Preclinical studies evaluate pivotal TNFα nanomedicine clinical trial design.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14646-e14646
Author(s):  
Naris Nilubol ◽  
David Oarr ◽  
Lawrence Tamarkin
Keyword(s):  
Clinical Trial ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Cell Lines ◽  
Cancer Cell ◽  
Single Agent ◽  
Fluid Pressure ◽  
Standard Of Care ◽  
Preclinical Studies ◽  
Preclinical Research

e14646 Background: The clinically-tested CYT-6091 nanomedicine is comprised of TNF alpha (TNF) bound to 27 nm pegylated gold nanoparticles. Preclinical research has shown that CYT-6091 disrupts solid tumor blood vessels, reduces interstitial fluid pressure and increases accumulation of follow-on chemotherapy in the tumor microenvironment. While systemic toxicity has limited treatment of cancer patients with TNF, isolated limb perfusion of patients with in-transit melanoma using 1-4 mg of TNF followed by chemotherapy has demonstrated up to 90% complete response rates with one treatment. In a single-agent, phase I clinical study in advanced-stage cancer patients, we found that multiple CYT-6091 treatments can systemically and safely deliver up to 1.2 mg of TNF per dose. Methods: Our current research was conducted to validate administering CYT-6091 prior to standard-of-care chemotherapy in a phase II clinical trial. As part of the NCI’s Experimental Therapeutics (NExT) evaluation, CYT-6091 was studied in combination with paclitaxel (PTX) in C57BL/6 murine xenografts, using three cancer cell lines: MC-38 colon carcinoma (cancer cells sensitive to TNF, but insensitive to PTX), B16/F10 melanoma (cancer cells insensitive to TNF, but sensitive to PTX), Lewis lung carcinoma (cancer cells insensitive to both TNF and PTX), where sensitivity was based on inhibiting cancer cell growth at the studied dosing amounts and frequency. CYT-6091 was administered 3-hours before PTX, and three PTX doses were administered in each model. Results: In every model, CYT-6091 + any dose of PTX was more effective in reducing or controlling tumor growth than the highest dose of PTX alone (p < 0.01). Interestingly, we also found that CYT-6091 alone demonstrated significant anti-cancer activity (p < 0.01), suggesting that additional studies may be warranted to determine optimal frequency and dose of CYT-6091 as a single agent. Conclusions: These preclinical studies demonstrate for the first time that CYT-6091 + PTX was superior to PTX (p < 0.01) or CYT-6091 alone (P < 0.05) in TNF insensitive cell lines, which represent the majority of cancers. Findings support systemically administering CYT-6091 plus standard-of-care chemotherapy in a pivotal clinical trial.

scholarly journals Antiplatelet Therapy Combined with Anastrozole Induces Features of Partial EMT in Breast Cancer Cells and Fails to Mitigate Breast-Cancer Induced Hypercoagulation

2021 ◽  
Vol 22 (8) ◽  
pp. 4153
Author(s):  
Kutlwano R. Xulu ◽  
Tanya N. Augustine
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Antiplatelet Therapy ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Cancer Cells ◽  
Cancer Cell Lines ◽  
Breast Cancer Cell Lines

Thromboembolic complications are a leading cause of morbidity and mortality in cancer patients. Cancer patients often present with an increased risk for thrombosis including hypercoagulation, so the application of antiplatelet strategies to oncology warrants further investigation. This study investigated the effects of anastrozole and antiplatelet therapy (aspirin/clopidogrel cocktail or atopaxar) treatment on the tumour responses of luminal phenotype breast cancer cells and induced hypercoagulation. Ethical clearance was obtained (M150263). Blood was co-cultured with breast cancer cell lines (MCF7 and T47D) pre-treated with anastrozole and/or antiplatelet drugs for 24 h. Hypercoagulation was indicated by thrombin production and platelet activation (morphological and molecular). Gene expression associated with the epithelial-to-mesenchymal transition (EMT) was assessed in breast cancer cells, and secreted cytokines associated with tumour progression were evaluated. Data were analysed with the PAST3 software. Our findings showed that antiplatelet therapies (aspirin/clopidogrel cocktail and atopaxar) combined with anastrozole failed to prevent hypercoagulation and induced evidence of a partial EMT. Differences in tumour responses that modulate tumour aggression were noted between breast cancer cell lines, and this may be an important consideration in the clinical management of subphenotypes of luminal phenotype breast cancer. Further investigation is needed before this treatment modality (combined hormone and antiplatelet therapy) can be considered for managing tumour associated-thromboembolic disorder.

scholarly journals 2467 PRMT5 is a master epigenetic regulator to promote repair of radiation-induced DNA damage

2018 ◽  
Vol 2 (S1) ◽  
pp. 24-24
Author(s):  
Jake L. Owens
Keyword(s):  
Prostate Cancer ◽  
Dna Damage ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Cell Lines ◽  
Cancer Cell ◽  
Target Genes ◽  
Prostate Cancer Cells ◽  
G2 Arrest ◽  
Dsb Repair

OBJECTIVES/SPECIFIC AIMS: We recently reported that PRMT5 epigenetically activates androgen receptor (AR) in prostate cancer cells. Because targeting AR signaling through androgen deprivation therapy is clinically used as a radiosensitization approach to treat high-risk prostate cancer, our finding raised an exciting possibility that targeting PRMT5 may improve RT for prostate cancer patients. Contrary to our expectation, targeting PRMT5 sensitized both AR expressing and AR negative (AR−) prostate cancer cell lines to radiation. The goal of our study was therefore to determine the role of PRMT5 in repair of IR-induced DSBs and to translate these findings to improving radiation therapy for cancer patients in general (not just prostate cancer patients). METHODS/STUDY POPULATION: The majority of experiments were basic science experiments analyzing PRMT5’s role in the DNA damage response in normal and cancer cell lines. For example, to extend our findings and determine if PRMT5’s role in DSB repair is conserved across multiple cell types, we performed similar experiments in AR− prostate cancer cells, luminal breast cancer cells, glioblastoma cells, and human embryonic kidney cells. To determine the clinical significance of our finding, we also analyzed mRNA expression of PRMT5, AR, and both PRMT5 and AR target genes involved in DSB repair across 43 clinical cancer data sets. RESULTS/ANTICIPATED RESULTS: (1) Targeting PRMT5 sensitizes prostate cancer cells to IR in an AR-independent manner, (2) PRMT5 regulates the repair of IR-induced DSBs in an AR-independent manner, (3) RNA-seq analysis reveals that PRMT5 likely regulates genes involved in the DNA damage response, (4) PRMT5 activates expression of several genes in the DDR including those involved in DSB repair, (5) PRMT5 functions as an epigenetic activator of genes involved in DDR, (6) PRMT5 is required for NHEJ, HR, and G2-Arrest upon IR treatment, (7) Upregulation of PRMT5 correlates with formation and repair of IR-induced DSBs, (8) PRMT5’s role in repair of IR-induced DSBs is conserved in several normal and cancer cell types, and (9) PRMT5 expression correlates with expression of DSB repair proteins in clinical cancer samples. DISCUSSION/SIGNIFICANCE OF IMPACT: In summary, we provide evidence that PRMT5 is a master epigenetic regulator of IR-induced DSB repair through epigenetic activation of multiple target genes involved both HR and NHEJ as well as G2 arrest. Interestingly, the majority of genes regulated by PRMT5 are well-characterized, “core repair proteins” involved in HR (RAD51, BRCA1, BRCA2, RAD51D, and RAD51AP1), NHEJ (NHEJ1, Ku80, XRCC4, and DNAPKcs), and G2 arrest (Cdk1, CDC25C, CCNB2, and WEE1), which may explain why PRMT5 is essential to repair IR-induced DSBs in several cell lines. Although AR may also regulate DSB repair via both HR and NHEJ, several pieces of evidence in our study suggest that PRMT5 also regulates DSB repair independent of AR. First, PRMT5 targeting sensitizes both AR+ and AR− prostate cancer cells to IR. Second, exogenous expression of AR only partially rescues the impairment of IR-induced DSB repair by PRMT5 knockdown. Third, PRMT5 knockdown increases IR-induced DSB in AR− DU145 cells and several other cancer cell lines and normal cells. Fourth, PRMT5 expression correlates positively with the expression of its target genes in multiple human cancer tissues. During preparation of this project, Braun et al. reported that PRMT5 post-translationally regulates the splicing out of detained-introns (DI)s of genes to modulate gene expression. However, analysis of their data showed that the majority of DEGs we identified either do not contain DIs or DI splicing was not affected by targeting PRMT5. In addition, Clarke et al. reported that PRMT5 participates in the DSB repair choice process and promotes HR through methylation of RUVBL1. It is therefore likely that PRMT5 regulates repair of IR-induced DSB via multiple mechanisms. As PRMT5 is overexpressed in many human cancers and its overexpression correlates with poor prognosis, our findings suggest that increased DSB repair by PRMT5 overexpression in these human cancers may confer survival advantages particularly following DNA damaging treatment. Because targeting DSB repair has been proven to be a valid therapeutic approach for cancer treatment, our findings here also suggest that PRMT5 targeting may be explored as a monotherapy or in combination therapy with RT or chemotherapy for cancer treatment.

scholarly journals MMP1 and MMP11 expression in Peripheral Blood Mononuclear Cells upon their interaction with Breast Cancer Cells and Fibroblasts

2020 ◽  
Author(s):  
Noemi Eiro ◽  
Sandra Cid ◽  
Nuria Aguado ◽  
María Fraile ◽  
Jorge Rubén Cabrera ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Cancer Cell Lines ◽  
Breast Cancer Patients ◽  
Inflammatory Genes

Abstract Background: Tumor-infiltrating immune cells phenotype is associated with tumor progression. However, little is known about the phenotype of the Peripheral Blood Mononuclear Cells (PBMC) from breast cancer patients. Here, we investigated the expression of MMP1 and MMP11 in PBMC from breast cancer patients and we analyzed gene expression changes upon their interaction with cancer cells and Cancer-Associated Fibroblasts (CAF). Finally, we measured the impact of PBMC in proinflammatory genes expression in normal fibroblast and CAF.Results: Gene expression of MMP1 and MMP11 in PBMC from breast cancer patients (n=54) and control (n=28), and expression of IL1A, IL6, IL17, IFNβ and NFB in breast cancer cell lines (MCF-7 and MDA-MB-231), CAF and in Normal Fibroblasts (NF) were analyzed by qRT-PCR before and after co-culture. Our results show the existence of a group of breast cancer patients (25.9%) with very high levels of MMP11 gene expression in PBMC. Also, we present evidence of increased gene expression of MMP1 and MMP11 in PBMC after co-culture with breast cancer cell lines, NF or CAF. Finally, we show a differential expression profile of inflammatory genes in NF and CAF when co-cultured with control or breast cancer PBMC.Conclusions: We have observed that MMPs expression in PBMC is regulated by the microenvironment, while the expression of inflammatory genes in NF or CAF is differentially regulated by control or breast cancer PBMC. These findings confirm the importance of the interaction and communication between stromal cells and suggest that PBMC would play a role to promote an aggressive tumor behavior.

scholarly journals Novel 2-Benzoyl-6-(2,3-Dimethoxybenzylidene)-Cyclohexenol Confers Selectivity toward Human MLH1 Defective Cancer Cells through Synthetic Lethality

2019 ◽  
Vol 24 (5) ◽  
pp. 548-562
Author(s):  
Dedrick Soon Seng Song ◽  
Sze Wei Leong ◽  
Kwok Wen Ng ◽  
Faridah Abas ◽  
Khozirah Shaari ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Patients ◽  
Cell Lines ◽  
Cancer Cell ◽  
Synthetic Lethality ◽  
Treatment Options ◽  
Cancer Cell Lines ◽  
Selective Toxicity ◽  
Synthetic Lethal ◽  
Dna Mismatch

DNA mismatch repair (MMR) deficiency has been associated with a higher risk of developing colorectal, endometrial, and ovarian cancer, and confers resistance in conventional chemotherapy. In addition to the lack of treatment options that work efficaciously on these MMR-deficient cancer patients, there is a great need to discover new drug leads for this purpose. In this study, we screened through a library of commercial and semisynthetic natural compounds to identify potential synthetic lethal drugs that may selectively target MLH1 mutants using MLH1 isogenic colorectal cancer cell lines and various cancer cell lines with known MLH1 status. We identified a novel diarylpentanoid analogue, 2-benzoyl-6-(2,3-dimethoxybenzylidene)-cyclohexenol, coded as AS13, that demonstrated selective toxicity toward MLH1-deficient cancer cells. Subsequent analysis suggested AS13 induced elevated levels of oxidative stress, resulting in DNA damage where only the proficient MLH1 cells were able to be repaired and hence escaping cellular death. While AS13 is modest in potency and selectivity, this discovery has the potential to lead to further drug development that may offer better treatment options for cancer patients with MLH1 deficiency.

scholarly journals Combined Treatment of Heteronemin and Tetrac Induces Antiproliferation in Oral Cancer Cells

Marine Drugs ◽  
2020 ◽  
Vol 18 (7) ◽  
pp. 348
Author(s):  
Chi-Hung Huang ◽  
Tung-Yung Huang ◽  
Wong-Jin Chang ◽  
Yi-shin Pan ◽  
Hung-Ru Chu ◽  
...  
Keyword(s):  
Oral Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Combined Treatment ◽  
Single Agent ◽  
Cancer Cell Lines ◽  
Cell Counting ◽  
P53 Expression ◽  
Oral Cancer Cells

Background: Heteronemin, a marine sesterterpenoid-type natural product, possesses an antiproliferative effect in cancer cells. In addition, heteronemin has been shown to inhibit p53 expression. Our laboratory has demonstrated that the thyroid hormone deaminated analogue, tetrac, activates p53 and induces antiproliferation in colorectal cancer. However, such drug mechanisms are still to be studied in oral cancer cells. Methods: We investigated the antiproliferative effects by Cell Counting Kit-8 and flow cytometry. The signal transduction pathway was measured by Western blotting analyses. Quantitative PCR was used to evaluate gene expression regulated by heteronemin, 3,3’,5,5’-tetraiodothyroacetic acid (tetrac), or their combined treatment in oral cancer cells. Results: Heteronemin inhibited not only expression of proliferative genes and Homo Sapiens Thrombospondin 1 (THBS-1) but also cell proliferation in both OEC-M1 and SCC-25 cells. Remarkably, heteronemin increased TGF-β1 expression in SCC-25 cells. Tetrac suppressed expression of THBS-1 but not p53 expression in both cancer cell lines. Furthermore, the synergistic effect of tetrac and heteronemin inhibited ERK1/2 activation and heteronemin also blocked STAT3 signaling. Combined treatment increased p53 protein and p53 activation accumulation although heteronemin inhibited p53 expression in both cancer cell lines. The combined treatment induced antiproliferation synergistically more than a single agent. Conclusions: Both heteronemin and tetrac inhibited ERK1/2 activation and increased p53 phosphorylation. They also inhibited THBS-1 expression. Moreover, tetrac suppressed TGF-β expression combined with heteronemin to further enhance antiproliferation and anti-metastasis in oral cancer cells.

scholarly journals Compound Kushen Injection Protects Skin From Radiation Injury via Regulating Bim

2021 ◽  
Vol 12 ◽  
Author(s):  
Jianxiao Zheng ◽  
Gong Li ◽  
Juanjuan Wang ◽  
Shujing Wang ◽  
Qing Tang ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Cancer Cell ◽  
Cell Apoptosis ◽  
Control Group ◽  
Human Skin Fibroblast ◽  
Protective Agent ◽  
Skin Injury ◽  
Compound Kushen Injection

Background: Radiation-induced skin injury is a major side-effect observed in cancer patients who received radiotherapy. Thus identifying new radioprotective drugs for prevention or treatment of post-irradiation skin injury should be prompted. A large number of clinical studies have confirmed that Compound Kushen injection (CKI) can enhance efficacy and reduce toxicity of radiotherapy. The aim of this study is to confirm the effect of CKI in alleviating radiotherapy injury in the skin and explore the exact mechanism.Methods: 60 patients who met the inclusion/exclusion criteria were allocated to treatment group (CKI before radiotherapy) or control group (normal saline before radiotherapy) randomly. MTT assay, flow cytometry, Western Blot, and transient transfection were performed to detect the cell viability, cell apoptosis and Bim expression after treatment with CKI or/and radiotherapy.Results: CKI had the effect of alleviating skin injury in cancer patients who received radiotherapy in clinic. CKI induced cancer cell apoptosis when combined with irradiation (IR), while it reversed the induction of cell apoptosis by IR in human skin fibroblast (HSF) cells. And Bim, as a tumor suppressor, was induced in cancer cells but had no change in HSF cells when treated with CKI. Moreover, the above effect could be attenuated when Bim was silenced by siRNA.Conclusion: We conclude that CKI represents a promising radio-protective agent with a potential differential beneficial effect on both cancer cells (inducing apoptosis) and HSF cells (providing radio-protection via inhibiting IR-induced apoptosis), via regulating Bim. Our study uncovers a novel mechanism by which CKI inhibits human cancer cell while protects skin from radiotherapy, indicating CKI might be a promising radio-protective drug.Clinical Trial Registration: Chinese Clinical Trial Registry (www.chictr.org.cn), identifier ChiCTR2100049164.

scholarly journals Synthetic lethality with cisplatin by targeting FACT complex in breast cancer

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Sarah Swiezy ◽  
Rebecca Dirks, MD ◽  
Harikrishna Nakshatri, PhD
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Synthetic Lethality ◽  
Standard Of Care ◽  
Cancer Cell Lines ◽  
Transformed Cells ◽  
Current Standard

Background and Hypothesis: Previous work by our lab has shown that FACT (FAcilitates Chromatin Transcription) is upregulated from P(1º) ➝I(immortalized)➝R(Ras-transformed) cells. The FACT complex is targeted by curaxins, small molecules that “trap” FACT on chromatin, decreasing its ability to destabilize histone tetramers and facilitate DNA replication and transcription. The lab has also observed selective sensitivity to curaxins in the same pattern, P➝I➝R, suggesting the dependency of Ras-transformed cells on FACT for survival. Therefore, we hypothesized that by impairing the cancer cell’s ability to repair DNA, curaxins sensitize breast cancer cells to DNA damage-inducing chemotherapeutics, such as cisplatin. Cisplatin represents the current standard of care for triple negative breast cancer (TNBC), but is associated with exceedingly toxic side effects as well as resistance. Combination therapies may permit cisplatin dose reduction while simultaneously improving response. Project Methods: We first determined which cancer cell lines (MCF7: ER+/PR+/HER2-; T47D: ER+/PR+/HER2-; and MDA-MB-453: TNBC) would be appropriate for demonstrating synergistic cisplatin + CBL0137 (specific curaxin) cytotoxicity. We then used BrdU assay and Western blot to assess the effects of the drugs individually and in combination on cancer cells. Results: We observed heterogeneity in sensitivity of cancer cell lines to CBL0137 as well as statistically significant synthetic lethality between cisplatin and CBL0137. Conclusion and Potential Impact: The knowledge gained by this research is actively being used to develop chemoprevention strategies and to enhance the effectiveness of chemotherapy. Prompted by our results, in vivo preclinical and clinical studies using cisplatin + CBL0137 to treat TNBC are planned.    

Synthesis and Characterization of Quinoline-3-Carboxamide Derivatives as Inhibitors of the ATM Kinase

2020 ◽  
Vol 20 (23) ◽  
pp. 2070-2079
Author(s):  
Srimadhavi Ravi ◽  
Sugata Barui ◽  
Sivapriya Kirubakaran ◽  
Parul Duhan ◽  
Kaushik Bhowmik
Keyword(s):  
Western Blot ◽  
Cancer Cells ◽  
Cell Line ◽  
Cell Lines ◽  
Cancer Cell ◽  
Blot Analysis ◽  
Western Blot Analysis ◽  
Cancer Cell Lines ◽  
Atm Kinase ◽  
Cytotoxicity Studies

Background: The importance of inhibiting the kinases of the DDR pathway for radiosensitizing cancer cells is well established. Cancer cells exploit these kinases for their survival, which leads to the development of resistance towards DNA damaging therapeutics. Objective: In this article, the focus is on targeting the key mediator of the DDR pathway, the ATM kinase. A new set of quinoline-3-carboxamides, as potential inhibitors of ATM, is reported. Methods: Quinoline-3-carboxamide derivatives were synthesized and cytotoxicity assay was performed to analyze the effect of molecules on different cancer cell lines like HCT116, MDA-MB-468, and MDA-MB-231. Results: Three of the synthesized compounds showed promising cytotoxicity towards a selected set of cancer cell lines. Western Blot analysis was also performed by pre-treating the cells with quercetin, a known ATM upregulator, by causing DNA double-strand breaks. SAR studies suggested the importance of the electron-donating nature of the R group for the molecule to be toxic. Finally, Western-Blot analysis confirmed the down-regulation of ATM in the cells. Additionally, the PTEN negative cell line, MDA-MB-468, was more sensitive towards the compounds in comparison with the PTEN positive cell line, MDA-MB-231. Cytotoxicity studies against 293T cells showed that the compounds were at least three times less toxic when compared with HCT116. Conclusion: In conclusion, these experiments will lay the groundwork for the evolution of potent and selective ATM inhibitors for the radio- and chemo-sensitization of cancer cells.

Design, Synthesis and Biological Evaluation: 5-amino-1H-pyrazole-1- carbonyl derivatives as FGFR Inhibitors

2020 ◽  
Vol 17 (11) ◽  
pp. 1330-1341
Author(s):  
Yan Zhang ◽  
Niefang Yu
Keyword(s):  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Biological Evaluation ◽  
Human Gastric Cancer ◽  
Design Synthesis ◽  
Carbonyl Derivatives ◽  
Ic50 Values ◽  
Inhibitory Activities

Background: Fibroblast growth factors (FGFs) and their high affinity receptors (FGFRs) play a major role in cell proliferation, differentiation, migration, and apoptosis. Aberrant FGFR signaling pathway might accelerate development in a broad panel of malignant solid tumors. However, the full application of most existing small molecule FGFR inhibitors has become a challenge due to the potential target mutation. Hence, it has attracted a great deal of attention from both academic and industrial fields for hunting for novel FGFR inhibitors with potent inhibitory activities and high selectivity. Objective: Novel 5-amino-1H-pyrazole-1-carbonyl derivatives were designed, synthesized, and evaluated as FGFR inhibitors. Methods: A series of 5-amino-1H-pyrazole-1-carbonyl derivatives were established by a condensation of the suitable formyl acetonitrile derivatives with either hydrazine or hydrazide derivatives in the presence of anhydrous ethanol or toluene. The inhibitory activities of the target compounds were screened against the FGFRs and two representative cancer cell lines. Tests were carried out to observe the inhibition of 8e against FGFR phosphorylation and downstream signal phosphorylation in human gastric cancer cell lines (SNU-16). The molecular docking of all the compounds were performed using Molecular Operating Environment in order to evaluate their binding abilities with the corresponding protein kinase. Results: A series of 5-amino-1H-pyrazole-1-carbonyl derivatives have been designed and synthesized, screened for their inhibitory activities against FGFRs and cancer cell lines. Most of the target compounds showed moderate to good anti-proliferate activities against the tested enzymes and cell lines. The most promising compounds 8e suppressed FGFR1-3 with IC50 values of 56.4, 35.2, 95.5 nM, and potently inhibited the SNU-16 and MCF-7 cancer cells with IC50 values of 0.71 1.26 μM, respectively. And 8e inhibited the growth of cancer cells containing FGFR activated by multiple mechanisms. In addition, the binding interactions were quite similar in the molecular models between generated compounds and Debio-1347 with the FGFR1. Conclusion: According to the experimental findings, 5-amino-1H-pyrazole-1-carbonyl might serve as a promising template of an FGFR inhibitor.

Small Molecular Leads Differentially Active Against HER2 Positive and Triple Negative Breast Cancer Cell Lines

2019 ◽  
Vol 15 (7) ◽  
pp. 738-742 ◽  
Author(s):  
Adnan Badran ◽  
Atia-tul-Wahab ◽  
Sharmeen Fayyaz ◽  
Elias Baydoun ◽  
Muhammad Iqbal Choudhary
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Triple Negative ◽  
Cancer Cell Lines ◽  
Breast Cancer Cell Lines ◽  
Cancer Type

Background:Breast cancer is the most prevalent cancer type in women globally. It is characterized by distinct subtypes depending on different gene expression patterns. Oncogene HER2 is expressed on the surface of cell and is responsible for cell growth regulation. Increase in HER2 receptor protein due to gene amplification, results in aggressive growth, and high metastasis in cancer cells.Methods:The current study evaluates and compares the anti-breast cancer effect of commercially available compounds against HER2 overexpressing BT-474, and triple negative MDA-MB-231 breast cancer cell lines.Results:Preliminary in vitro cell viability assays on these cell lines identified 6 lead molecules active against breast cancer. Convallatoxin (4), a steroidal lactone glycoside, showed the most potent activity with IC50 values of 0.63 ± 0.56, and 0.69 ± 0.59 µM against BT-474 and MDA-MB-231, respectively, whereas 4-[4-(Trifluoromethyl)-phenoxy] phenol (3) a phenol derivative, and Reserpine (5) an indole alkaloid selectively inhibited the growth of BT-474, and MDA-MB-231 breast cancer cells, respectively.Conclusion:These results exhibited the potential of small molecules in the treatment of HER2 amplified and triple negative breast cancers in vitro.

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