Adaphostin Tyrosine Kinase Inhibitor Or Nontyrosine Kinase Inhibitor

Adaphostin (NSC 680410, National Cancer Institute, Bethesda, Maryland, U.S.A.) is the adamanyl ester of the tyrphostin, AG957 (10). Tyrphostins are a group of structurally diverse compounds that were synthesized and evaluated as potential inhibitors of tyrosine kinases. AG957 was identified as a non-ATP inhibitor of p210Bcr-Abl (11), which interfered with the binding of protein substrates to this tyrosine kinase. Several lines of evidence suggest that, currently, adaphostin should be considered as a "non-TKI" agent. Although AG957 has been reported as being a potent inhibitor of the tyrosine kinase activity of Bcr-Abl, adaphostin is less potent in this respect (10). Furthermore, although adaphostin induced rapid apoptosis in K562 cells, its effect upon tyrosine phosphorylation was gradual with detectable phosphorylated species persisting for at least six hours (12). In contrast, imatinib treatment of the same cell line abrogated phosphorylation within an hour but led to a much slower induction of apoptosis (12). Clearly, the cytotoxic action of adaphostin on CML cells is mediated via a mechanism distinct from that of imatinib. Significantly, adaphostin has also been reported to induce cell death in human cell lines that do not express Bcr-Abl including Jurkat (T-cell acute lymphoblastic leukemia cells), HL-60 (promyelocytic leukemia cells), and ML-1 (acute myeloid leukemia cells) (11). These findings indicate that the pro-apoptotic activity of adaphostin cannot be solely due to an effect upon Bcr-Abl. Curiously, adaphostin does not exhibit selectivity for murine cell lines transformed with BCR-ABL, but it does cause a selective inhibition in the growth of CML granulocyte colony forming units (CFU-G), relative to normal progenitors (12).

Several groups have reported that in vitro treatment of cells with adaphostin results in a rapid (within eight hours) down regulation of p210Bcr-Abl protein (1013). In addition, adaphostin treatment leads to a rapid rise in intracellular reactive oxygen species (ROS) in both Bcr-Abl expressing and nonexpressing cells (11,13). Pretreatment of cells with antioxidants diminishes the cytoxicity of adaphostin but has no effect upon the down regulation of Bcr-Abl protein indicating that this phenomenon precedes or parallels the generation of ROS (11,13). The down regulation of Bcr-Abl protein by adaphostin was similarly unaffected by proteasome inhibitors and an inhibitor of protein translation, cycloheximide (11). Decreased levels of p210Bcr-Abl protein have also been reported for cells treated with AG957 (10,14) and this has been attributed to the drug, causing covalent crosslinks between Bcr-Abl and its substrate proteins, Grb2 and Shc (14). It has been suggested that the p210Bcr-Abl band is lost from immunoblots as Bcr-Abl is "shifted" to higher molecular weight complexes (14).

The mechanism underlying the apparent selectivity of adaphostin for primary CML cells remains elusive. It has been postulated that since Bcr-Abl overexpression leads to the production of ROS in haematopoietic cells (15), ada-phostin may be inducing cytotoxicity in CML cells by further stimulating ROS, leading to intolerable oxidative stress (13). Regardless of its mode of action, ada-phostin is considered a promising therapeutic agent in CML and may be of particular benefit to patients who develop resistance to imatinib. Imatinib-resistant cells do not exhibit cross resistance to adaphostin (12,13) and the combination of the two drugs induces greater cell death than when the two drugs are induced as single compounds (12). Recently, murine cell lines transfected with BCR-ABL containing Abl-kinase domain mutations, including the T315I mutation, were shown to be sensitive to adaphostin (13). Intriguingly, Ph+ leukemia samples obtained from patients who had developed resistance to imatinib were found to be more sensitive to adaphostin than the samples obtained from patients who had never received imatinib (13). Synergistic induction of apoptosis by the combination of adaphostin and bortezomib has recently been reported in an in vitro study, involving murine cell lines transformed with BCR-ABL, containing Abl-kinase domain mutations (E255K, T315I, M351T) (16). All of the mutants were susceptible to this combination. At the time of writing, Spring 2006, adaphostin was still undergoing preclinical evaluation at the National Cancer Institute, Bethesda, Maryland, U.S.A. (13).

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