Omega-3 Fatty Acids DHA and EPA for Overcoming Drug Resistance in Multiple Myeloma: Investigations into The Mechanism of Action, Activities and Rational Use

Multiple myeloma (MM) is the second most prevalent hematological malignancy. Currently, this disease is still considered incurable since most MM patients become refractory or suffer from repeated relapses after initial therapeutic successes, particularly due to the development of drug resistance during chemotherapy. Therefore, it remains an urgent need for developing novel drugs or combination therapeutic strategies to combat chemoresistance for MM treatment. Omega-3 polyunsaturated fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), which are largely contained in fish or fish oils and have been traditionally used as nutrients additives in regular food, were found to show direct anticancer effects in various cancer types including MM. Importantly, these unique fatty acids were reported to selectively kill patient-derived primary MM cells but showed almost no effect on normal cells. The work in this thesis provides insights into a rational and effective strategy using DHA or EPA in combination with chemotherapy bortezomib to overcome chemoresistance in MM cells, potentially guiding their future usage in clinics during chemotherapy. Furthermore, the molecular mechanisms relevant for the cell-killing effects of DHA/EPA and their combination treatment with bortezomib in MM cells were comprehensively investigated, which extends our understanding of bortezomib-associated resistance and provides novel therapeutic targets for overcoming chemoresistance in MM.