Antiproliferative activity, mechanism of action and oral antitumor activity of CP-4126, a fatty acid derivative of gemcitabine, in in vitro and in vivo tumor models

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.

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Antiproliferative activity of contragestazol (DL111-IT) in murine and human tumor models in vitro and in vivo

Cancer Chemotherapy and Pharmacology ◽

10.1007/s00280-005-0049-9 ◽

2005 ◽

Vol 57 (2) ◽

pp. 268-273 ◽

Cited By ~ 10

Author(s):

Bo Yang ◽

Qiao-jun He ◽

Dan-yan Zhu ◽

Yi-jia Lou ◽

Rui-ying Fang

Keyword(s):

Antiproliferative Activity ◽

Human Tumor ◽

Tumor Models

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The Combi-Targeting Concept: Dissection of the Binary Mechanism of Action of the Combi-Triazene SMA41 in Vitro and Antitumor Activity in Vivo

Journal of Pharmacology and Experimental Therapeutics ◽

10.1124/jpet.104.071977 ◽

2004 ◽

Vol 311 (3) ◽

pp. 1163-1170 ◽

Cited By ~ 20

Author(s):

Stephanie L. Matheson ◽

James P. McNamee ◽

Taiqui Wang ◽

Moulay A. Alaoui-Jamali ◽

Ana M. Tari ◽

...

Keyword(s):

Antitumor Activity ◽

Mechanism Of Action

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Effectiveness of isolated compound from Aloe barbadensis Miller and its formulated ointment against bacteria and fungi

Journal of Applied Biotechnology & Bioengineering ◽

10.15406/jabb.2021.08.00251 ◽

2021 ◽

Vol 8 (2) ◽

pp. 47-53

Author(s):

Martin Ntiamoah Donkor ◽

Ngmenpone Kuubabongnaa ◽

Addai-Mensah Donkor

Keyword(s):

Fatty Acid ◽

Acid Derivative ◽

Fungal Infections ◽

Fatty Acid Derivative ◽

Aloe Vera ◽

Skin Wound ◽

Pure Compound ◽

Aloe Barbadensis ◽

Talaromyces Flavus

Ethnomedicinally, the family Liliaceae is prominent in controlling skin, wound and fungal infections. A carboxylic fatty acid derivative has been isolated from Aloe vera leaves and its structure was elucidated on the basis of NMR and FT-IR analysis. The compound was formulated as ointment with the aid of polymer based delivery agent. The ointment and the uncontaminated fatty acid have been scrutinized aimed at their anti-infectious potential. Individually, the pure compound and the formulated ointment exhibited growth inhibitory activity against Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Candida albicans and Talaromyces flavus. Minimum inhibitory concentration (MIC) values were found to be appreciably low, ranging between 0.30 and 2.50 mg/ml. The formulated ointment displayed highly significant inhibitory activities against all six pathogens compared to the unformulated compound. The MIC values of the ointment ranged between 0.08 and 1.25 mg/g. The in vitro antibiotic activity studies discovered that, both the pure compound and the formulated ointment showed potency against the selected multi-resistant microorganisms tested in the current work. These findings suggest that the isolated carboxylic acid derivative may be beneficial in the discovery of antibiotics highly potent against drug-resistant pathogens. Furthermore, it may add to the improvement of preservatives in the food industry. Lastly, it could be considered as new source of natural antibiotics in the pharmaceutical industry.

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

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e14086 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e14086-e14086 ◽

Cited By ~ 1

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.

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A new synthetic spiroketal: studies on antitumor activity on murine melanoma model In vivo and mechanism of action In vitro

10.3390/ecmc-4-05621 ◽

2018 ◽

Author(s):

Pietro Spanu ◽

Maria Pia Fuggetta ◽

Franco Morelli ◽

Fausta Ulgheri ◽

Francesco Deligia ◽

...

Keyword(s):

Antitumor Activity ◽

Mechanism Of Action ◽

Murine Melanoma ◽

Melanoma Model

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

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520619666191021162411 ◽

2020 ◽

Vol 20 (4) ◽

pp. 450-463 ◽

Cited By ~ 2

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.

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Abstract 3258: Preclinical evaluation of enhanced irofulven antitumor activity in an ERCC3 mutant background by in vitro and in vivo tumor models

10.1158/1538-7445.am2018-3258 ◽

2018 ◽

Author(s):

Sabine Topka ◽

Sara Khalil ◽

Elisa De Stanchina ◽

Joseph Vijai ◽

Kenneth Offit

Keyword(s):

Antitumor Activity ◽

Tumor Models ◽

Preclinical Evaluation

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Influence of liposomal irinotecan (nal-IRI) and non-liposomal irinotecan, alone and in combination, on tumor growth and angiogenesis in colorectal cancer (CRC) models.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.4_suppl.711 ◽

2018 ◽

Vol 36 (4_suppl) ◽

pp. 711-711 ◽

Cited By ~ 1

Author(s):

Annette K Larsen ◽

Cristiano Trindade ◽

Anaïs Bouygues ◽

Lila K Louadj ◽

Sandrine K Thouroude ◽

...

Keyword(s):

Antitumor Activity ◽

Tumor Cell ◽

Clinical Investigation ◽

Tumor Cell Death ◽

Tumor Models ◽

Antiangiogenic Effect ◽

Biomarker Analysis ◽

Liposomal Irinotecan

711 Background: The long circulating liposomal irinotecan nal-IRI (MM-398/PEP02, Onivyde) is approved for treatment of metastatic pancreatic cancer after disease progression with gemcitabine-based therapy. Besides their direct cytotoxic activity, camptothecins are thought to inhibit tumor angiogenesis via downregulating hypoxia-inducible factor 1 leading to attenuation of VEGF expression. Due to different deposition kinetics, irinotecan HCl and nal-IRI are likely to show different activities in vivo suggesting that a combination of the two agents may optimize intratumoral exposure and improve treatment efficacy. Methods: The activities of nal-IRI, irinotecan and their combination were compared in three human CRC xenograft models with different sensitivity to SN-38, the active metabolite of irinotecan, in vitro. Nal-IRI was dosed at 5 mg/kg q7d, while irinotecan HCl was dosed at 25 mg/kg at days 1 and 2 q7d. The activity of different regimens on tumor cell viability, hypoxia markers and the microvascular density was determined by quantitative biomarker analysis. Results: The relative antitumor activity of nal-IRI was most pronounced in tumor models with natural or acquired irinotecan resistance. Combinations of nal-IRI with irinotecan HCl was significantly better than irinotecan HCl alone in all tumor models although nal-IRI only provided 10% additional irinotecan. The antitumor activity of nal-IRI and Irintecan HCl in combination was accompanied by up to two times more tumor cell death and a marked 3-7 fold reduction of the microvessel density. Despite the strong antiangiogenic effect resulting in tumor hypoxia, the increase in HIF1α and, to lesser degree, HIF2α, was relatively modest and VEGF signal intensity remained at 85-115% of control values. Conclusions: Our results suggest that both irinotecan HCl and nal-IRI can counteract the hypoxia-mediated increase of HIF1α in vivo as previously reported in vitro. Furthermore, the combination of the two formulations demonstrated significant efficacy benefits. A combination of irinotecan HCl and nal-IRI merits further clinical investigation.

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