Aplidin, a Marine Organism–Derived Compound with Potent Antimyeloma Activity <i>In vitro</i> and <i>In vivo</i>

Mitsiades, Constantine S.; Ocio, Enrique M.; Pandiella, Atanasio; Maiso, Patricia; Gajate, Consuelo; Garayoa, Mercedes; Vilanova, David; Montero, Juan Carlos; Mitsiades, Nicholas; McMullan, Ciaran J.; Munshi, Nikhil C.; Hideshima, Teru; Chauhan, Dharminder; Avilés, Pablo; Otero, Gabriel; Faircloth, Glynn; Mateos, María Victoria; Richardson, Paul G.; Mollinedo, Faustino; San-Miguel, Jesús F.; Anderson, Kenneth C.

doi:10.1158/0008-5472.can-07-5725

Cited by 96 publications

(80 citation statements)

References 39 publications

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“…We therefore compared the effect of the whole BM-MSC compartment using normal BM-MSCs, MM BM-MSCs, or HS-5 cells -and their related exosomal counterparts -on MM cell proliferation. We found that primary MM BM-MSCs clearly increased MM cell proliferation (36%-38%), and both HS-5 cells and normal BM-MSCs exerted similar effects (15%-32% and 9%-16%, respectively), thus recapitulating previous findings (30)(31)(32)(33)(34)(35)(36). Importantly, MM BM-MSC-derived pure exosomes exerted a proproliferative effect of about 22%-30% on MM cells, whereas HS-5 cells and normal BM-MSC-derived pure exosomes inhibited MM cell proliferation (28%-31% and 30%-40%, respectively; Supplemental Figure 3B).…”

Section: Figuresupporting

confidence: 90%

“…Similar findings were obtained using 4 MM, 2 monoclonal gammopathy of undetermined significance (MGUS), 2 smoldering MM, and 4 normal BM-MSC-derived exosome samples ( Figure 2, A and B). It was previously reported that the whole BM stromal cell population promotes MM cell proliferation, due the presence of either autocrine or paracrine circuits of growth that support MM cell proliferation (30)(31)(32)(33)(34)(35). This was previously established using primary MM BM-MSCs and HS-5 cells as a model of normal BMMSCs (36).…”

Section: Figurementioning

confidence: 99%

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BM mesenchymal stromal cell–derived exosomes facilitate multiple myeloma progression

et al. 2013

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BM mesenchymal stromal cells (BM-MSCs IntroductionThe BM microenvironment plays a crucial role in multiple myeloma (MM) pathogenesis by supporting plasma cell growth, survival, and drug resistance, which has been partially attributed to the ability of MM BM mesenchymal stromal cells (BM-MSCs) to secrete growth factors and cytokines such as IL-6, IGF-1, VEGF, and many others (1-3). These observations are indicative of paracrine growth circuits between BM-MSCs and clonal plasma cells and vice versa, which suggests that the BM niche provides an optimal substrate for MM cell localization and growth. Nevertheless, little is known about the putative mechanisms by which the BM microenvironment can lead to initiation or progression of oncogenesis in this disease.It was recently reported that cell-cell communication is mediated by exosomes. Exosomes are small nanometer-sized (50-100 nm) vesicles of endocytic origin that are released in the extracellular milieu by several cell types (4-11) under physiological and pathological conditions, including antigen presentation, transmission of infectious agents, and tumors (12, 13). The role of exosomes in tumor progression is due to the ability of tumor cell-derived exosomes to modulate and mold the host microenvironment, thereby promoting tumor cell growth and disease progression (14-17).

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Section: Figuresupporting

confidence: 90%

Section: Figurementioning

confidence: 99%

BM mesenchymal stromal cell–derived exosomes facilitate multiple myeloma progression

et al. 2013

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“…16,[25][26][27][28][29] Also, various new candidate anti-MM agents, such as the histone deacetylase inhibitor PXD101, induce apoptosis by activating the p38 MAPK pathway in myeloma cells. [30][31][32][33] These findings lead us to suggest that both JNK and p38 pathways activation are the logical molecular targets for the development of new therapeutic strategies for MM. On the other hand, although earlier studies suggest that Anti-myeloma effect of galectin-9 T Kobayashi et al NF-kB signaling inactivation or the activation of Ca 2 þ -calpaincaspase-1 pathway are involved in the anti-proliferative effect of hGal9 in other cancers, 13,14,34 those were not the case in the myelomas (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Galectin-9 exhibits anti-myeloma activity through JNK and p38 MAP kinase pathways

et al. 2010

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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.

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“…Xenograft tumor modeling was conducted as previously described (12,30,31). CB-17 severe combined immunodeficiency (SCID) mice (SLAC, Laboratory Animal, Shanghai, China) were subcutaneously inoculated in the flanks with H929 cells (3 Â 10 7 per mouse) or RPMI 8226 cells (1 Â 10 7 per mouse) in 100 mL serum-free RPMI 1640 medium.…”

Section: Human Plasmacytoma Xenograft Modelmentioning

confidence: 99%

“…To further investigate the therapeutic efficacy of manipulating autophagy, we therefore focused our subsequent studies on either HCQ/ doxorubicin or HCQ/melphalan combinations due to their potential clinical relevance. Having shown that HCQ enhances doxorubicin-or melphalan-induced apoptosis in MM cells in vitro, we next examined in vivo efficacy of HCQ using a human plasmacytoma xenograft mouse model (12,30,31). When the H929 tumors were measurable, mice were matched for tumor volumes and randomly assigned to receive HCQ, doxorubicin, or melphalan or a combination of HCQ with either drug.…”

Section: Knockdown Of Beclin 1 or Atg5 Sensitizes MM Cells To Dna-dammentioning

confidence: 99%

Targeting Autophagy Augments In Vitro and In Vivo Antimyeloma Activity of DNA-Damaging Chemotherapy

Pan

Gao

Chen

et al. 2011

Clinical Cancer Research

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Purpose: Although autophagy occurs in most tumor cells following DNA damage, it is still a mystery how this DNA-damaging event turns on the autophagy machinery in multiple myeloma (MM) and how the functional status of autophagy impacts on its susceptibility to death in response to DNA-damaging chemotherapy.Experimental Design: We investigate the effects of DNA damage on autophagy in MM cells and elucidate its underlying molecular mechanism. Then, we examined the impacts of pharmacologic or genetic inhibition of autophagy on DNA damage-induced apoptosis. Furthermore, the antimyeloma activity of autophagy inhibitor in combination with DNA-damaging agents was evaluated in MM xenograft models.Results: We showed that DNA-damaging drugs, doxorubicin and melphalan, induce caspase-dependent apoptosis and concurrently trigger Beclin 1-regulated autophagy in human MM cell lines H929 and RPMI 8226. Mechanistically, association of autophagy execution proteins Beclin 1 with class III phosphoinositide 3-kinase, which is inhibited by Bcl-2 recruitment, contributes directly to the autophagic process. Importantly, targeting suppression of autophagy by minimally toxic concentrations of pharmacologic inhibitors (hydroxychloroquine and 3-methyladenine) or short hairpin RNAs against autophagy genes, Beclin 1 and Atg5, dramatically augments proapoptotic activity of DNA-damaging chemotherapy both in vitro using MM cell lines or purified patient MM cells and in vivo in a human plasmacytoma xenograft mouse model.Conclusion: These data can help unravel the underlying molecular mechanism of autophagy in DNAdamaged MM cells and also provide a rationale for clinical evaluation of autophagy inhibitors in combination with DNA-damaging chemotherapy in MM. Clin Cancer Res; 17(10); 3248-58. Ó2011 AACR.

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Aplidin, a Marine Organism–Derived Compound with Potent Antimyeloma Activity In vitro and In vivo

Cited by 96 publications

References 39 publications

BM mesenchymal stromal cell–derived exosomes facilitate multiple myeloma progression

BM mesenchymal stromal cell–derived exosomes facilitate multiple myeloma progression

Galectin-9 exhibits anti-myeloma activity through JNK and p38 MAP kinase pathways

Targeting Autophagy Augments In Vitro and In Vivo Antimyeloma Activity of DNA-Damaging Chemotherapy

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