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Combined effects of a sulfoxide-containing anticancer prodrug and Herceptin against breast cancer
Background: Breast cancer now ranks first among cancers affecting women throughout the world. Anthracyclines, such as doxorubicin, are the most commonly used anticancer agents against breast cancer whether given as a single agent or in combination with other antitumor agents, such as Herceptin. However, the use of anthracyclines is often hampered by their cumulative dose-limiting cardiotoxicity or development of drug resistance. Therefore, it is tempting to search for novel therapies such as alternatives to anthracyclines or combination strategies against breast cancer. A novel anticancer agent, acridiol-sulfoxide, has recently been developed by our group as a hypoxia-selective bioreductive prodrug against solid tumor. Acridiol-sulfoxide was found to be bioreduced to its ultimate drug form, acridiol-sulfide, under anaerobic condition. The acridiol-sulfide had been demonstrated to inhibit the activity of both topoisomerase II and nuclear factor-kappaB (NF-kappaB); in addition, it can induce apoptosis and is highly active in vivo against p388 leukemia bearing mice. Our preliminary data also suggests that acridiol-sulfide is a potent cytotoxin against MCF-7 breast carcinoma cell line (IC50 = 0.1 microM). Therefore, we hypothesize that the combination of acridiol-sulfoxide and Herceptin would be an effective alternative to the combination of doxorubicin and Herceptin against breast cancer. To test our hypothesis, in aim1, a LC-MS SIM method will be used to analyze the metabolic activation of acridiol-sulfoxide by MCF-7 breast cancer cells under hypoxia condition. In aim 2, we will examine the anticancer effects of both acridiol-sulfide and its prodrug, acridiol-sulfoxide, alone or combined with Herceptin to the HER-2/neu overexpressed cell line in both cell culture and nude mouse model. In Aim 3, we will identify potential predictive biomarkers for acridiol-sulfoxide in MCF-7 cells treated with acridiol-sulfide using both surface enhanced laser desorption/ionization (SELDI) technology and immunoblotting. The goal of the current study is to evaluate the potential use of a solid tumor prodrug, acridiol-sulfoxide, as an alternative to anthracyclines in breast cancer treatment. The outcomes of this study should provide enough preclinical evidences for the future clinical study of acridiol-sulfoxide.
Background: Breast cancer now ranks first among cancers affecting women throughout the world. Anthracyclines, such as doxorubicin, are among the most widely used chemotherapeutic agent for the treatment of breast cancer either as a single agent or in combination with other drugs, such as Herceptin. However, the development of heart toxicity and drug resistance by doxorubicin leads to a need in finding safe alternatives. A novel anticancer agent, acridiol-sulfoxide, which was expected to selectively kill solid tumor cells by being converted to its active form in the oxygen deficient environment of cancer, has recently been developed by our group. Our preliminary results suggest acridiol-sulfoxide is a potential agent to treat breast cancer. Therefore, we hypothesize that the combination of acridiol-sulfoxide and Herceptin would be an effective alternative to the combination of doxorubicin and Herceptin against breast cancer. To prove our hypothesis, we will first demonstrate that breast cancer could convert acridiol-sulfoxide into its active form under oxygen deficient environment in Aim 1. Then, the combined anticancer effects of Herceptin and acridiol-sulfoxide to treat breast cancer will be evaluated in Aim 2 using both cell culture and animal model. Subsequently in Aim 3, we will search for the predictive protein markers for breast cancer treatment by acridiol-sulfoxide using proteomic approach. The goal of current study is to establish the potential use of acridiol-sulfoxide as an alternative of anthracyclines in combination with Herceptin to treat breast cancer clinically.