The Role of Mechanical Stress in Mitigating Side Effects of Chemotherapy

First line platinum-based chemotherapies kill cancer cells through formation of bulky DNA adducts, however, these adducts also form in healthy tissues leading to side effects that significantly impact patients’ quality of life. Post-therapy bone loss has been linked to chemotherapy-induced stem cell senescence, while neurotoxicity and secondary tumors are linked to increased mutagenesis in stem cell DNA, ultimately forcing clinicians to use lower doses that are less effective. Consequently, there is a need to improve DNA repair capacity in healthy cells without compromising drug effectiveness on cancer cells. We propose to selectively increase nucleotide excision repair (NER) of platinum-DNA adducts in healthy cells, while maintaining cancer cell killing efficacy, through the application of passive mechanical stress via low intensity vibration (LIV). Not addressing this problem will continue to decrease the effectiveness of chemotherapy regimens and the quality of life for cancer survivors. Our objective for this proposal is to determine whether LIV preferentially enhances NER capacity of platinum- based DNA adducts in healthy cells, thus mitigating chemotherapeutic side-effects. The central hypothesis is that LIV will upregulate NER in a LINC-dependent manner reducing platinum-based chemotherapy toxicity and senescence in healthy stem cells. Further, cancer-associated downregulation and depletion of LINC complex elements will reduce the effectiveness of LIV on NER. This hypothesis was formulated based on our preliminary findings that cancer cells with reduced LINC complex expression fail to initiate LIV-induced mechanosignaling and that LIV enhances NER of bulky UV-induced DNA adducts in healthy stem cells and loss of LINC complex disrupts NER. The aims of this study are to determine 1) LIV-induced changes in platinum toxicity in healthy, LINC-disabled and cancer cells. 2) LINC-mediated alterations in chromatin dynamics and initiation of the DNA damage response. If successful, results from our R15 AREA proposal will yield a novel understanding of how external mechanical force in the form of LIV is involved in DNA repair in a LINC complex dependent manner, potentially opening up non-pharmacologic and targeted therapeutic interventions to decrease side effects and long-term sequelae following chemotherapeutic treatment modalities. This research will improve undergraduate retention in the biomedical workforce and give students an opportunity to continue their education in our department at Boise State University, which offers the only Biomedical Engineering Ph.D. program in Idaho.