Synthetic, Natural And Semi-synthetic Compounds Against Multiple Myeloma: Insights Into The Antiproliferative Activity And Mechanism Of Action

Diplôme Thèse Synthetic, Natural And Semi-synthetic Compounds Against Multiple Myeloma: Insights Into The Antiproliferative Activity And Mechanism Of Action eng 2024 2024 director Cuendet Muriel 0000-0002-1523-1907 686755 Section des sciences pharmaceutiques (FARMA) author Ferro Angelica 918779 161 10.13097/archive-ouverte/unige:178718 urn:nbn:ch:unige-1787189 Sc. Vie - Pharma. 294 Multiple myeloma is a bone marrow-resident hematological disease arising from the uncontrolled proliferation of malignant plasma cells leading to end-organ dysfunctions. It is the second most recurrent blood cancer following non-Hodgkin lymphoma, and it accounts for approximately 13% of all hematological malignancies, 1% of all cancers, and 1.2% of all cancer-related deaths. Despite the introduction of novel classes of drugs, patients inevitably experience serial relapses and finally become drug refractory. Therefore, searching for novel therapeutic avenues has gained particular interest. In the framework of this thesis project, synthetic, natural, and semi-synthetic compounds were evaluated for their antiproliferative activity in multiple myeloma in vitro models, and the mechanism of action of the active ones was further explored. Of particular interest is compound 13, a withanolide derivative, which showed IC50 values around the 20 nM range in diverse multiple myeloma models including cells resistant and sensitive to standard regimens. Besides, compound 13 exhibited the highest selectivity towards multiple myeloma cells over primary dermal fibroblasts and a selectivity towards primary malignant plasma cells isolated from a patient over normal primary plasma cells received from a donor. One of the hypotheses based on various mechanistic and functional studies is that compound 13 inactivates the canonical NF-ĸB cascade after targeting B cell maturation antigen on the plasma cell surface, which leads to cell growth arrest. These findings highlight compound 13 as a possible molecule against multiple myeloma to bring into the preclinical setting. The present standard of care for multiple myeloma typically involves drugs with different mechanism of action compared to what is hypothesized for compound 13. Therefore, compound 13 may lead to a valuable therapeutic option for frontline and maintenance treatments. Drug resistance Multiple myeloma Treatment Dewey 615 31 Section des sciences pharmaceutiques 17 false 884 Pharmacognosie 02bff861-10e3-4a2d-bdc0-3127726a96f2 Thesis Private 240712_Thesis_FINAL_FERRO_ANGELICA.pdf 6017856 application/pdf 7c5148f4454d92f1cb2f682814e937703df68789ffaa8bd5d9f964bb66fe0f51 f2e83e75-46d9-45c9-ac20-3cc3659eb2ad Imprimatur Public Imprimatur.pdf 297544 application/pdf 6e4c19c801b5d2ff880df167f52a2a330b0fa728201f372fd6ac5c371168cb59 closedAccess Faculté des sciences / Section des sciences pharmaceutiques

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