Selenocompounds in leukemia treatment : advantages and pitfalls

Abstract: In 2018, cancer was reported to be the second top cause of morbidity and mortality globally with over 9 million deaths. Hematological malignancies including leukemia constitute about 7% of the total cancer cases. Substantial developments in treatment modalities and strategies have increased the 5-year survival rate in leukemia to around 60% in developed countries. However, complete remission and long-term disease control are not yet achieved. Oxidative stress is imprinted in many types of cancer including leukemia and represents a valuable trait for achieving leukemiaselective cytotoxicity. The present thesis represents a systematic study of the role of redox-active selenocompounds (SeCs) in leukemia treatment. Six diverse selenocompounds representing different compound classes were studied. Among them, p-xyelenselenocyanate (p-XSC) was shown to have the most potent cytotoxic activity against several leukemia cell lines carrying distinct oncogenes. p-XSC exerted its cytotoxicity in a concentration- and time-dependent manner. Mechanistic studies revealed that the cytotoxicity of p-XSC was mediated by upregulation of oxidative stress and accompanied with massive mitochondria damages. Importantly, the cytotoxicity of SeCs was antagonized by albumin which is ubiquitously present in biological conditions. By the combination of two distinct, but complementary selenium speciation methods including liquid chromatographymass spectrometry and X-ray absorption spectroscopy, we showed that cytotoxic SeCs were capable of transforming into selenol intermediates that subsequently bound to albumin via selenium-sulfur bond. Furthermore, we found that the macromolecular selenocompound-albumin conjugate was also internalized and able to kill leukemia cells. In addition to interfering with cytotoxicity, binding of SeCs to albumin also hindered the quantification of these compounds in biological matrix e.g. plasma. To elucidate the pharmacokinetics properties of SeCs for in vivo applications, we developed a novel REductive Cleavage and Instant Derivatization (RECID) method, by which we were able to measure both free and albumin-bound SeCs. In the leukemia mouse model, intravenous administration of p-XSC was shown to reduce the disease burden in whole body as well as in bone marrow. In conclusion, the results obtained in the present thesis provide substantial experimental evidences that redox-active SeCs, in particular p-XSC, possess high therapeutic potential as treatment for leukemia. Further investigations to optimize treatment regimen and to design an appropriate drug carrier are needed to achieve successful clinical trials.