Flubendazole induces mitotic catastrophe and senescence in colon cancer cells <i>in vitro</i>

Králová, Věra; Hanušová, Veronika; Rudolf, Emil; Čáňová, Kristýna; Skálová, Lenka

doi:10.1111/jphp.12503

Cited by 40 publications

(31 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…FLU treatment was found to induce mitotic catastrophe, in agreement with previous findings. 30 Four TNBC cell lines significantly accumulated G2/M phase cell populations following FLU challenge (Fig. 3a).…”

Section: Flu-induced Apoptosis Is Mediated By Caspase-3/-7 Activationmentioning

confidence: 99%

Flubendazole elicits anti‐metastatic effects in triple‐negative breast cancer via STAT3 inhibition

Kim

et al. 2018

Intl Journal of Cancer

View full text Add to dashboard Cite

Tumor metastasis remains the cause of 90% of cancer-related deaths. Cancer stem cells (CSC) are thought to be responsible for the aggressive and metastatic nature of triple-negative breast cancers (TNBC), and new therapeutic strategies are being devised to target them. Flubendazole (FLU) is a widely used anthelmintic agent that also exhibits anticancer activity in several cancer types. The aim of this study was to characterize the mechanism of action of FLU on breast cancer stem cell (BCSC)-like properties and metastasis in TNBC. FLU treatment caused a significant induction of apoptosis, accompanied by G2/M phase accumulation, caspase-3/-7 activation and the dysregulation of STAT3 activation in TNBC cells. The latter phenomenon was associated with impairment of cancer stem-like traits, concomitant with a reduction in the CD24 /CD44 , CD24 /CD49f subpopulation, ALDH1 activity and mammosphere formation. The BCSC-enriched populations exhibited enhanced metastasis with higher STAT3 activation, while FLU administration inhibited tumor growth, angiogenesis and lung and liver metastasis, coinciding with decreased MMP-2 and MMP-9 levels in circulating blood. FLU kills not only rapid proliferating tumor cells but also effectively eradicates BCSC-like cells in vitro and in vivo. Our findings warrant further investigation of FLU as a treatment for metastatic TNBC.

show abstract

Section: Flu-induced Apoptosis Is Mediated By Caspase-3/-7 Activationmentioning

confidence: 99%

Flubendazole elicits anti‐metastatic effects in triple‐negative breast cancer via STAT3 inhibition

Kim

et al. 2018

Intl Journal of Cancer

View full text Add to dashboard Cite

show abstract

“…Some members of benzimidazole-based anthelmintic family, such as albendazole, mebendazole and flubendazole, are being considered for repurposing in cancer therapy [12]. These drugs are widely used in animals and humans as safe and effective treatments for intestinal parasites [13][14][15], but there is also evidence of their antitumor effects in melanoma, leukemia, medulloblastoma, breast and colorectal cancers [16][17][18][19][20][21][22]. Interestingly, very little is known about the effects of these drugs in PC.…”

Section: Introductionmentioning

confidence: 99%

The Benzimidazole-Based Anthelmintic Parbendazole: A Repurposed Drug Candidate That Synergizes with Gemcitabine in Pancreatic Cancer

Florio

Veschi

Giacomo

et al. 2019

Cancers

View full text Add to dashboard Cite

Pancreatic cancer (PC) is one of the most lethal, chemoresistant malignancies and it is of paramount importance to find more effective therapeutic agents. Repurposing of non-anticancer drugs may expand the repertoire of effective molecules. Studies on repurposing of benzimidazole-based anthelmintics in PC and on their interaction with agents approved for PC therapy are lacking. We analyzed the effects of four Food and Drug Administration (FDA)-approved benzimidazoles on AsPC-1 and Capan-2 pancreatic cancer cell line viability. Notably, parbendazole was the most potent benzimidazole affecting PC cell viability, with half maximal inhibitory concentration (IC50) values in the nanomolar range. The drug markedly inhibited proliferation, clonogenicity and migration of PC cell lines through mechanisms involving alteration of microtubule organization and formation of irregular mitotic spindles. Moreover, parbendazole interfered with cell cycle progression promoting G2/M arrest, followed by the emergence of enlarged, polyploid cells. These abnormalities, suggesting a mitotic catastrophe, culminated in PC cell apoptosis, are also associated with DNA damage in PC cell lines. Remarkably, combinations of parbendazole with gemcitabine, a drug employed as first-line treatment in PC, synergistically decreased PC cell viability. In conclusion, this is the first study providing evidence that parbendazole as a single agent, or in combination with gemcitabine, is a repurposing candidate in the currently dismal PC therapy.

show abstract

“…4 The molecular mechanism of action of benzimidazoles is based on specific binding to tubulin, the microtubule subunit protein. 7 When FLU was tested for its effects on the viability of 461 cancer cell lines in total, neuroblastoma was identified as a highly FLU-sensitive cancer entity. 5 The microtubule-disrupting properties of benzimidazoles has raised interest in these compounds as possible anti-cancer agents, as microtubules play key roles in the proliferation, trafficking and migration of eukaryotic cells, including the invasion and metastatic spread of tumor cells.…”

Section: Introductionmentioning

confidence: 99%

“…FLU in low concentration temporarily inhibits cell proliferation and induces mitotic catastrophe and premature senescence in human colon cancer cells. 7 When FLU was tested for its effects on the viability of 461 cancer cell lines in total, neuroblastoma was identified as a highly FLU-sensitive cancer entity. 8 In intestinal cancer cells, FLU showed a significant cytostatic effect and potentiated the efficacy of paclitaxel.…”

Section: Introductionmentioning

confidence: 99%

The metabolism of flubendazole in human liver and cancer cell lines

Stuchlíková

Králová

Lněničková

et al. 2018

Drug Testing and Analysis

Self Cite

View full text Add to dashboard Cite

Flubendazole (FLU), a benzimidazole anthelmintic drug widely used in veterinary medicine, has been approved for the treatment of gut-residing nematodes in humans. In addition, FLU is now considered a promising anti-cancer agent. Despite this, information about biotransformation of this compound in human is lacking. Moreover, there is no information regarding whether cancer cells are able to metabolize FLU in order to deactivate it. For these reasons, the present study was designed to identify all metabolites of Phase I and Phase II of FLU in human liver and in various cancer cells using ultra high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) analysis. Precision-cut human liver slices and 9 cell lines of different origin (breast, colon, oral cavity) were used as in vitro model systems. Our study showed that FLU with a reduced carbonyl group (FLUR) is the only FLU metabolite formed in the human liver. All human cancer cell lines were able to form FLUR. In addition, methylated FLUR was detected in breast cells MCF7 and intestinal SW480 cells. The accumulation of FLU and its reduction to FLUR markedly differed among cells. The extent of FLU reduction was in a good correlation with the detected expression level of carbonyl reductase 1. In most cases, FLU entered in a higher amount and was reduced to a lesser extent in proliferating (metastatic) cells than in differentiated (non-cancerous, non-metastatic) ones. These results support the promising potential of FLU in anti-cancer therapy.

show abstract

Flubendazole induces mitotic catastrophe and senescence in colon cancer cells in vitro

Abstract: Flubendazole in low concentration temporarily inhibits cell proliferation and induces mitotic catastrophe and premature senescence in human colon cancer cells in vitro.

Cited by 40 publications

References 46 publications

Flubendazole elicits anti‐metastatic effects in triple‐negative breast cancer via STAT3 inhibition

Flubendazole elicits anti‐metastatic effects in triple‐negative breast cancer via STAT3 inhibition

The Benzimidazole-Based Anthelmintic Parbendazole: A Repurposed Drug Candidate That Synergizes with Gemcitabine in Pancreatic Cancer

The metabolism of flubendazole in human liver and cancer cell lines

Contact Info

Product

Resources

About