Penfluridol overcomes paclitaxel resistance in metastatic breast cancer

Gupta, Nehal; Gupta, Parul; Srivastava, Sanjay

doi:10.1038/s41598-019-41632-0

Cited by 45 publications

(38 citation statements)

References 48 publications

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“…About 30% of patients with breast cancer show overexpression of HER2, which contributes to tumor development and progression (7,8). Few studies including a recent study from our laboratory found that HER2 overexpression is responsible for chemotherapeutic resistance (9,10). Another study suggested that under certain conditions, cleavage of HER2 leads to the activation of intrinsic apoptotic path-way (11).…”

Section: Introductionmentioning

confidence: 99%

Atovaquone: An Antiprotozoal Drug Suppresses Primary and Resistant Breast Tumor Growth by Inhibiting HER2/β-Catenin Signaling

Gupta

Srivastava

2019

Molecular Cancer Therapeutics

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Breast cancer is the second leading cause of cancer-related mortality in women. In the current study, we evaluated the anticancer effects of an antiprotozoal drug, atovaquone, against several breast cancer cell lines. Our results showed that atovaquone treatment induced apoptosis and inhibited the growth of all the breast cancer cell lines tested, including several patient-derived cells. In addition, atovaquone treatment significantly reduced the expression of HER2, b-catenin, and its downstream molecules such as pGSK-3b, TCF-4, cyclin D1, and c-Myc in vitro. Efficacy of atovaquone was further evaluated in an in vivo tumor model by orthotropic implantation of two highly aggressive 4T1 and CI66 breast cancer cells in the mammary fat pad of female mice. Our results demonstrated that oral administration of atovaquone suppressed the growth of CI66 and 4T1 tumors by 70% and 60%, respectively. Paclitaxel is the first-line chemotherapeutic agent for metastatic breast cancer. We demonstrate that atovaquone administration suppressed the growth of 4T1 paclitaxel-resistant tumors by 40%. Tumors from atovaquone-treated mice exhibited reduced HER2, b-catenin, and c-Myc levels alongside an increase in apoptosis in all the three tumor models when analyzed by Western blotting, IHC, and TUNEL assay. Taken together, our results indicate that atovaquone effectively reduces the growth of primary and paclitaxel-resistant breast tumors. Atovaquone is already in the clinics with high safety and tolerability profile. Therefore, the findings from our studies will potentially prompt further clinical investigation into repurposing atovaquone for the treatment of patients with advanced breast cancer.

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Section: Introductionmentioning

confidence: 99%

Atovaquone: An Antiprotozoal Drug Suppresses Primary and Resistant Breast Tumor Growth by Inhibiting HER2/β-Catenin Signaling

Gupta

Srivastava

2019

Molecular Cancer Therapeutics

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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%

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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“…Despite substantial advances in therapeutic strategies, breast cancer remains the second leading cause of cancer-related deaths in women [ 1 ]. In fact, the World Health Organization (WHO) reported that breast cancer is the most common type of cancer, impacting over 1.5 million women every year.…”

Section: Introductionmentioning

confidence: 99%

“…In fact, the World Health Organization (WHO) reported that breast cancer is the most common type of cancer, impacting over 1.5 million women every year. According to the American Cancer Society, 40,610 women were likely to die as a result of breast cancer in 2017 [ 1 , 2 ], indicating a high disease burden.…”

Section: Introductionmentioning

confidence: 99%

“…PTX is a systemic chemotherapeutic agent used to treat advanced and metastatic breast cancer due to its microtubule-stabilizing property [ 3 , 4 ]. Its response rate against breast cancer ranges from 30–70% [ 1 ]. The therapeutic efficacy tends to be limited due to energy-dependent efflux of the drug following its internalization into cancer cells via passive diffusion, leading to the development of multidrug resistance (MDR) [ 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

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Optimization and Formulation of Nanostructured and Self-Assembled Caseinate Micelles for Enhanced Cytotoxic Effects of Paclitaxel on Breast Cancer Cells

et al. 2020

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Background: Paclitaxel (PTX) is a widely used anti-cancer drug for treating various types of solid malignant tumors including breast, ovarian and lung cancers. However, PTX has a low therapeutic response and is linked with acquired resistance, as well as a high incidence of adverse events, such as allergic reactions, neurotoxicity and myelosuppression. The situation is compounded when its complex chemical structure contributes towards hydrophobicity, shortening its circulation time in blood, causing off-target effects and limiting its therapeutic activity against cancer cells. Formulating a smart nano-carrier may overcome the solubility and toxicity issues of the drug and enable its more selective delivery to the cancerous cells. Among the nano-carriers, natural polymers are of great importance due to their excellent biodegradability, non-toxicity and good accessibility. The aim of the present research is to develop self-assembled sodium caseinate nanomicelles (NaCNs) with PTX loaded into the hydrophobic core of NaCNs for effective uptake of the drug in cancer cells and its subsequent intracellular release. Methods: The PTX-loaded micelle was characterized with high-performance liquid chromatography (HPLC), Fourier Transform Infrared Spectra (FTIR), High Resolution-Transmission Electron Microscope (HR-TEM), Field Emission Scanning Electron Microscope (FESEM) and Energy Dispersive X-Ray (EDX). Following treatment with PTX-loaded NaCNs, cell viability, cellular uptake and morphological changes were analyzed using MCF-7 and MDA-MB 231 human breast cancer cell lines. Results: We found that PTX-loaded NaCNs efficiently released PTX in an acidic tumor environment, while showing an enhanced cytotoxicity, cellular uptake and in-vivo anti-tumor efficacy in a mouse model of breast cancer when compared to free drug and blank micelles. Additionally, the nanomicelles also presented improved colloidal stability for three months at 4 °C and −20 °C and when placed at a temperature of 37 °C. Conclusions: We conclude that the newly developed NaCNs is a promising carrier of PTX to enhance tumor accumulation of the drug while addressing its toxicity issues as well.

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Penfluridol overcomes paclitaxel resistance in metastatic breast cancer

Cited by 45 publications

References 48 publications

Atovaquone: An Antiprotozoal Drug Suppresses Primary and Resistant Breast Tumor Growth by Inhibiting HER2/β-Catenin Signaling

Atovaquone: An Antiprotozoal Drug Suppresses Primary and Resistant Breast Tumor Growth by Inhibiting HER2/β-Catenin Signaling

Low Dose of Penfluridol Inhibits VEGF-Induced Angiogenesis

Optimization and Formulation of Nanostructured and Self-Assembled Caseinate Micelles for Enhanced Cytotoxic Effects of Paclitaxel on Breast Cancer Cells

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