aq4n and Colorectal-Neoplasms

Banoxantrone is a topoisomerase II inhibitor that is selectively activated in hypoxia. Although it has exhibited anti-tumor activity against several types of cancers in preclinical models, its efficacy against colorectal cancer (CRC) remains unclear.. We examined the antitumor effects of 1,4-bis[2-(dimethylamino)ethylamino]-5,8-dihydroxyanthracene-9,10-dione (AQ4), an activated metabolite of banoxantrone, in CRC cell lines (HT-29, CaR-1) using in vitro experiments under normoxic and hypoxic conditions. The inhibition of cell growth was assessed using a proliferation assay. The induction of apoptosis and changes in the cell cycle were measured using flow cytometry. Signaling pathways involved in apoptosis and hypoxia were analyzed. The anti-tumor activity of temsirolimus, an inhibitor of mammalian target of rapamycin, and the combined effects of temsirolimus and AQ4 were also evaluated.. Regardless of the oxygen condition, a single drug treatment with AQ4 or temsirolimus inhibited proliferation and induced apoptosis in both cell lines, accompanied by a reduction in the phosphorylation of S6. AQ4 induced G2/M cell cycle arrest, whereas temsirolimus induced G0/G1 arrest. Moreover, the combined treatment markedly reduced the proportion of cells in the S phase and enhanced apoptosis, as evidenced by an increased Bax/Bcl-2 ratio. The hypoxia-induced activation of the HIF-1α pathway was suppressed by AQ4 and temsirolimus.. Based on the cooperative anti-tumor activity of AQ4 and temsirolimus in vitro, the combination of banoxantrone plus temsirolimus has potential as a treatment option for CRC in preclinical and clinical settings.

Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Humans; Hypoxia

Complications associated with the development of lung metastases have a detrimental effect on the overall survival rate of many cancer patients. Preclinical models that mimic the clinical aspects of lung metastases are an important tool in developing new therapy options for these patients. The commonly used intravenous models only recapitulate dissemination of cancer cells to the lungs via the haematological route. Here we compared spontaneous and intravenous lung metastases of the highly metastatic KHT mouse fibrosarcoma cells after injecting KHT cells into the subcutaneous layer of the skin or directly into the tail vein. In contrast to the intravenous model, metastases spontaneously arising from the subcutaneous tumours disseminated most consistent with the lymph nodes/lymphatics route and were more hypoxic than the metastases observed following tail-vein administration and haematological spread. To ascertain whether this impacted on drug response, we tested the effectiveness of the hypoxia-sensitive cytotoxin AQ4N (Banoxantrone) in both models. AQ4N was more effective as an anti-metastatic drug in mice with subcutaneous KHT tumours, significantly reducing the metastatic score. Complementing the KHT studies, pathology studies in additional models of spontaneous lung metastases showed haematological (HCT116 intrasplenic implant) or mixed haematological/lymphatic (B16 intradermal implant) spread. These data suggest that preclinical models can demonstrate differing, clinically relevant dissemination patterns, and that careful selection of preclinical models is required when evaluating new strategies for targeting metastatic disease.

Topics: Animals; Anthraquinones; Colorectal Neoplasms; Female; Fibrosarcoma; Humans; Hypoxia; Immunoenzyme Techniques; Lung Neoplasms; Lymph Nodes; Lymphatic Metastasis; Lymphatic Vessels; Melanoma, Experimental; Mice; Mice, Inbred C3H; Sarcoma, Experimental; Tumor Cells, Cultured