acriflavine and Colorectal-Neoplasms

Crosstalk between cancer-associated fibroblasts (CAFs) and colorectal cancer cells promotes tumor growth and contributes to chemoresistance. In this study, we assessed the sensitivity of a primary CAF cell line, CT5.3hTERT, to standard-of-care and alternative cytotoxic treatments. Paclitaxel (PTX) and acriflavine (ACF) were identified as the most promising molecules to inhibit CAF development. To allow the translational use of both drugs, we developed lipid nanocapsule (LNC) formulations for PTX and ACF. Finally, we mixed CAFs and tumor cell lines in a cocultured spheroid, and the effect of both drugs was investigated by histological analyses. We demonstrated CAF inhibition by LNC-ACF and whole tumor inhibition by LNC-PTX. Altogether, we proposed a new strategy to reduce CAF populations in the colorectal microenvironment that should be tested in vivo.

Topics: Acriflavine; Antineoplastic Agents; Cancer-Associated Fibroblasts; Cell Line, Tumor; Cell Survival; Chemistry, Pharmaceutical; Colorectal Neoplasms; Drug Carriers; HCT116 Cells; Humans; Lipids; Nanocapsules; Paclitaxel; Tumor Microenvironment

Doxorubicin (DOX) liposome is a widely used nano-medicine for colorectal cancer treatment. However, doxorubicin therapy increases the level of reactive oxygen species (ROS) in tumor cells, such as hydrogen peroxide (H

Topics: Acriflavine; Animals; Antibiotics, Antineoplastic; Cell Hypoxia; Colorectal Neoplasms; Doxorubicin; Drug Resistance, Neoplasm; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Mice; Mice, Inbred BALB C; Neoplasms, Experimental; Particle Size; Polyethylene Glycols; Reactive Oxygen Species; Surface Properties; Tumor Microenvironment

Hypoxia-inducible factors (HIFs) accumulate in both neoplastic and inflammatory cells within the tumor microenvironment and impact the progression of a variety of diseases, including colorectal cancer. Pharmacological HIF inhibition represents a novel therapeutic strategy for cancer treatment. We show here that acriflavine (ACF), a naturally occurring compound known to repress HIF transcriptional activity, halts the progression of an autochthonous model of established colitis-associated colon cancer (CAC) in immunocompetent mice. ACF treatment resulted in decreased tumor number, size and advancement (based on histopathological scoring) of CAC. Moreover, ACF treatment corresponded with decreased macrophage infiltration and vascularity in colorectal tumors. Importantly, ACF treatment inhibited the hypoxic induction of M-CSFR, as well as the expression of the angiogenic factor (vascular endothelial growth factor), a canonical HIF target, with little to no impact on the Nuclear factor-kappa B pathway in bone marrow-derived macrophages. These effects probably explain the observed in vivo phenotypes. Finally, an allograft tumor model further confirmed that ACF treatment inhibits tumor growth through HIF-dependent mechanisms. These results suggest pharmacological HIF inhibition in multiple cell types, including epithelial and innate immune cells, significantly limits tumor growth and progression.

Topics: Acriflavine; Animals; Antineoplastic Agents; Aryl Hydrocarbon Receptor Nuclear Translocator; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Disease Models, Animal; Disease Progression; Female; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Macrophages; Mice; Neovascularization, Pathologic; Signal Transduction; Transcription, Genetic; Tumor Burden; Xenograft Model Antitumor Assays

A high-throughput screen of the cytotoxic activity of 2000 molecules from a commercial library in three human colon cancer cell lines and two normal cell types identified the acridine acriflavin to be a colorectal cancer (CRC) active drug. Acriflavine was active in cell spheroids, indicating good drug penetration and activity against hypoxic cells. In a validation step based on primary cultures of patient tumor cells, acriflavine was found to be more active against CRC than ovarian cancer and chronic lymphocytic leukemia. This contrasted to the activity pattern of the CRC active standard drugs 5-fluorouracil, irinotecan and oxaliplatin. Mechanistic studies indicated acriflavine to be a dual topoisomerase I and II inhibitor. In conclusion, the strategy used seems promising for identification of new diagnosis-specific cancer drugs.

Topics: Acriflavine; Camptothecin; Cell Line, Tumor; Colorectal Neoplasms; DNA Topoisomerases, Type I; DNA Topoisomerases, Type II; Drug Screening Assays, Antitumor; Female; Fluorouracil; High-Throughput Screening Assays; Humans; Irinotecan; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Organoplatinum Compounds; Ovarian Neoplasms; Oxaliplatin; Topoisomerase I Inhibitors; Topoisomerase II Inhibitors

A confocal laser endoscopy system has recently been developed that may allow subsurface imaging of living cells in colonic tissue in vivo. The aim of the present study was to assess its potential for prediction of histology during screening colonoscopy for colorectal cancer.. Twenty-seven patients underwent colonoscopy with the confocal endoscope using acriflavine hydrochloride or fluorescein sodium with blue laser illumination. Furthermore, 42 patients underwent colonoscopy with this system using fluorescein sodium. Standardized locations and circumscript lesions were examined by confocal imaging before taking biopsy specimens. Confocal images were graded according to cellular and vascular changes and correlated with conventional histology in a prospective and blinded fashion.. Acriflavine hydrochloride and fluorescein sodium both yielded high-quality images. Whereas acriflavine hydrochloride strongly labeled the superficial epithelial cells, fluorescein sodium offered deeper imaging into the lamina propria. Fluorescein sodium was thus used for the prospective component of the study in which 13,020 confocal images from 390 different locations were compared with histologic data from 1038 biopsy specimens. Subsurface analysis during confocal laser endoscopy allowed detailed analysis of cellular structures. The presence of neoplastic changes could be predicted with high accuracy (sensitivity, 97.4%; specificity, 99.4%; accuracy, 99.2%).. Confocal laser endoscopy is a novel diagnostic tool to analyze living cells during colonoscopy, thereby enabling virtual histology of neoplastic changes with high accuracy. These newly discovered diagnostic possibilities may be of crucial importance in clinical practice and lead to an optimized rapid diagnosis of neoplastic changes during ongoing colonoscopy.

Topics: Acriflavine; Carcinoma in Situ; Colonoscopy; Colorectal Neoplasms; Contrast Media; Fluorescein; Fluorescent Dyes; Humans; Mass Screening; Microscopy, Confocal; Predictive Value of Tests; Prospective Studies