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Identification of a Potent Cytotoxic Pyrazole with Anti-Breast Cancer Activity That Alters Multiple Pathways.

ABSTRACT: In this study, we identified a novel pyrazole-based derivative (P3C) that displayed potent cytotoxicity against 27 human cancer cell lines derived from different tissue origins with 50% cytotoxic concentrations (CC50) in the low micromolar and nanomolar range, particularly in two triple-negative breast cancer (TNBC) cell lines (from 0.25 to 0.49 µM). In vitro assays revealed that P3C induces reactive oxygen species (ROS) accumulation leading to mitochondrial depolarization and caspase-3/7 and -8 activation, suggesting the participation of both the intrinsic and extrinsic apoptotic pathways. P3C caused microtubule disruption, phosphatidylserine externalization, PARP cleavage, DNA fragmentation, and cell cycle arrest on TNBC cells. In addition, P3C triggered dephosphorylation of CREB, p38, ERK, STAT3, and Fyn, and hyperphosphorylation of JNK and NF-kB in TNBC cells, indicating the inactivation of both p38MAPK/STAT3 and ERK1/2/CREB signaling pathways. In support of our in vitro assays, transcriptome analyses of two distinct TNBC cell lines (MDA-MB-231 and MDA-MB-468 cells) treated with P3C revealed 28 genes similarly affected by the treatment implicated in apoptosis, oxidative stress, protein kinase modulation, and microtubule stability.

SUBMITTER: Gutierrez DA

PROVIDER: S-EPMC8773755 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Identification of a Potent Cytotoxic Pyrazole with Anti-Breast Cancer Activity That Alters Multiple Pathways.

Gutierrez Denisse A DA Contreras Lisett L Villanueva Paulina J PJ Borrego Edgar A EA Morán-Santibañez Karla K Hess Jessica D JD DeJesus Rebecca R Larragoity Manuel M Betancourt Ana P AP Mohl Jonathon E JE Robles-Escajeda Elisa E Begum Khodeza K Roy Sourav S Kirken Robert A RA Varela-Ramirez Armando A Aguilera Renato J RJ

Cells 20220112 2

In this study, we identified a novel pyrazole-based derivative (P3C) that displayed potent cytotoxicity against 27 human cancer cell lines derived from different tissue origins with 50% cytotoxic concentrations (CC<sub>50</sub>) in the low micromolar and nanomolar range, particularly in two triple-negative breast cancer (TNBC) cell lines (from 0.25 to 0.49 µM). In vitro assays revealed that P3C induces reactive oxygen species (ROS) accumulation leading to mitochondrial depolarization and caspase ...[more]

PMID: 35053370

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Project description:BackgroundInfluenza viruses are a major cause of morbidity and mortality around the world. More recently, a swine-origin influenza A (H1N1) virus that is spreading via human-to-human transmission has become a serious public concern. Although vaccination is the primary strategy for preventing infections, influenza antiviral drugs play an important role in a comprehensive approach to controlling illness and transmission. In addition, a search for influenza-inhibiting drugs is particularly important in the face of high rate of emergence of influenza strains resistant to several existing influenza antivirals.MethodsWe searched for novel anti-influenza inhibitors using a cell-based neutralization (inhibition of virus-induced cytopathic effect) assay. After screening 20,800 randomly selected compounds from a library from ChemDiv, Inc., we found that BPR1P0034 has sub-micromolar antiviral activity. The compound was resynthesized in five steps by conventional chemical techniques. Lead optimization and a structure-activity analysis were used to improve potency. Time-of-addition assay was performed to target an event in the virus life cycle.ResultsThe 50% effective inhibitory concentration (IC50) of BPR1P0034 was 0.42 +/- 0.11 microM, when measured with a plaque reduction assay. Viral protein and RNA synthesis of A/WSN/33 (H1N1) was inhibited by BPR1P0034 and the virus-induced cytopathic effects were thus significantly reduced. BPR1P0034 exhibited broad inhibition spectrum for influenza viruses but showed no antiviral effect for enteroviruses and echovirus 9. In a time-of-addition assay, in which the compound was added at different stages along the viral replication cycle (such as at adsorption or after adsorption), its antiviral activity was more efficient in cells treated with the test compound between 0 and 2 h, right after viral infection, implying that an early step of viral replication might be the target of the compound. These results suggest that BPR1P0034 targets the virus during viral uncoating or viral RNA importation into the nucleus.ConclusionsTo the best of our knowledge, BPR1P0034 is the first pyrazole-based anti-influenza compound ever identified and characterized from high throughput screening to show potent (sub-microM) antiviral activity. We conclude that BPR1P0034 has potential antiviral activity, which offers an opportunity for the development of a new anti-influenza virus agent.

Project description:BackgroundGastric cancer (GC) is a life-threatening malignant tumor with high incidence rate. Despite great progress, there are still many GC sufferers that cannot benefit from the existing anti-GC treatments. Therefore, it is still necessary to develop novel medicines against GC. Emetine, a natural small molecule isolated from Psychotria ipecacuanha, has been broadly used for medicinal purposes including cancer treatment. Here, we conducted a comprehensive study on the anti-GC effects of emetine and the related mechanisms of action.MethodsThe cell viability was evaluated by MTT and colony formation assay. Cellular proliferation and apoptosis were analyzed by edu incorporation assay and Annexin V-PI staining, respectively. Moreover, wound healing assay and transwell invasion assay were conducted to detect cell migration and invasion after treatment with emetine. To elucidate the molecular mechanism involved in the anti-GC effects of emetine, RNA sequencing and functional enrichment analysis were carried out on MGC803 cells. Then, the western blot analysis was performed to further verify the anti-GC mechanism of emetine. In vivo anti-tumor efficacy of emetine was evaluated in the MGC803 xenograft model.ResultsMTT and colony formation assay exhibited a strong potency of emetine against GC cell growth, with IC50 values of 0.0497 μM and 0.0244 μM on MGC803 and HGC-27 cells, respectively. Further pharmacodynamic studies revealed that emetine restrained the growth of GC cells mainly via proliferation inhibition and apoptosis induction. Meanwhile, emetine also had the ability to block GC cell migration and invasion. The results of RNA sequencing and western blot showed that emetine acted through regulating multiple signaling pathways, including not only MAPKs and Wnt/β-catenin signaling axes, but also PI3K/AKT and Hippo/YAP signaling cascades that were not found in other tumor types. Notably, the antitumor efficacy of emetine could also be observed in MGC803 xenograft models.ConclusionOur data demonstrate that emetine is a promising lead compound and even a potential drug candidate for GC treatment, deserving further structural optimization and development.

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Identification of a Potent Cytotoxic Pyrazole with Anti-Breast Cancer Activity That Alters Multiple Pathways.

Publications

Identification of a Potent Cytotoxic Pyrazole with Anti-Breast Cancer Activity That Alters Multiple Pathways.

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