An Antioxidant, Probucol, Induces Anti‐angiogenesis and Apoptosis in Athymic Nude Mouse Xenografted Human Head and Neck Squamous Carcinoma Cells

Abstract

Probucol is a very strong synthetic antioxidant that was been safely used for the treatment of hyperlipidemia in Japan since 1985. It has been reported that lipid oxidation products can alter growth factor production, which could influence smooth muscle cell proliferation. Oxidized low density lipoprotein can influence smooth muscle cell proliferation by enhancing the expression of platelet-derived growth factor (PDGF)-AA gene and PDGF receptor in vascular smooth muscle cell. Further, free radical reactions can cause irreversible alterations of genomic constituents during the initiation phase of carcinogenesis. Antioxidant is considered to protect lipids and low density lipoprotein (LDL) from oxidation, which potentially inhibits angiogenesis, and rapid removal of free radicals by antioxidants could have an anti-carcinogenic effect. In the present study, we investigated whether antioxidant treatment with probucol had an antitumor effect on KB cells, a human head and neck squamous carcinoma cell line. Probucol did not have any effect on KB cells in vitro, but probucol treatment of KB cells xenografts in mice had a significant antitumor effect through anti-angiogenic and apoptosis-inducing actions. These results support the idea that probucol is useful for preventing and/or treating cancer.

An Experimental Model of Tumor Dormancy Therapy for Advanced Head and Neck Carcinoma

“…This is not in conflict with our previous reports, 1,2) because the drugs at the doses used in the present study are not expected to be effective.…”

“…7) Probucol has a superoxide scavenging effect, inhibits the production of PDGF, and also protects LDL from oxidation, which potentially reduces smooth muscle cell proliferation. Probucol does not directly act on tumor cells in vitro, 2) but showed an antitumor effect in tumor-bearing nude mice via an anti-angiogenic action, which may induce cellular apoptosis as a result of decreased blood supply.…”

“…We previously investigated anti-tumor effects on the growth of head and neck carcinoma cells in animal models using tiracoxib, 1) probucol 2) and S-1.…”

“…In vivo tumor growth assay To evaluate the addictive effects of tiracoxib, probucol and S-1 on tumor growth inhibition, each drug was used at a not significantly effective dosage, based on our previous data. [1][2][3] KB cells (5×10 6 ) were injected subcutaneously into the left flanks of mice. The tumor size was measured once a week by determining two perpendicular dimensions with calipers, and the volume in mm 3 was calculated from the formula (a×b 2 )/2, where a is the longer and b is the smaller dimension.…”

“…However, it is impossible to be sure that there are no remnant tumor cells in the entire locoregional field. We have already reported inhibitory effects of tiracoxib, 1) probucol 2) and S-1 3) on tumor growth. According to the concept of tumor dormancy therapy, which aims to prolong the life of patients with cancer, these drugs might be efficacious for maintenance therapy to reduce the tumor-relapse rate.…”