Fenbendazole and its synthetic analog interfere with HeLa cells’ proliferation and energy metabolism via inducing oxidative stress and modulating MEK3/6-p38-MAPK pathway

Peng, Yi; Pan, Jie; Ou, Fengting; Wang, Qianqian; Chen, Lu; Zeng, Su; Zeng, Kui; Yu, Lushan

doi:10.1016/j.cbi.2022.109983

Cited by 8 publications

(6 citation statements)

References 52 publications

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“…FZ decreases the activation of mTOR and several MAPK members, which are involved in the regulation of cell survival and apoptosis, depending upon the cell type [ 23 24 ]. To identify the effect of FZ in regulating cell proliferation or apoptosis, we evaluated the PI3K/mTOR pathway in EOC cells by Western blot analysis.…”

Section: Resultsmentioning

confidence: 99%

Anti-cancer effect of fenbendazole-incorporated PLGA nanoparticles in ovarian cancer

et al. 2023

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Objective Fenbendazole (FZ) has potential anti-cancer effects, but its poor water solubility limits its use for cancer therapy. In this study, we investigated the anti-cancer effect of FZ with different drug delivery methods on epithelial ovarian cancer (EOC) in both in vitro and in vivo models. Methods EOC cell lines were treated with FZ and cell proliferation was assessed. The effect of FZ on tumor growth in cell line xenograft mouse model of EOC was examined according to the delivery route, including oral and intraperitoneal administration. To improve the systemic delivery of FZ by converting fat-soluble drugs to hydrophilic, we prepared FZ-encapsulated poly(D,L-lactide-co-glycolide) acid (PLGA) nanoparticles (FZ-PLGA-NPs). We investigated the preclinical efficacy of FZ-PLGA-NPs by analyzing cell proliferation, apoptosis, and in vivo models including cell lines and patient-derived xenograft (PDX) of EOC. Results FZ significantly decreased cell proliferation of both chemosensitive and chemoresistant EOC cells. However, in cell line xenograft mouse models, there was no effect of oral FZ treatment on tumor reduction. When administered intraperitoneally, FZ was not absorbed but aggregated in the intraperitoneal space. We synthesized FZ-PLGA-NPs to obtain water solubility and enhance drug absorption. FZ-PLGA-NPs significantly decreased cell proliferation in EOC cell lines. Intravenous injection of FZ-PLGA-NP in xenograft mouse models with HeyA8 and HeyA8-MDR significantly reduced tumor weight compared to the control group. FZ-PLGA-NPs showed anti-cancer effects in PDX model as well. Conclusion FZ-incorporated PLGA nanoparticles exerted significant anti-cancer effects in EOC cells and xenograft models including PDX. These results warrant further investigation in clinical trials.

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Section: Resultsmentioning

confidence: 99%

Anti-cancer effect of fenbendazole-incorporated PLGA nanoparticles in ovarian cancer

et al. 2023

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“…Since then, the anticancer effects of FBZ have been studied in vitro using various cancer cells. The anticancer effects of FBZ include the inhibition of p38-mitogen-activated protein kinase (MAPK) pathway activity and glucose metabolism in HeLa (cervical cancer) cells [11], ROS production in HL-60 (leukemia) cells [7,8], and G2/M phase arrest in 5-fluorouracil-resistant colon cancer cells SNU-C5 [10]. FBZ reportedly inhibits the growth of actively growing H4IIE (hepatocellular carcinoma) cells via inducing p21-mediated G1/S…”

Section: Discussionmentioning

confidence: 99%

“…The anticancer effects of FBZ include the inhibition of p38-mitogen-activated protein kinase (MAPK) pathway activity and glucose metabolism in HeLa (cervical cancer) cells [11], ROS production in HL-60 (leukemia) cells [7,8], and G2/M phase arrest in 5-fluorouracil-resistant colon cancer cells SNU-C5 [10]. FBZ reportedly inhibits the growth of actively growing H4IIE (hepatocellular carcinoma) cells via inducing p21-mediated G1/S and G2/M phase arrest; however, the MAPK pathway, glucose metabolism, and ROS production were not the deemed the main mechanisms [9].…”

Section: Discussionmentioning

confidence: 99%

“…This mechanism is similar to that of anticancer drugs targeting microtubules in cancer cells, such as paclitaxel and vinca alkaloids such as vincristine and vinblastine [6]. Studies have shown that FBZ exerts anticancer effects by inhibiting reactive oxygen species (ROS) production in cancer cells [7,8], arresting the G2/M phase [9,10], and impairing glucose metabolism [11]. Furthermore, the interest in FBZ has been fueled by a report of anticancer effects of FBZ in an American patient [12].…”

Section: Introductionmentioning

confidence: 86%

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Fenbendazole Exhibits Differential Anticancer Effects In Vitro and In Vivo in Models of Mouse Lymphoma

Jung,

Kim,

Joo

2023

CIMB

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Fenbendazole (FBZ) has been safely used as an antiparasitic agent in animals for decades, and the anticancer effects of FBZ have been studied through various mechanisms. However, there is a lack of in vivo studies that include lymphoma. Therefore, this study examined the effects of FBZ on EL-4 cells and a mouse T lymphoma model. FBZ induced G2/M phase arrest in EL-4 cells, resulting in cell death and decreased metabolic activity. However, FBZ had no anticancer effects on an EL-4 mouse lymphoma model in vivo, as evident by rapid weight loss and tumor growth comparable to the control. The FBZ-treated EL-4 cells expressed higher levels of PD-L1 and CD86, which are associated with T cell immunity in the tumor microenvironment (TME), than the controls. Furthermore, the hematoxylin and eosin staining of the FBZ-treated tumor tissues showed a starry sky pattern, which is seen in actively proliferating cancer tissues, and an immunohistochemical analysis revealed a high percentage of immunosuppressive M2 macrophages. These changes in the immune activity in the TME contradict the results of the in vitro experiments, and further studies are needed to determine the detailed mechanisms by which FBZ induces these responses.

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“…In addition, FZ activated the p38-MAPK signaling pathway to inhibit the proliferation and increase the apoptosis of HeLa cells. FZ also impaired glucose metabolism, and prevented HeLa cell migration and invasion [ 37 ]. Koh et al found that FZ, MBZ, and oxibendazole possess remarkable anticancer activities at the cellular level via tubulin depolymerization, but their poor pharmacokinetic parameters limit their use as systemic anticancer drugs.…”

Section: Anticancer Activity Of Fz In Preclinical Modelsmentioning

confidence: 99%

Exceptional Repositioning of Dog Dewormer: Fenbendazole Fever

Sultana

Jan

Lee

et al. 2022

CIMB

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Fenbendazole (FZ) is a benzimidazole carbamate drug with broad-spectrum antiparasitic activity in humans and animals. The mechanism of action of FZ is associated with microtubular polymerization inhibition and glucose uptake blockade resulting in reduced glycogen stores and decreased ATP formation in the adult stages of susceptible parasites. A completely cured case of lung cancer became known globally and greatly influenced the cancer community in South Korea. Desperate Korean patients with cancer began self-administering FZ without their physician’s knowledge, which interfered with the outcome of the cancer treatment planned by their oncologists. On the basis of presented evidence, this review provides valuable information from PubMed, Naver, Google Scholar, and Social Network Services (SNS) on the effects of FZ in a broad range of preclinical studies on cancer. In addition, we suggest investigating the self-administration of products, including supplements, herbs, or bioactive compounds, by patients to circumvent waiting for long and costly FZ clinical trials.

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Fenbendazole and its synthetic analog interfere with HeLa cells’ proliferation and energy metabolism via inducing oxidative stress and modulating MEK3/6-p38-MAPK pathway

Cited by 8 publications

References 52 publications

Anti-cancer effect of fenbendazole-incorporated PLGA nanoparticles in ovarian cancer

Anti-cancer effect of fenbendazole-incorporated PLGA nanoparticles in ovarian cancer

Fenbendazole Exhibits Differential Anticancer Effects In Vitro and In Vivo in Models of Mouse Lymphoma

Exceptional Repositioning of Dog Dewormer: Fenbendazole Fever

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