The application and biology of immunomodulatory drugs (IMiDs) in cancer

Pan, Bei-Qing; Lentzsch, Suzanne

doi:10.1016/j.pharmthera.2012.07.004

Cited by 61 publications

(45 citation statements)

References 146 publications

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“…Indeed, immunomodulatory drugs based on thalidomide, mainly amino-substituted thalidomide analogs, have been reported to be superior candidates as antitumor agents [45,46]. Despite thalidomide had not led to spleen morphological alterations in this work, it is known that some phthalimide analogues are co-stimulatory substances, increasing the response of T-lymphocytes to T-cellreceptor-mediated stimulation, the production of interleukin-2 and interferon-γ as well as the number of natural killer cells [17,47]. On the other hand, most clinical chemotherapy drugs are immunosuppressive and has negative side effects [48], such as leucocyte suppression, hypoplasia of the splenic white pulp and small lymphoid aggregates in 5-FU-treated mice [46].…”

Section: Discussionmentioning

confidence: 87%

Improvement of in vivo anticancer and antiangiogenic potential of thalidomide derivatives

Costa

Carvalho

et al. 2015

Chemico-Biological Interactions

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The strategy of antiangiogenic drugs is based on inhibiting formation of new blood vessels as alternative to limit cancer progression. In this work, we investigated the antitumor and antiangiogenic potential of eight thalidomide derivatives. Most of the molecules was not cytotoxic but 2a, 2d and 3d revealed weak antiproliferative activity on HL-60, Sarcoma 180 (S180) and normal peripheral blood mononuclear cells. Thalidomide, 2a and 2b were able to inhibit tumor growth (53.5%, 67.9% and 67.4%, respectively) in S180-bearing mice and presented moderate and reversible toxicity on liver, kidneys and spleens. Both analogs (2a and 2b) inhibited cell migration of endothelial (HUVEC) and melanoma cells (MDA/MB-435) at 50μg/mL. Immunohistochemistry labeling assays with CD-31 (PECAM-1) antibody showed microvascular density (MVD) was significantly reduced in thalidomide, 2a and 2b groups (30±4.9, 64.6±1.8 and 46.5±19.5%, respectively) (p<0.05). Neovascularization evaluated by Chorioallantoic Membrane Assay (CAM) with compounds 2a and 2b showed reduction of vessels' number (12. 9±2.3 and 14.8±3.3%), neovascularization area (13.1±1.7 and 14.3±1.7%) and total length of vessels (9.2±1.5 and 9.9±1.9%). On the other hand, thalidomide did not alter vascularization parameters. Consequently, addition of thiosemicarbazone pharmacophore group into the phthalimidic ring improved the in vivo antitumor and antiangiogenic potential of the analogs 2a and 2b.

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Section: Discussionmentioning

confidence: 87%

Improvement of in vivo anticancer and antiangiogenic potential of thalidomide derivatives

Costa

Carvalho

et al. 2015

Chemico-Biological Interactions

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“…CRBN, a member of the CRL4 complex, was recently identified as the target of the anti-myeloma drug lenalidomide, which is a derivative of thalidomide. [22][23][24] In search of the target genes of Blimp-1 or Aiolos in MM cells from our ChIP-chip data, we found that CUL4A, encoding a scaffold protein of the CRL complex, is directly bound by Blimp-1 at two potential binding sites (Figure 6a). A ChIP assay further confirmed that Blimp-1 binds to both sites in CUL4A intron 3 in MM cells (Figure 6b, upper panel).…”

Section: Resultsmentioning

confidence: 99%

Aiolos collaborates with Blimp-1 to regulate the survival of multiple myeloma cells

Hung

Chen

et al. 2016

Cell Death Differ

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The transcriptional repressor B lymphocyte-induced maturation protein-1 (Blimp-1) has crucial roles in the control of plasma cell differentiation and in maintaining survival of plasma cells. However, how Blimp-1 ensures the survival of plasma cell malignancy, multiple myeloma (MM), has remained elusive. Here we identified Aiolos, an anti-apoptotic transcription factor of MM cells, as a Blimp-1-interacting protein by mass spectrometry. ChIP coupled with DNA microarray was used to profile the global binding of Aiolos and Blimp-1 to endogenous targets in MM cells, which revealed their co-binding to a large number of genes, including apoptosis-related genes. Accordingly, Blimp-1 and Aiolos regulate similar transcriptomes in MM cells. Analysis of the binding motifs for Blimp-1 and Aiolos uncovered a partial motif that was similar across sites for both proteins. Aiolos promotes the binding of Blimp-1 to target genes and thereby enhances Blimp-1-dependent transcriptional repression. Furthermore, treatment with an anti-MM agent, lenalidomide, caused ubiquitination and proteasomal degradation of Blimp-1, leading to the de-repression of a new Blimp-1 direct target, CULLIN 4A (CUL4A), and reduced Aiolos levels. Accordingly, lenalidomide-induced cell death was partially rescued by reintroduction of Blimp-1 or knockdown of CUL4A. Thus, we demonstrated the functional impacts and underlying mechanisms of the interaction between Aiolos and Blimp-1 in maintaining MM cell survival. We also showed that interruption of Blimp-1/Aiolos regulatory pathways contributes to lenalidomide-mediated anti-MM activity.

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“…Indeed, immunomodulatory drugs based on thalidomide, mainly amino-substituted thalidomide analogs, have been reported to be superior candidates as antitumor agents (Bartlett et al 2004). Despite thalidomide not leanding to spleen morphological alterations in this work, it is known that some phthalimide analogues act as costimulators, increasing the response of T-lymphocytes to T-cellreceptor-mediated stimulation, the production of interleukin-2 and interferon-γ as well as the number of natural killer cells (Haslett et al 1998, Pan and Lentzsch 2012. On the other hand, most chemotherapy drugs are immunosuppressive and have negative side effects (Gonen and Assaraf 2012), which explain the leucocyte suppression, and hypoplasia of the splenic white pulp and small lymphoid aggregates in 5-FU-treated mice, findings which display the importance about enhancement of host defenses as an alternative to the traditional cancer cytotoxic chemotherapy since it involves minor side effects.…”

Section: Discussionmentioning

confidence: 99%

Cytotoxic and toxicological effects of phthalimide derivatives on tumor and normal murine cells

Ferreira

Costa

et al. 2015

An. Acad. Bras. Ciênc.

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Eleven phthalimide derivatives were evaluated with regards to their antiproliferative activity on tumor and normal cells and possible toxic effects. Cytotoxic analyses were performed against murine tumors (Sarcoma 180 and B-16/F-10 cells) and peripheral blood mononuclear cells (PBMC) using MTT and Alamar Blue assays. Following, the investigation of cytotoxicity was executed by flow cytometry analysis and antitumoral and toxicological potential by in vivo techniques. The molecules 3b, 3c, 4 and 5 revealed in vitro cytotoxicity against Sarcoma 180, B-16/F-10 and PBMC. Since compound 4 was the most effective derivative, it was chosen to detail the mechanism of action after 24, 48 and 72 h exposure (22.5 and 45 µM). Sarcoma 180 cells treated with compound 4 showed membrane disruption, DNA fragmentation and mitochondrial depolarization in a time-and dose-dependent way. Compounds 3c, 4 and 5 (50 mg/kg/day) did not inhibit in vivo tumor growth. Compound 4-treated animals exhibited an increase in total leukocytes, lymphocytes and spleen relative weight, a decreasing in neutrophils and hyperplasia of spleen white pulp. Treated animals presented reversible histological changes. Molecule 4 had in vitro antiproliferative action possibly triggered by apoptosis, reversible toxic effects on kidneys, spleen and livers and exhibited immunostimulant properties that can be explored to attack neoplasic cells.

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The application and biology of immunomodulatory drugs (IMiDs) in cancer

Cited by 61 publications

References 146 publications

Improvement of in vivo anticancer and antiangiogenic potential of thalidomide derivatives

Improvement of in vivo anticancer and antiangiogenic potential of thalidomide derivatives

Aiolos collaborates with Blimp-1 to regulate the survival of multiple myeloma cells

Cytotoxic and toxicological effects of phthalimide derivatives on tumor and normal murine cells

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