Other mechanisms of arsenicinduced apoptosis

As2O3 may additionally affect tumor-cell growth by inhibiting angiogenesis, the formation of blood vessels that support the tumor growth.70 In mice with methylcholanthrene-induced fibrosarcomas, a single dose of As2O3 was sufficient to induce preferential vascular shutdown in tumor tissue and massive necrosis in the central portion of the tumor, whereas skin, muscle and kidney vasculature remained relatively unaffected.71

The cytoskeleton has also been suggested as a potential cellular target for arsenic because its major constituent, tubulin, has a relatively high sulfhydryl content. Arsenic-induced growth inhibition appeared to be related to changes in the cytoskeleton, leading to a decreased production or secretion of interleukin-2 (IL-2).72 Disruption of microtubule assembly and spindle formation during mitosis can promote apoptosis. In myeloid leukemic cells, As2O3 markedly inhibited GTP-induced polymerization of monomeric tubulin for microtubule formation.73 Although As2O3 effectively induced apoptosis in ovarian and prostate cancer cells, addition of the strong anti-oxidant butylated hydroxyanisole did not rescue the cells from As2O3-induced apoptosis.50 This showed that the cytotoxic effects of As2Ü3 were not mediated by superoxide generation in these cells. It was proposed that apoptosis is induced in these cells via an alternate mechanism, perhaps involving interactions with tubulin or other cytoskeletal elements.50

16.4 Pharmacokinetic Profiles

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