and transcriptions factors which are controlling the protein, thus changing the phenotypes in human [5]. Bookmarking of mitosis constitutes a mechanism that transmits transcriptional patterns by cell division. Bookmarking factors, comprising a subset of TFs, and multiple histone modifications retained in mitotic chromatin facilitate reactivation of transcription in the early G1 phase [6]. It is possible that Sp1 phosphorylation may change its interaction with other transcription factors [7]. Specificity protein 1 (Sp1) is one such ubiquitous and multifunctional TF from the Sp/Kru...

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Penfluridol Represses Integrin Expression in Breast Cancer through Induction of Reactive Oxygen Species and Downregulation of Sp Transcription Factors

Cited by 52 publications

References 44 publications

Penfluridol suppresses glioblastoma tumor growth by Akt-mediated inhibition of GLI1

Penfluridol suppresses glioblastoma tumor growth by Akt-mediated inhibition of GLI1

Low Dose of Penfluridol Inhibits VEGF-Induced Angiogenesis

Understanding the Role of the Transcription Factor Sp1 in Ovarian Cancer: from Theory to Practice

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