Molecular Therapy Using Ultrasound : Mechanisms Involved in Drug Activation, Apoptosis Induction, Gene Transfer, and Alterations of Gene Expression

Interest in molecular imaging and in molecularly-targeted therapy has grown tremendously, and ultrasound may offer new tools for modern cancer therapy. To understand how therapeutic ultrasound works, it is necessary to understand its biological effects at the molecular level. In this review, investigations on the molecular aspects of ultrasound are discussed, with emphasis on apoptosis induction, gene expression, and gene transfection. In these studies, apoptosis induction was assayed with flow cytometry and with other methods targeting indicators of apoptosis. Gene expression was evaluated using western blotting, real-time polymerase chain reaction, and microarray analysis. Gene transfection was investigated using a luciferase assay and other methods. The reported results show that low intensity ultrasound can induce apoptosis in cancer cell lines, and that this effect can be optimized using pulsed ultrasound. Exposure to ultrasound can result in the down-regulation or up-regulation of some genes. Of particular interest is the striking up-regulation of the heme oxygenase-1 gene, a gene usually associated with oxidative stress in human lymphoma U937 cells. Introducing genes using ultrasound with or without microbubbles also exhibited promising results. Membrane damage is pivotal to biological effects, and using ultrasound to modify or affect cell membranes can either promote or inhibit desired effects. In summary, it is concluded that ultrasound has the potential to help develop useful methods which can be utilized in therapies which require apoptosis induction, gene introduction into cells, alterations in gene regulation, and drug-activation.