Synergistic Effects Of Combining Therapeutic Radiation And ß-Lapachone Against Tumors

Abstract

Understanding the mechanisms of the experimental anti-cancer drug β-Lapachone is crucial for optimizing its mode of action - especially when it is used in conjunction with other treatment regimens, namely therapeutic radiation, due to possible interactions. It is our aim to exploit the knowledge gained from studying the interaction between β-Lapachone and radiation for better tumor control. β-Lapachone is a novel anti-cancer compound that is activated intracellularly by the enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1), which is over-expressed in many cancer cells. It has been reported that concentrations of NQO1 can be further up-regulated by various cellular stressors including radiation. Therefore radiation potentiates β-Lapachone's cytotoxicity when radiation is used as a pre-treatment. Treating with β-Lapachone in fractionated radiation treatments, have been shown to suppress sub-lethal damage (SLD) repair of radiation damage. Therefore combined treatments of radiation and β-Lapachone have been observed to involve synergistic interactions based on two complementary actions: pretreatment of cancer cells with radiation to increase NQO1 which potentiate β-Lapachone's cytotoxicity and suppression of SLD repair by β-Lapachone post irradiation. In an attempt to illuminate important factors for designing an optimal treatment for solid tumor control, a deeper understanding of the interactions between the two treatments was needed, such as, the changes made in the cell cycle of several cell lines by various treatment combinations involving radiation and β-Lapachone, changes made in the concentrations of NQO1 pre/post-treatments involving β-Lapachone, and the impact of treatment on the tumor micro-environment in regards to in vivo tumor response to fractionated radiation in the presents of β-Lapachone. Our results shows a marked sensitization towards radiation of FSaII and A549 cells treated with β-Lapachone and a significant suppression of sub-lethal damage (SLD) repair. β- Lapachone's cytotoxicity appears to be agnostic towards cell cycle phase and hypoxic cells. β- Lapachone has also been shown to be effective in delaying growth of FSaII tumors grown in C3H mice when treated in a single β-Lapachone dose and a single fraction of radiation as opposed to its fractionated regimen analog, and so placing it as a candidate for steriotatic body radiation therapy (SBRT) and steriotatic radiosurgery (SRS) combined treatments.