scholarly journals Improvements in the Oral Absorption and Anticancer Efficacy of an Oxaliplatin-Loaded Solid Formulation: Pharmacokinetic Properties in Rats and Nonhuman Primates and the Effects of Oral Metronomic Dosing on Colorectal Cancer

2020 ◽  
Vol Volume 15 ◽  
pp. 7719-7743
Author(s):  
Rudra Pangeni ◽  
Laxman Subedi ◽  
Saurav Kumar Jha ◽  
Seho Kweon ◽  
Seo-Hee Kang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Nonhuman Primates ◽  
Oral Absorption ◽  
Anticancer Efficacy ◽  
Pharmacokinetic Properties ◽  
Metronomic Dosing

scholarly journals Antiproliferative Efficacy of N-(3-chloro-4-fluorophenyl)-6,7-dimethoxyquinazolin-4-amine, DW-8, in Colon Cancer Cells Is Mediated by Intrinsic Apoptosis

Molecules ◽  
2021 ◽  
Vol 26 (15) ◽  
pp. 4417
Author(s):  
Rabin Neupane ◽  
Saloni Malla ◽  
Mariam Sami Abou-Dahech ◽  
Swapnaa Balaji ◽  
Shikha Kumari ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Colon Cancer Cells ◽  
Apoptotic Pathway ◽  
Anticancer Efficacy ◽  
Colon Cell ◽  
Ic50 Values ◽  
Induced Apoptosis

A novel series of 4-anilinoquinazoline analogues, DW (1–10), were evaluated for anticancer efficacy in human breast cancer (BT-20) and human colorectal cancer (CRC) cell lines (HCT116, HT29, and SW620). The compound, DW-8, had the highest anticancer efficacy and selectivity in the colorectal cancer cell lines, HCT116, HT29, and SW620, with IC50 values of 8.50 ± 2.53 µM, 5.80 ± 0.92 µM, and 6.15 ± 0.37 µM, respectively, compared to the non-cancerous colon cell line, CRL1459, with an IC50 of 14.05 ± 0.37 µM. The selectivity index of DW-8 was >2-fold in colon cancer cells incubated with vehicle. We further determined the mechanisms of cell death induced by DW-8 in SW620 CRC cancer cells. DW-8 (10 and 30 µM) induced apoptosis by (1) producing cell cycle arrest at the G2 phase; (2) activating the intrinsic apoptotic pathway, as indicated by the activation of caspase-9 and the executioner caspases-3 and 7; (3) nuclear fragmentation and (4) increasing the levels of reactive oxygen species (ROS). Overall, our results suggest that DW-8 may represent a suitable lead for developing novel compounds to treat CRC.

scholarly journals Cytotoxic Efficacy and Resistance Mechanism of a TRAIL and VEGFA-Peptide Fusion Protein in Colorectal Cancer Models

2021 ◽  
Vol 22 (6) ◽  
pp. 3160
Author(s):  
Michal Kopczynski ◽  
Malgorzata Statkiewicz ◽  
Magdalena Cybulska ◽  
Urszula Kuklinska ◽  
Katarzyna Unrug-Bielawska ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Lines ◽  
Transmembrane Protein ◽  
Acquired Resistance ◽  
Protein A ◽  
Resistance Mechanism ◽  
Receptor Expression ◽  
Human Colorectal Cancer ◽  
Protein Activity ◽  
Anticancer Efficacy

TNF-related apoptosis-inducing ligand (TRAIL) is a type II transmembrane protein capable of selectively inducing apoptosis in cancer cells by binding to its cognate receptors. Here, we examined the anticancer efficacy of a recently developed chimeric AD-O51.4 protein, a TRAIL fused to the VEGFA-originating peptide. We tested AD-O51.4 protein activity against human colorectal cancer (CRC) models and investigated the resistance mechanism in the non-responsive CRC models. The quantitative comparison of apoptotic activity between AD-O51.4 and the native TRAIL in nine human colorectal cancer cell lines revealed dose-dependent toxicity in seven of them; the immunofluorescence-captured receptor abundance correlated with the extent of apoptosis. AD-O51.4 reduced the growth of CRC patient-derived xenografts (PDXs) with good efficacy. Cell lines that acquired AD-O51.4 resistance showed a significant decrease in surface TRAIL receptor expression and apoptosis-related proteins, including Caspase-8, HSP60, and p53. These results demonstrate the effectiveness of AD-O51.4 protein in CRC preclinical models and identify the potential mechanism underlying acquired resistance. Progression of AD-O51.4 to clinical trials is expected.

scholarly journals Lemongrass Extract Possesses Potent Anticancer Activity Against Human Colon Cancers, Inhibits Tumorigenesis, Enhances Efficacy of FOLFOX, and Reduces Its Adverse Effects

2019 ◽  
Vol 18 ◽  
pp. 153473541988915 ◽  
Author(s):  
Ivan Ruvinov ◽  
Christopher Nguyen ◽  
Benjamin Scaria ◽  
Caleb Vegh ◽  
Ola Zaitoon ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Anticancer Activity ◽  
Cancer Cells ◽  
Human Colon ◽  
Dependent Manner ◽  
Anticancer Efficacy ◽  
Colon Cancers ◽  
Induced Apoptosis

Current chemotherapeutics for metastatic colorectal cancers have limited success and are extremely toxic due to nonselective targeting. Some natural extracts have been traditionally taken and have shown anticancer activity. These extracts have multiple phytochemicals that can target different pathways selectively in cancer cells. We have shown previously that lemongrass ( Cymbopogon citratus) extract is effective at inducing cell death in human lymphomas. However, the efficacy of lemongrass extract on human colorectal cancer has not been investigated. Furthermore, its interactions with current chemotherapies for colon cancer is unknown. In this article, we report the anticancer effects of ethanolic lemongrass extract in colorectal cancer models, and importantly, its interactions with FOLFOX and Taxol. Lemongrass extract induced apoptosis in colon cancer cells in a time and dose-dependent manner without harming healthy cells in vitro. Oral administration of lemongrass extract was well tolerated and effective at inhibiting colon cancer xenograft growth in mice. It enhanced the anticancer efficacy of FOLFOX and, interestingly, inhibited FOLFOX-related weight loss in animals given the combination treatment. Furthermore, feeding lemongrass extract to APCmin/+ transgenic mice led to the reduction of intestinal tumors, indicating its preventative potential. Therefore, this natural extract has potential to be developed as a supplemental treatment for colorectal cancer.

scholarly journals Mucosal Microbiota and Metabolome along the Intestinal Tract Reveal a Location-Specific Relationship

mSystems ◽  
2020 ◽  
Vol 5 (3) ◽  
Author(s):  
Ce Yuan ◽  
Melanie Graham ◽  
Christopher Staley ◽  
Subbaya Subramanian
Keyword(s):  
Colorectal Cancer ◽  
Cardiovascular Disease ◽  
Nonhuman Primates ◽  
Current Knowledge ◽  
Distal Colon ◽  
Food Sources ◽  
Integrated Analysis ◽  
Strongly Correlated ◽  
Dietary Component ◽  
Metabolic Interactions

ABSTRACT The intestinal microbiota is highly metabolically active and plays an important role in many metabolic processes absent from the human host. Altered microbiota metabolism has been linked to diseases such as obesity, cardiovascular disease, and colorectal cancer. However, there is a gap in the current knowledge on how the microbiota interact with its host in terms of metabolic interactions. Here, we performed an integrated analysis between the mucosa-associated microbiota and the mucosa metabolome in healthy, nonhuman primates to investigate these relationships. The microbiota composition was distinct at each tissue location, with variation by host individual also observed. Microbiota-metabolome dynamics were primarily driven by interactions in the distal colon. These interactions were strongly correlated with dietary component, indicating a possibility to modulate microbiota-metabolomic interactions using prebiotic strategies. IMPORTANCE In a healthy colon, the microbiota produces a vast amount of metabolites that are essential to maintaining homeostasis in the colon microenvironment. In fact, these metabolites produced by the microbiota have been linked to diseases such as obesity, cardiovascular disease, and colorectal cancer. In this study, we used healthy nonhuman primate models to investigate the relationship between microbiota and tissue metabolites. We found that both microbiota and metabolites have location-specific signatures along the intestine. Most importantly, we found that metabolites from food sources correlate with multiple bacteria in different intestinal locations. Overall, this work presents a systems-level map of the association between the microbiota and the metabolites in healthy nonhuman primates, provides candidates for experimental validation, and suggests a possibility to regulate the gut microbiota through specific prebiotic combinations.

GRPR-targeted SPECT imaging using a novel bombesin-based peptide for colorectal cancer detection

2020 ◽  
Vol 8 (23) ◽  
pp. 6764-6772 ◽  
Author(s):  
Peifei Liu ◽  
Yuanbiao Tu ◽  
Ji Tao ◽  
Zicun Liu ◽  
Fang Wang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Detection ◽  
Tumor Targeting ◽  
Spect Imaging ◽  
Intestinal Activity ◽  
Cancer Models ◽  
Pharmacokinetic Properties ◽  
Targeting Peptide ◽  
Targeting Ability

The designed novel targeting peptide GB-6 binding to GRPR possesses more favorable pharmacokinetic properties with lower intestinal activity as well as superior tumor-targeting ability in colorectal cancer models than BBN7–14.

Retrospective evaluation of patients with colorectal cancer (CRC) and type II non-insulin-dependent diabetes (NIDDM).

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 507-507
Author(s):  
H. Hassabo ◽  
M. Hassan ◽  
B. George ◽  
S. Wen ◽  
V. Baladandayuthapani ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Cox Regression ◽  
Residual Tumor ◽  
Colorectal Adenomas ◽  
Anticancer Efficacy ◽  
Cancer Data ◽  
Increased Risk ◽  
Risk Of Cancer ◽  
Niddm Patients

507 Background: Patients with NIDDM have an increased risk of colorectal adenomas and CRC possibly mediated through the insulin growth factor receptor pathway. Metformin is associated with anticancer efficacy in preclinical models and a lower risk of cancer mortality in patients with NIDDM. We undertook to evaluate the difference in outcome in NIDDM patients with CRC based upon their medications taken for glycemic control. Methods: We conducted an IRB-approved (DR09-0719) retrospective analysis of 4,758 patients seen at a single institution (University of Texas M. D. Anderson) with CRC between the years of 2005-2008, to determine the prevalence of NIDDM in this patient population, in addition to determining whether patient survival differs based upon their diabetic therapy. Results: 425 out of 4,758 CRC patients (8.9%) were identified as having NIDDM. Gender, male:female 283:142 (67%, 33%), age, mean 62 years (range 31-91), stage I/II/III/IV 37:55:175:158 (8.7%, 12.9%, 41.2%, 37.2%). Overall survival (OS) for the 397 patients with follow-up data available, by univariable Kaplan Meier analysis, was 63.7 months (95% confidence interval (CI), 52.3-75.5). Patients with NIDDM and CRC treated with metformin as one of their diabetic medications had a survival of 76.9 months (95% CI, 61.4-102.4) as compared to 56.9 months in those patients not treated with metformin (95% CI, 44.8- 68.8), p = 0.048. By using a Cox regression model adjusted for age, sex, race, body mass index, and initial stage of disease we demonstrated that NIDDM patients treated with metformin had a 30% improvement in OS when compared to NIDDM patients treated with other diabetic agents. There was a non-statistically significant trend toward higher complete and minor pathologic response rate (≤ 10% residual tumor) in NIDDM patients with rectal cancer receiving chemoradiation who were treated with metformin when compared to those who were not (14/19, 74% vs. 9/19, 47%, p = 0.09). Conclusions: In this analysis the use of metformin in NIDDM patients with CRC was associated with an improved overall survival. While these results are consistent with the findings in other solid tumors they will need to be validated in other colorectal cancer data sets. No significant financial relationships to disclose.

Molecular Docking, Physicochemical Properties, Pharmacokinetics and Toxicity of Flavonoids Present in Euterpe Oleracea Martius

2020 ◽  
Vol 16 ◽  
Author(s):  
Nayana Keyla Seabra de Oliveira ◽  
Marcos Rafael Silva Almeida ◽  
Franco Márcio Maciel Pontes ◽  
Mariana Pegrucci Barcelos ◽  
Guilherme Martins Silva ◽  
...  
Keyword(s):  
Physicochemical Properties ◽  
Oral Absorption ◽  
Antioxidant Properties ◽  
Euterpe Oleracea ◽  
Docking Simulations ◽  
Lipinski’S Rule ◽  
Antioxidant Agents ◽  
Pharmacokinetic Properties

Background: Euterpe oleracea Martius, popularly known as açaí, is a fruit rich in α-tocopherols, fibers, lipids, mineral ions and polyphenols. It is believed that the high content of polyphenols, specially flavonoids, provides several health-promoting effects to the açaí fruit, including anti-inflammatory, immunomodulatory, antinociceptive and antioxidant properties. Most of flavonoids are antioxidant molecules from vegetable origin that act as a trap for free radicals, reacting and neutralizing them, thus offering perspectives in preventing oxidative damage. Objective: In this study we aim to perform an in silico evaluation of flavonoids present in the pulp and in the oil of Euterpe oleracea Martius, and their potential to represent antioxidant agents. Methods: First, we selected 16 flavonoid molecules present in Euterpe oleracea Martius pulp and oil, and then their physicochemical properties were analysed with respect to the Lipinski’s rule of five. Moreover, we evaluated their pharmacokinetic properties using the QikProp module of the Schrödinger software and their toxicity profile using the DEREK software. Docking simulations in the GOLD 4.1 software and calculation of the pharmacophore hypothesis of molecules were also performed. Results: Flavonoids present in the açaí pulp, catechin, epicatechin, luteolin, chrisoeriol, taxifolin, apigenin, dihydrokaempferol, isovitexin and vitexin presented good oral bioavailability. Regarding pharmacokinetic properties, the compounds catechin, epicatechin, isovitexin, luteolin, chrisoeriol, taxifolin and isorhamnetina rutinoside presented the best results and high human oral absorption. In the prediction of toxicological properties, compounds isorhamnetin rutinoside and rutin presented alert concerning mutagenicity for hydroxynaphthalene or derivate, and in docking simulations all the compounds presented key interactions with the corresponding targets tested. Conclusion: The flavonoids catechin, chrysoeriol and taxifolin presented overall best results, allowing such computational results to serve as a theoretical basis for future studies of developing drug candidates for biological tests in vitro and in vivo, which can contribute to the treatment of neurodegenerative diseases.

Folate-Functionalized Amphiphilic Chitosan Polymeric Micelles Containing Andrographolide Analogue (3A.1) for Colorectal Cancer

2019 ◽  
Vol 819 ◽  
pp. 15-20
Author(s):  
Teeratas Kansom ◽  
Ekachai Dumkliang ◽  
Prasopchai Patrojanasophon ◽  
Warayuth Sajomsang ◽  
Rungnapha Saeeng ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Physicochemical Properties ◽  
Cancer Cells ◽  
Delivery System ◽  
Polymeric Micelles ◽  
Loading Capacity ◽  
Site Specific ◽  
Anticancer Efficacy ◽  
Colorectal Cancer Cells

A site-specific drug delivery system of anticancer agents has been delveloped to enhance the therapeutic efficacy and reduce toxicity to the normal tissue. Semi-synthetic andrographolide analogue 3A.1 (19-tert-butyldiphenylsilyl-8,17-epoxy andrographolide) is one of the potential natural anticancer compounds against many types of cancer including colorectal cancer cells. However, the clinical applications of this compound are limited because of low water solubility and lack of suitable delivery carriers. This study aimed to increase the aqueous solubility and improve the anticancer efficacy of 3A.1 via active targeting approaches. In this study, 3A.1 was loaded into the polymeric micelles self-assembled from N-naphthyl-N,O-succinyl chitosan (NSC). The micelles were conjugated with folate moiety (Fol-NSC) for targeting to the cancer cells. All of the 3A.1-loaded micelles were prepared by dropping method, and the physicochemical properties (size, charge, morphology, encapsulating efficiency, loading capacity), in vitro release behavior and in vitro anticancer activities against HT29 colorectal cancer cells were investigated. The 3A.1-loaded micelles were successfully formulated by dropping method using NSC or Fol-NSC. The micelles loaded with 40% initial 3A.1 showed the maximum encapsulating efficiency and loading capacity. The micelles were in the nanometer range, having a negative surface charge and a spherical structure. The colon site-specific release of the 3A.1 from the 3A.1-loaded micelles was obtained. The release of 3A.1 from the Fol-NSC micelles was slower than that from the NSC micelles. Moreover, the Fol-NSC micelles exhibited superior anticancer efficacy than that of the NSC micelles and free 3A.1. In conclusions, the 3A.1-loaded Fol-NSC micelles developed in the present study had suitable physicochemical properties. These nanocarriers may be a potential delivery system for targeted delivery of the 3A.1 to colorectal cancer cells.

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