Galectins constitute a family of lectins that specifically exhibit the affinity for b-galactosides and modulate various biological events. Galectin-9 is a tandem-repeat type galectin with two carbohydrate recognition domains and has recently been shown to have an anti-proliferative effect on cancer cells. We investigated the effect of recombinant protease-resistant galectin-9 (hGal9) on multiple myeloma (MM). In vitro, hGal9 inhibited the cell proliferation of five myeloma cell lines examined, including a bortezomib-resistant subcell line, with IC 50 between 75.1 and 280.0 nM, and this effect was mediated by the induction of apoptosis with the activation of caspase-8, -9, and -3. hGal9-activated Jun NH 2 -terminal kinase (JNK) and p38 MAPK signaling pathways followed by H2AX phosphorylation. Importantly, the inhibition of either JNK or p38 MAPK partly inhibited the anti-proliferative effect of hGal9, indicating the crucial role of these pathways in the anti-MM effect of hGal9. hGal9 also induced cell death in patient-derived myeloma cells, some with poor-risk factors, such as chromosomal deletion of 13q or translocation t(4;14)(p16;q32). Finally, hGal9 potently inhibited the growth of human myeloma cells xenografted in nude mice. These suggest that hGal9 is a new therapeutic target for MM that may overcome resistance to conventional chemotherapy.
Tyrosine kinase inhibitors (TKI) against Bcr-Abl are the first-line therapeutics for chronic myelogenous leukemia (CML). However, the resistance to Bcr-Abl TKIs is induced in leukemic cells not only by loss of sensitivity to TKIs through Bcr-Abl-related molecular mechanisms but also by loss of addiction to Bcr-Abl TK activity by acquiring Bcr-Abl-unrelated additional oncogenic mutations. Therefore, the identification of an additional therapeutic target has been anticipated for achievement of a complete cure and to overcome resistance to treatment. We here showed that modified human Galectin-9 (hGal9), a lectin that show specific affinity for β-galactosides, inhibits the proliferation of five CML-derived cell lines by inducing apoptosis at their IC 50 s from 17.5 to 164.9 nmol/L. Our study revealed that activating transcription factor 3 (ATF3), a member of the ATF/ cAMP-responsive element binding protein family transcription factors, is the critical mediator for cell killing by hGal9, and that Noxa is one of the downstream effector molecules of ATF3. Bim, on the other hand, the BH3-only protein essential for apoptosis by Bcr-Abl TKIs, was not associated with hGal9-induced cell death. ATF3-mediated cell death by hGal9 was not hampered by the absence of p53, the presence of mutant Abl T315I , or by P-glycoprotein overexpression. In addition, hGal9 showed the additive growth-inhibitory effect with imatinib on CML cell lines.
The immunosuppressiveeffects of prodigiosin 25-C were studied in comparison with FK506. Both prodigiosin 25-C and FK506suppressed T cell proliferation in response to concanavalin A (con A) or phytohemagglutinin (PHA) more significantly than that to lipopolysaccharide.However, prodigiosin 25-C inhibited con A-mediated mitogenic response more strongly than PHA-mediated one. FK506showed no selectivity amongthose responses. In addition, whenhigher concentration of con A was used an inhibitory effect of prodigiosin 25-C becamemore evident whereas that of FK506 became less evident. Furthermore, prodigiosin 25-C affected neither interleukin-2 (IL-2) production nor IL-2 receptor (IL-2R) and transferrin receptor (TF-R) expression in vitro, though FK506 extensively inhibited IL-2 production and significantly suppressed IL-2R and TF-R expression.Whencomparing the effects of prodigiosin 25-C and FK506in vivo by injecting antigens of different nature to a mouse, prodigiosin 25-C selectively inhibited cytotoxic T lymphocyte (CTL) activity induced by an allogenic mastocytoma, P8 1 5, without affecting production of antibody against a thymus dependent (TD) antigen, sheep red blood cell (SRBC). On the contrary, FK506 significantly inhibited both CTLinduction and the antibody production. WhenBrucella abortus, a thymus independent (TI) antigen, and SRBCwere simultaneously challenged to a mouse, neither prodigiosin 25-C nor FK506affected antibody production against the TI antigen while the effect on the TD antigen werethe sameas described above. Thepresent results revealed the unique immunosuppressive property of prodigiosin 25-C which was different from that of FK506.During the course of our screening for new immunomodulatory substances, which utilizes mitogenic responses of mouse splenocytes to polyclonal mitogens1}, prodigiosin 25-C was found as a potent immunosuppressant2).Prodigiosin 25-C, MW393, is a red pigment produced by Streptomyces hiroshimensis, which has three conjugated pyrrole rings and a hydrophobic hydrocarbon chain (Fig. 1). Prodigiosin 25-C inhibited the responses of murine splenocytes to T cell specific mitogens, concanavalin A (con A) and phytohemagglutinin (PHA), more extensively than to a B cell specific mitogen lipopolysaccharide (LPS)2). Prodigiosin 25-C inhibited both con A and interleukin-2 (IL-2)-dependent proliferative response of con A-primed splenocytes3), which indicated that prodigiosin 25-C had a distinct property from a fungal metabolite, ciclosporin (cyclosporin A, CsA), which selectively inhibited con A-dependent proliferative response. It was also shown that prodigiosin 25-C inhibited the induction of H-2 specific cytotoxic T lymphocyte (CTL) both in vitro and in vivo, but not that of anti-sheep red blood cell (SRBC) antibody production at the same dose as suppression of CTLinduction wasobserved in vivo2'3). Prodigiosin 25-C has little myelotoxicity because the numbers of peripheral blood leukocytes and splenocytes of prodigiosin 25-C treated mice were not affected (our unpublished results).
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