Photochemically Generated Elemental Selenium Forms Conjugates with Serum Proteins That Are Preferentially Cytotoxic to Leukemia and Selected Solid Tumor Cells

Abstract

The objective of this study was to determine if and how photoproducts contribute to the anti-tumor effect of merocyanine-mediated PDT. A panel of barbituric, thiobarbituric and selenobarbituric acid analogues of Merocyanine 540 was photobleached, and the resulting photoproducts were characterized by absorption, fluorescence emission, mass, energy dispersive X-ray, and X-ray photoelectron spectroscopy, and tested for cytotoxic activity against tumor cell lines and freshly explanted bone marrow cells. While all dyes were readily photobleached, only photoproducts of selone dyes showed cytotoxic activity. One-hour incubations with micromolar concentrations of selone-derived photoproducts were sufficient to reduce leukemia/lymphoma cells ≥10,000 fold while preserving virtually all normal CD34-positive bone marrow cells. Of 6 multi-drug resistant tumor cell lines tested, 5 were as sensitive or more sensitive to photoproducts than the corresponding wild-type lines. Physicochemical characterizations of the cytotoxic activity indicated that it consisted of conjugates of subnano particles of elemental selenium and (lipo)proteins. The discovery of cytotoxic Se-protein conjugates provides a rare example of photoproducts contributing substantially to the anti-tumor effect of PDT and challenges the long-held view that Se in oxidation state zero is biologically inert. Agents modeled after our Se-protein conjugates may prove useful for the treatment of leukemia.

Selenium Species in Diabetes Mellitus Type 2

“…However, the SeNPs metabolism in human biological systems, the correlation with main selenoproteins, and their role in pharmacological protection should be studied more closely to understand their biological activities. Elemental selenium can form conjugate with proteins containing free thiol groups, which shows that elemental Se is not biologically inert and it may provide the basis of a new class of anticancer agents [ 104 , 105 ]. It would be interesting to find if selenium nanoparticles have a similar U -shape dose-depend association with a risk of DM.…”

Incorporating Selenium into Heterocycles and Natural Products─From Chemical Properties to Pharmacological Activities

“…Under photoirradiation, a portion of the generated singlet oxygen oxidized the selone group to selone oxide, which was unstable and spontaneously decomposed to release Se(0) and the barbituric acid analog of the original compound. Se(0) could then interact with suitable serum (lipo)­proteins to generate cytotoxic conjugates. , …”

“…Se(0) could then interact with suitable serum (lipo)proteins to generate cytotoxic conjugates. 60,61 2.7.2. Excretion.…”

Design and synthesis of novel thiobarbituric acid derivatives targeting both wild-type and BRAF-mutated melanoma cells

“…In recent years, thiobarbituric acids have been reported to exhibit a broad spectrum of biological properties such as anti-convulsant,[6] anti-inflammatory,[7, 8] anti-bacterial,[9] anti-HIV,[10] anti-hypnotic,[11] anti-parkinsonian,[12] and anti-cancer activities,[13–15] including anti-melanoma properties. [16, 17] Among them some thiobarbituric acid derivatives, such as merbarone,[18] merocyanine 540[19] and its selenium analog selenomerocyanine 56[20] (Figure 1) have been identified as possible modulators of apoptosis in several cancer cells, including glioblastoma multiforme (GBM), melanoma, leukemia, and cancers of breast, lung, prostate, and cervix; albeit not particularly for cancers that are resistant to current therapy. An effective lead thiobaribituic acid analog 2a was recently identified in our laboratory from a library of 50,000 chemicals, originally screened to identify compounds that could target temozolomide (TMZ) resistant brain tumor cells.…”