Neutral and positively charged thiols synergize the effect of the immunomodulator AS101 as a growth inhibitor of Jurkat cells, by increasing its uptake.

The immunomodulator amonium trichloro[1,2-ethanediolato-O,O'] tellurate (AS101), a nontoxic tellurium(IV) compound, exhibited antitumoral activity in several preclinical and clinical studies. In this study, we investigated the synergism between thiols and AS101 in its antitumoral activity on Jurkat cells. AS101 induced a G2/M arrest in the cell cycle after 24h. Addition of the thiols 2-mercaptoethanol or cysteamine led to an induction of apoptosis. Other thiols, including glutathione (GSH) and cysteine, did not potentiate the effect of AS101. We propose that this is due to the alpha-carboxylate group present in the compounds formed between AS101 and these thiols. Programmed cell death was associated with the loss of mitochondrial transmembrane potential and activation of caspase-3 and -9. Elevation of intracellular reactive oxygen species (ROS) production was also demonstrated; the antioxidant catalase significantly reduced the apoptosis, suggesting that ROS play a key role in the apoptosis induced by AS101 and the thiols. Finally, we quantified the intracellular concentration of tellurium, using electron microscopy and energy-dispersive spectroscopy (EDS) analysis. The addition of cysteamine to AS101 significantly increased the concentration of tellurium within the cells. The results indicate that neutral or positively charged thiols but not negatively charged ones, increase the antitumoral effect of AS101 by increasing its uptake into the cells.

Ammonium trichloro(dioxoethylene-o,o')tellurate (AS101) sensitizes tumors to chemotherapy by inhibiting the tumor interleukin 10 autocrine loop.

Cancer cells of different solid and hematopoietic tumors express growth factors in respective stages of tumor progression, which by autocrine and paracrine effects enable them to grow autonomously. Here we show that the murine B16 melanoma cell line and two human primary cultures of stomach adenocarcinoma and glioblastoma multiforme (GBM) constitutively secrete interleukin (IL)-10 in an autocrine/paracrine manner. This cytokine is essential for tumor cell proliferation because its neutralization decreases clonogenicity of malignant cells, whereas addition of recombinant IL-10 increases cell proliferation. The immunomodulator ammonium trichloro(dioxoethylene-o,o')tellurate (AS101) decreased cell proliferation by inhibiting IL-10. This activity was abrogated by exogenous addition of recombinant IL-10. IL-10 inhibition by AS101 results in dephosphorylation of Stat3, followed by reduced expression of Bcl-2. Moreover, these activities of AS101 are associated with sensitization of tumor cells to chemotherapeutic drugs, resulting in their increased apoptosis. More importantly, AS101 sensitizes the human aggressive GBM tumor to paclitaxel both in vitro and in vivo by virtue of IL-10 inhibition. AS101 sensitizes GBM cells to paclitaxel at concentrations that do not affect tumor cells. This sensitization can also be obtained by transfection of GBM cells with IL-10 antisense oligonucleotides. Sensitization of GBM tumors to paclitaxel (Taxol) in vivo was obtained by either AS101 or by implantation of antisense IL-10-transfected cells. The results indicate that the IL-10 autocrine/paracrine loop plays an important role in the resistance of certain tumors to chemotherapeutic drugs. Therefore, anti-IL-10 treatment modalities with compounds such as AS101, combined with chemotherapy, may be effective in the treatment of certain malignancies.