Honors Capstone Project
Date of Submission
Thomas Fondy, Professor
Stephen Dorus, Associate Professor
Arts and Science
Capstone Prize Winner
Won Capstone Funding
Sciences and Engineering
Sonodynamic therapy (SDT) is a potential cancer treatment modality that has been gaining support due to its effectiveness in both in vitro and in vivo studies. The therapeutic method combines ultrasonic irradiation with drugs known as sonosensitizers that amplify its ability to inflict preferential damage on malignant cells. This is based on the idea that ultrasonic waves have the ability to exhibit profound physical and chemical changes on cellular structure. The mechanisms by which ultrasound disrupts cellular functioning can be further amplified when sonosensitizers are applied. Combining multiple sonosensitizers with ultrasound to create a substantial synergistic effect could be an effective method for destroying tumorigenic growths, while decreasing the likelihood of drug resistance.
Perhaps one of the most intriguing capabilities of ultrasound is its ability to preferentially lyse cells based on size. This known fact invariably gives rise to the idea of grossly enlarging tumor cells to increase their already noticeable size difference with normal cells. Cytochalasin B is a known pharmacological agent that disrupts the actin cytoskeleton and inhibits cytokinesis by interfering with formation of the contractile ring as well as the development of the cleavage furrow. Consequently, the cell does not divide and an immature actin cytoskeleton remains. However, the cell continues to form nuclei and eventually becomes grossly enlarged and multinucleated. Such cells invariably have more DNA targets, increasing the likelihood of apoptosis. Furthermore, the multinucleated cells have a large cell volume, making them more susceptible for direct cell destruction. Preferential damage of malignant cells is actually easily attainable as normal cells exposed to cytochalasin B exit the cell cycle and enter a resting state until sufficient actin levels are restored. Therefore, only malignant cells that have lost the ability to enter the rest phase will become grossly enlarged and multinucleated, providing an ideal target for ultrasonic irradiation.
Work from our lab has indicated that cytochalasin B does indeed only damage leukemia cells, leaving normal blood cells, unaffected. The designated cell line has been promyleocytic leukemia U937 cells as they are a frequent choice for in vitro studies. The U937 cells have routinely become grossly enlarged and multinucleated, providing an ideal target based on size. The typical erythrocyte is 6-8µm, while leukocytes fair slightly better with a range of 10-15µm and an average of 12µm. By contrast, work from our lab has shown that cytochalasin B treated leukemia cells easily grow in excess of 20µm with some reaching 40µm in diameter after enough exposure. Such cells have reduced cytoskeletal integrity and are easy targets for ultrasonic irradiation. Furthermore, cytochalasin B treated leukemia cells are substantially multinucleated as cytokinesis is inhibited. This provides plenty of targets for a nucleic acid directed agent such as cisplatin or doxorubicin to attack. To investigate the extent of preferential damage inflicted by cytochalasin B on U937 leukemia/human blood populations, cell mixtures were treated with cytochalasin B and then sonicated under a relatively low intensity (3W/cm2). Results indicated that cytochalasin B preferentially damages U937 cells both before and after sonications. The agent also demonstrates the capability to eliminate rapid proliferation as U937 cells have a marked decrease in clonogenicity. Such findings suggest that cytochalasin B may have profound therapeutic applications when combined with SDT.
Sonodynamic Therapy, Ultrasound, Sonosensitizers, Inertial Cavitation, Reactive Oxygen Species, Tumor Vasculature, Preferential Damage
Trendowski, Matthew, "The Promise of Sonodynamic Therapy: Using Ultrasonic Irradiation and Chemotherapeutic Agents as a Treatment Modality" (2014). Honors Capstone Projects - All. 766.
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