The Antitumor Activity of a Novel Fluorobenzamidine against Dimethylhydrazine- Induced Colorectal Cancer in Rats

2020 ◽  
Vol 20 (4) ◽  
pp. 450-463 ◽  
Author(s):  
Mohammed Abdel-Rasol ◽  
Nadia M. El-Beih ◽  
Shaymaa M.M. Yahya ◽  
Mohamed A. Ismail ◽  
Wael M. El-Sayed
Keyword(s):  
Colorectal Cancer ◽  
Antitumor Activity ◽  
Antiproliferative Activity ◽  
Male Rats ◽  
Group 4 ◽  
Extrinsic Apoptosis ◽  
Hct 116 ◽  
Group 5

Background: Colorectal cancer is among the leading causes of death worldwide. The incidence of deaths is expected to be 11.4 million in 2030. Objective: We aimed to evaluate the in vitro and in vivo antioxidant and antitumor activities of a novel Bithiophene- Fluorobenzamidine (BFB) against DMH-induced colorectal cancer in rats. Methods: The antiproliferative activity of BFB against HCT-116 colon cancer cells and apoptotic genes was assessed. In vivo study was also conducted in which 80 adult male rats were divided into 5 groups; control, BFB, and the other 3 groups were injected with DMH (20mg/kg, s.c., for 9 weeks). Group 4 was injected with 5 doses of cisplatin (2.5mg/kg, i.p over 21 weeks) and group 5 was injected with 3 doses/week of BFB (2.5mg/kg, i.p, for 21 weeks). Results: BFB exhibited weak to moderate in vitro antioxidant activity. It had a strong antiproliferative activity with IC50 ~0.3µg/ml. BFB induced extrinsic apoptosis through the upregulation of FasL, TRAL, p53 and caspase-8, and intrinsic apoptosis through the downregulation of Bcl-2 and survivin. BFB decreased the tumor incidence, multiplicity and size and improved the decreased body weight. BFB also ameliorated the functions of kidney and liver and antioxidants deteriorated by DMH. BFB significantly improved the pathological changes caused by DMH in colon tissues. Conclusion: BFB showed a very promising antitumor activity against colorectal cancer induced by DMH in rats without causing hepato- or nephrotoxicity.

scholarly journals Design, Synthesis, Molecular Modeling and Antitumor Evaluation of Novel Indolyl-Pyrimidine Derivatives with EGFR Inhibitory Activity

Molecules ◽  
2021 ◽  
Vol 26 (7) ◽  
pp. 1838
Author(s):  
Naglaa M. Ahmed ◽  
Mahmoud M. Youns ◽  
Moustafa K. Soltan ◽  
Ahmed M. Said
Keyword(s):  
Molecular Modeling ◽  
Antitumor Activity ◽  
Cell Lines ◽  
Cancer Cell ◽  
Antiproliferative Activity ◽  
Antitumor Agents ◽  
Cancer Cell Lines ◽  
Normal Cells

Scaffolds hybridization is a well-known drug design strategy for antitumor agents. Herein, series of novel indolyl-pyrimidine hybrids were synthesized and evaluated in vitro and in vivo for their antitumor activity. The in vitro antiproliferative activity of all compounds was obtained against MCF-7, HepG2, and HCT-116 cancer cell lines, as well as against WI38 normal cells using the resazurin assay. Compounds 1–4 showed broad spectrum cytotoxic activity against all these cancer cell lines compared to normal cells. Compound 4g showed potent antiproliferative activity against these cell lines (IC50 = 5.1, 5.02, and 6.6 μM, respectively) comparable to the standard treatment (5-FU and erlotinib). In addition, the most promising group of compounds was further evaluated for their in vivo antitumor efficacy against EAC tumor bearing mice. Notably, compound 4g showed the most potent in vivo antitumor activity. The most active compounds were evaluated for their EGFR inhibitory (range 53–79 %) activity. Compound 4g was found to be the most active compound against EGFR (IC50 = 0.25 µM) showing equipotency as the reference treatment (erlotinib). Molecular modeling study was performed on compound 4g revealed a proper binding of this compound inside the EGFR active site comparable to erlotinib. The data suggest that compound 4g could be used as a potential anticancer agent.

scholarly journals A Novel Lactic Acid Bacteria Mixture: Macrophage-Targeted Prophylactic Intervention in Colorectal Cancer Management

2020 ◽  
Vol 8 (3) ◽  
pp. 387
Author(s):  
Petra Hradicka ◽  
Jane Beal ◽  
Monika Kassayova ◽  
Andrew Foey ◽  
Vlasta Demeckova
Keyword(s):  
Colorectal Cancer ◽  
Male Rats ◽  
Cancer Management ◽  
Immune Parameters ◽  
Chemically Induced ◽  
Tnf Α ◽  
Vitro Model ◽  
Macrophage Subsets

Colorectal cancer (CRC) is one of the most common forms of cancer. Its onset from chronic inflammation is widely accepted. Moreover, dysbiosis plays an undeniable role, thus the use of probiotics in CRC has been suggested. They exhibit both anti- and pro-inflammatory properties and restore balance in the microbiota. The aim of this study was to investigate the immunomodulatory properties of six lactobacilli with probiotic features in an in vitro model of macrophage-like cells and to test these pooled probiotics for their anti-tumour properties in a chemically induced CRC model using Wistar male rats. Upon co-culture of M1- and M2-like macrophages with lactobacilli, cytokine release (TNF-α, IL-1β, IL-18, IL-23) and phagocytic activity using fluorescent-labelled bacteria were tested. The effects of orally administered probiotics on basic cancer and immune parameters and cytokine concentration (TNF-α, IL-1β, IL-18) in colon tumours were studied. Tested lactobacilli exhibited both pro- and anti-inflammatory properties in in vitro conditions. In vivo study showed that the administration of probiotics was able to decrease multiplicity, volume and total tumour numbers, restore colon length (p < 0.05) and increase IL-18 production (p < 0.05) in tumour tissue. These data indicate both an immunomodulatory effect of probiotics on distinct macrophage subsets and a protective effect against chemically-induced CRC.

scholarly journals Aspirin suppresses chemoresistance and enhances antitumor activity of 5-Fu in 5-Fu-resistant colorectal cancer by abolishing 5-Fu-induced NF-κB activation

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Jinbo Fu ◽  
Yiming Xu ◽  
Yushan Yang ◽  
Yun Liu ◽  
Lulu Ma ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Antitumor Activity ◽  
Therapeutic Agent ◽  
Inhibitory Effect ◽  
Antitumor Activities ◽  
Tumor Cell Apoptosis ◽  
Tumor Growth And Metastasis ◽  
Resistant Cells

AbstractChemoresistance to 5-fluorouracil (5-Fu)-based chemotherapy is a leading obstacle in achieving effective treatment for colorectal cancer (CRC). Typically, NF-κB activation induced by the chemotherapeutics themselves is an important cause resulting in chemoresistance. Specifically, NF-κB activation can inhibit tumor cell apoptosis and induce chemoresistance. Drugs that can prevent NF-κB activation induced by chemotherapeutics are urgently needed to overcome chemoresistance. Obviously, aspirin is one of these agents, which has been demonstrated to possess antitumor activities and as an inhibitor of NF-κB. The current study aimed to investigate whether aspirin was able to overcome the chemoresistance to 5-Fu in CRC, together with the potential synergistic mechanisms. Our results suggested that aspirin remarkably potentiated the inhibitory effect of 5-Fu on the growth and invasion of resistant cells in vitro. In vivo, aspirin markedly enhanced the antitumor activity of 5-Fu in suppressing tumor growth and metastasis, and down-regulating the expression of NF-κB-regulated genes in the 5-Fu-resistant cells. Obviously, aspirin completely eradicated the 5-Fu-induced NF-κB activation, without inducing pronounced adverse effects. Taken together, findings in this study suggest that aspirin can reverse chemoresistance and potentiate the antitumor effect of 5-Fu, which is achieved through abolishing the 5-Fu-induced NF-κB activation, suggesting that aspirin may be a promising adjuvant therapeutic agent for CRC.

scholarly journals Effect of Oxaliplatin-Loaded Poly (d,l-Lactide-co-Glycolic Acid) (PLGA) Nanoparticles Combined with Retinoic Acid and Cholesterol on Apoptosis, Drug Resistance, and Metastasis Factors of Colorectal Cancer

Pharmaceutics ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 193 ◽  
Author(s):  
Ana Luiza C. de S. L. Oliveira ◽  
Raimundo Fernandes de Araújo Júnior ◽  
Thaís Gomes de Carvalho ◽  
Alan B. Chan ◽  
Timo Schomann ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Drug Resistance ◽  
Retinoic Acid ◽  
Antitumor Activity ◽  
Glycolic Acid ◽  
Plga Nanoparticles ◽  
Ki 67 ◽  
Apoptotic Proteins

Apoptosis signaling pathways, drug resistance, and metastasis are important targets to develop new cancer treatments. We developed cholesterol-coated Poly(d,l-Lactide-co-Glycolic Acid) (PLGA) nanoparticles for effective encapsulation and delivery of retinoic acid and oxaliplatin to analyze their antitumor activity in colorectal cancer. The cell viability and proliferation of tumoral cells lines (CT-26 and SW-480) decreased when compared to control in vitro after treatment with the nanoparticles. In addition, apoptosis of CT-26 cells increased. Importantly, cytoprotection of nontumor cells was detected. Expression of pro-apoptotic proteins was upregulated, while anti-apoptotic proteins were downregulated either in vitro or in vivo. In addition, drug resistance and metastasis factors were downregulated in vivo. Human colorectal tumors that highly expressed BCL-2 and Ki-67 had a greater tendency towards death within 60 months. Our results show that loading oxaliplatin combined with retinoic acid and cholesterol in a nanoparticle formulation enables determination of optimal antitumor activity and subsequent treatment efficacy.

Atractylenolide III induces apoptosis by regulating the Bax/Bcl-2 signaling pathway in human colorectal cancer HCT-116 Cells in vitro and in vivo

2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Dan Zhang ◽  
Xiaofang Xiao ◽  
Daqiang Song ◽  
Siwei Chen ◽  
Zhuo Zhang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Signaling Pathway ◽  
Human Colorectal Cancer ◽  
Hct 116 ◽  
Hct 116 Cells ◽  
Atractylenolide Iii

In vitro and in vivo effects of the mTOR inhibitors everolimus (EVE) and temsirolimus (TEM).

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 466-466
Author(s):  
David Chen ◽  
Michael Terence O'Reilly ◽  
Paul M.J. McSheehy
Keyword(s):  
Cell Proliferation ◽  
Antitumor Activity ◽  
A549 Cells ◽  
Human Tumor ◽  
Mtor Inhibitors ◽  
In Vivo Models ◽  
Hct 116 ◽  
Xenograft Models

466 Background: Two mTOR inhibitors are approved for treating mRCC: EVE following the failure of VEGF-targeted therapy and TEM as first-line therapy in poor-risk patients. Both agents exert their clinical effect by binding to FKBP-12, which then interacts with mTOR to inhibit its kinase activity. We compared the activity of EVE and TEM in in vitro and in vivo models. Methods: EVE and TEM binding to mTOR was assessed using time-resolved fluorescence resonance energy transfer. Inhibition of cell proliferation in A549, NCI-H460, and MCF7 human tumor cell lines was assessed by methylene blue protein staining. Phosphorylation of the downstream mTOR target pS6 was assessed via immunohistochemistry in A549 cells. Antitumor activity of EVE (oral) and TEM (intraperitoneal) at doses between 0.1 and 2.5 mg/kg once daily was assessed in vivo in A549, KB-31, KB-8511, and HCT-116 human tumor xenograft models. Results: The binding efficiency of TEM for mTOR was reduced 10-fold compared with that of EVE (EC50, 56 nM vs 6 nM; p < 0.01). EVE demonstrated 6- to 7-fold greater inhibition of cell proliferation than TEM (IC50, 1.0 nM vs 6.5 nM in A549 [p < 0.001], 0.7 nM vs 4.7 nM in NCI-H460 [p < 0.01], and 19.4 nM vs 150 nM in MCF7 [p < 0.001]). Complete inhibition of pS6 phosphorylation in A549 cells at 24 hours was achieved with 6.7 nM EVE, but required 20 nM TEM. In all xenograft models, EVE and TEM showed a dose-response relationship over the range of 0.1-2.5 mg/kg/day. EVE was significantly more potent than TEM in the A549 model (EC50, 0.11 mg/kg vs 0.51 mg/kg; p = 0.002); no appreciable differences between EVE and TEM were observed in the KB-31, KB-8511, and HCT-116 xenograft models. However, correcting for drug exposure suggests increased potency of EVE over TEM. Conclusions: Compared with TEM, EVE had a higher affinity for the molecular target of FKBP-12. This was consistent with more potent antitumor activity in vitro and in vivo. Whether these data would translate into a better therapeutic index for EVE is unknown. However, the results suggest that these mTOR inhibitors may not be clinically interchangeable.

scholarly journals Co-administration of vitamin E and selenium in vivo and in vitro ameliorates the toxic effects caused by ivermection and doramectin

2020 ◽  
Vol 65 (No. 2) ◽  
pp. 71-83 ◽  
Author(s):  
AE Ahmed ◽  
MA Al-Kahtani ◽  
AM Khalil ◽  
AS Alshehri ◽  
AA Elghoneimy ◽  
...  
Keyword(s):  
Vitamin E ◽  
Caspase 3 ◽  
Saline Group ◽  
Male Rats ◽  
Skin Cells ◽  
Group 5 ◽  
Group 2 ◽  
Cellular Dna

Avermectins are used in animals and humans for their broad-spectrum effects against parasites causing cytotoxicity and damage to the cellular DNA. In this study, we examined the toxicological changes of ivermectin (IVM) and doramectin (DME) with or without the co-administration of vitamin E (Vit. E) and selenium (Se). The drugs used were for animal use. Twenty-five adult male rats were divided into five groups. Group 1 (control) was given saline, Group 2 was given IVM (0.2 mg/kg b.w.), Group 3 was given IVM and Vit. E/Se (80/1.6 mg/kg b.w., respectively), Group 4 received DME (0.2 mg/kg b.w.), and Group 5 received DME and Vitamin E/Se. Both IVM and DME were given by subcutaneous injections whereas Vit. E and Se were given orally. All the treatments were given once per week throughout the eight weeks. Although the doses were off-label use, they were given in a long-term course to unveil their toxicity effects in a clear manner and the response of the amelioration. By 24-h after the 8<sup>th</sup> week, the rats were sacrificed. Their blood was sampled for the haematological and serobiochemical examinations. Histopathological changes and caspase-3 were determined in the hepatic and renal tissues. The histopathological findings showed that Vit. E and Se reduced the cellular changes induced by IVM or DME, indicating that Vit. E and Se protect against both types of avermectins, and that DME was safer than IVM. The cytotoxicity was assessed on a human embryo kidney (HEK) and skin cells by the SRB/IC<sub>50</sub> method and AO/EB (acridine orange-ethidium bromide) staining. Both IVM and DME caused apoptosis in the cultured HEK more than in the skin cells (80% vs. 30%, respectively). The cellular apoptosis in response to the IVM was more than that of DME, and the use of Vit. E and Se reduced the cytotoxicity as observed by caspase-3, in vivo, and IC<sub>50</sub>, in vitro.

Preclinical in vitro and in vivo study of UD-017, a novel highly selective and orally available CDK7 inhibitor, in a variety of cancers.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14086-e14086 ◽  
Author(s):  
Kazuhiro Onuma ◽  
Yasuhiro Aga ◽  
Sayaka Ogi ◽  
Takashi Matsushita ◽  
Hidetoshi Sunamoto ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Cancer Cells ◽  
Antiproliferative Activity ◽  
Xenograft Model ◽  
Antitumor Efficacy ◽  
Expression Levels ◽  
Oncogenic Driver ◽  
Xenograft Models

e14086 Background: Cyclin dependent kinase 7 (CDK7) modulates mRNA transcription and some oncogenes are reported to be sensitive to inhibition of transcription in certain cancer cells. CDK7 inhibitors have been considered as an intriguing approach to treat cancers that depend on transcriptional regulation of their oncogenes. We synthesized a novel highly selective CDK7 inhibitor, UD-017, and found that the compound showed antitumor potency in a variety of cancers in vitro and in vivo. We therefore explored underlying mechanisms especially focusing on an oncogenic driver, c-Myc. Methods: We examined CDK7 selectivity of UD-017 against the other CDKs and kinases. We evaluated an antiproliferative activity of UD-017 in over 200 multiple types of cancer cell lines including patients-derived cancer cells. We then investigated the correlation between c-Myc expression levels and an antiproliferative activity of UD-017 in cancer cells. Antitumor efficacy of UD-017 was assessed in multiple types of cancer xenograft models and patients-derived xenograft model. We determined whether an intratumoral c-Myc expression levels correlated with in vivo antitumor efficacy of UD-017 in xenograft models. Results: UD-017 inhibited CDK7 enzyme (IC50= 16 nM) highly selectively among the CDKs (over 300-fold) and almost mono-specifically in a panel of 313 kinases assay. In a cellular antiproliferative panel assay, UD-017 broadly inhibited the proliferation of a variety of cancer cells and c-Myc expression levels showed the good correlation with antiproliferative activity. UD-017 showed favorable PK profile and good oral absorbability and showed the potent antitumor activity in multiple types of cancer xenograft models in mice. In correlation with the PK, UD-017 reduced the intratumoral c-Myc mRNA levels time-dependently after dosing of UD-017 in the colorectal cancer xenograft model. Conclusions: We identified a highly selective and orally available CDK7 inhibitor that showed the broad in vitro and in vivo antitumor activity in a variety of cancers, modulating c-Myc as an oncogenic driver. These data support the rationale for further advancing towards clinical development.

Effects of SM08502, a novel, oral small-molecule inhibitor of Wnt pathway signaling, on gene expression and antitumor activity in colorectal cancer (CRC) models.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15185-e15185 ◽  
Author(s):  
Carine Bossard ◽  
Kevin Chiu ◽  
Heekyung Chung ◽  
John Duc Nguyen ◽  
Emily Creger ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Proliferation ◽  
Antitumor Activity ◽  
Wnt Signaling ◽  
Cell Lines ◽  
Wnt Pathway ◽  
Pathway Gene ◽  
Hct 116

e15185 Background: Aberrant activation of Wnt signaling contributing to tumorigenesis is most commonly associated with CRC (90% harbor Wnt pathway mutations). SM08502, a novel, oral Wnt signaling pathway inhibitor, was evaluated in preclinical CRC models. Methods: In vitro Wnt signaling: assessed using TOPflash β-catenin/TCF reporter assay in SW480 human CRC cells. In vitro Wnt pathway gene expression: measured by qRT-PCR in SW480 and Wnt3a-stimulated cells (HEK-293T, IEC-6), and with the Nanostring Wnt pathway array (180 genes) across a panel of 16 CRC cell lines. In vitro cell proliferation: 17 CRC cell lines were used to test cell viability following treatment. In vivo antitumor activity: Oral SM08502 was tested in CRC mouse xenografts (SW480, HCT 116) and a PDX model over 20-21 days (QD, QOD). 24-hr pharmacodynamic (PD) analysis of Wnt pathway gene expression was done in SW480 tumor explants from mice following one 25 mg/kg dose. Results: SM08502 inhibited Wnt pathway signaling (EC50 = 46 nM) in SW480 cells. Wnt pathway gene expression was inhibited by SM08502 (0.3-3 µM) in Wnt3a-stimulated cells ( AXIN2, LEF1) and SW480 ( AXIN2, CTNNB1, LEF1, MYC, TCF7, TCF7L2) at 24 hrs ( P < .05 vs. vehicle) . Corresponding effects on protein expression were confirmed for all genes except CTNNB1, suggesting SM08502 acted independently of β-catenin. Nanostring array screening identified inhibition of LRP5, DVL2, BTRC, and ERBB2 by SM08502. Cell proliferation was inhibited in all 17 lines (avg. EC50 = 177 nM). In vivo, SM08502 was well tolerated and induced dose-dependent antitumor effects in xenografts and PDX models. Tumor growth inhibition for 25 mg/kg QD (max dose) was 83%, 56%, and 70% in SW480, HCT 116, and PDX, respectively. PD analysis showed significant inhibition ( P< .05 vs. vehicle) of TCF7, MYC, LRP5, DVL2, and BTRC expression 8 hrs post treatment. Conclusions: In preclinical CRC models, SM08502 was a potent inhibitor of Wnt pathway signaling and gene expression. It showed strong antitumor activity in human tumor models with activating Wnt pathway mutations. The safety, tolerability, and PK of SM08502 are being evaluated in an ongoing phase 1 study (NCT03355066).

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