naphthoquinones and Rectal-Neoplasms

The induction of reactive oxygen species (ROS) represents a viable strategy for enhancing the activity of radiotherapy. The authors hypothesized that napabucasin would increase ROS via its ability to inhibit NAD(P)H:quinone oxidoreductase 1 and potentiate the response to chemoradiotherapy in rectal cancer via distinct mechanisms.. Proliferation studies, colony formation assays, and ROS levels were measured in HCT116 and HT29 cell lines treated with napabucasin, chemoradiation, or their combination. DNA damage (pγH2AX), activation of STAT, and downstream angiogenesis were evaluated in both untreated and treated cell lines. Finally, the effects of napabucasin, chemoradiotherapy, and their combination were assessed in vivo with subcutaneous mouse xenograft models.. Napabucasin significantly potentiated the growth inhibition of chemoradiation in both cell lines. Napabucasin increased ROS generation. Inhibition of ROS by N-acetylcysteine decreased the growth inhibitory effect of napabucasin alone and in combination with chemoradiotherapy. Napabucasin significantly increased pγH2AX in comparison with chemoradiotherapy alone. Napabucasin reduced the levels of pSTAT3 and VEGF and inhibited angiogenesis through an ROS-mediated effect. Napabucasin significantly potentiated the inhibition of growth and blood vessel formation by chemoradiotherapy in mouse xenografts.. Napabucasin is a radiosensitizer with a novel mechanism of action: increasing ROS production and inhibiting angiogenesis. Clinical trials testing the addition of napabucasin to chemoradiotherapy in rectal cancer are needed.

Topics: Animals; Benzofurans; Cell Proliferation; Chemoradiotherapy; DNA Damage; HCT116 Cells; HT29 Cells; Humans; Mice; Mice, Nude; Naphthoquinones; Neovascularization, Pathologic; Radiation-Sensitizing Agents; Reactive Oxygen Species; Rectal Neoplasms; Signal Transduction; STAT3 Transcription Factor; Treatment Outcome; Tumor Burden; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays

1-Naphthol was selectively toxic to human colorectal tumours compared to corresponding normal colonic tissue removed at surgery and maintained in short-term organ culture. Nineteen of 24 tumours studied have shown a significant differential response. Three human colonic adenocarcinoma xenografts, in the short-term organ culture system, displayed the same response to 1-naphthol as primary tumours removed at surgery. 1-Naphthol, 1,2- and 1,4-naphthoquinone were also toxic to two human colonic adenocarcinoma cell lines, LoVo and COLO 206. The selective toxicity of 1-naphthol is mediated in part through an accumulation of 1-naphthol in the tumour tissue due to impaired conjugation by the tumour. The higher concentrations of 1-naphthol may then exert their toxicity either directly or by formation of naphthoquinones. Some indirect evidence was obtained for the possible involvement of 1,2- or 1,4-naphthoquinone in the cytotoxicity of 1-naphthol. Our studies suggest that further studies are warranted of the possible use of 1-naphthol or related compounds as antitumour agents.

Topics: Cell Line; Cell Survival; Colon; Colonic Neoplasms; Humans; Naphthols; Naphthoquinones; Neoplasm Proteins; Organ Culture Techniques; Rectal Neoplasms; Time Factors

Topics: Adult; Esophageal Neoplasms; Female; Humans; Lung Neoplasms; Male; Middle Aged; Naphthoquinones; Peritoneal Neoplasms; Radiation-Sensitizing Agents; Radiotherapy Dosage; Rectal Neoplasms; Urinary Bladder Neoplasms