Aplidin (plitidepsin) is a novel anti-myeloma agent with potent anti-resorptive activity mediated by direct effects on osteoclasts.
Aplidin (plitidepsin) is a novel anti-myeloma agent with potent anti-resorptive activity mediated by direct effects on osteoclasts.
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DOI：
10.18632/oncotarget.26831
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发表时间：
2019-04-12
期刊：
影响因子：
--
通讯作者：
Bellido, Teresita
中科院分区：
文献类型：
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作者：
Delgado-Calle, Jesus;Kurihara, Noriyoshi;Bellido, Teresita
尽管最近在其治疗方面取得了进展，但多发性骨髓瘤（MM）仍然无法治愈，即使在完全缓解后，其相关的骨病仍然存在。因此，鉴定同时抑制MM生长和保护骨的新治疗剂是未满足的需求。在此，我们研究了一种新型抗癌海洋衍生化合物Aplidin对MM和骨细胞的影响。在体外，Aplidin有效地抑制MM细胞生长并诱导凋亡，地塞米松（Dex）和硼替佐米（Btz）增强了这种作用。Aplidin适度降低骨细胞/成骨细胞活力，降低成骨细胞矿化，Dex增强了这种作用，Btz部分阻止了这种作用。此外，Aplidin显着减少破骨细胞前体细胞的数量和分化，并减少成熟破骨细胞的数量和吸收活性。此外，Aplidin减少了Dex诱导的破骨细胞分化，并在与Btz组合时进一步减少破骨细胞数量。最后，单独的Aplidin，或次优剂量的Aplidin与Dex或Btz组合，在体外骨器官培养物中减少肿瘤生长和骨吸收，所述体外骨器官培养物再现MM/骨髓小生境的3D组织和细胞多样性。这些结果表明，Aplidin具有有效的抗骨髓瘤和抗再吸收特性，并增强蛋白酶体抑制剂对MM生长和骨破坏的阻断。
Despite recent progress in its treatment, Multiple Myeloma (MM) remains incurable and its associated bone disease persists even after complete remission. Thus, identification of new therapeutic agents that simultaneously suppress MM growth and protect bone is an unmet need. Herein, we examined the effects of Aplidin, a novel anti-cancer marine-derived compound, on MM and bone cells. In vitro, Aplidin potently inhibited MM cell growth and induced apoptosis, effects that were enhanced by dexamethasone (Dex) and bortezomib (Btz). Aplidin modestly reduced osteocyte/osteoblast viability and decreased osteoblast mineralization, effects that were enhanced by Dex and partially prevented by Btz. Further, Aplidin markedly decreased osteoclast precursor numbers and differentiation, and reduced mature osteoclast number and resorption activity. Moreover, Aplidin reduced Dex-induced osteoclast differentiation and further decreased osteoclast number when combined with Btz. Lastly, Aplidin alone, or suboptimal doses of Aplidin combined with Dex or Btz, decreased tumor growth and bone resorption in ex vivo bone organ cultures that reproduce the 3D-organization and the cellular diversity of the MM/bone marrow niche. These results demonstrate that Aplidin has potent anti-myeloma and anti-resorptive properties, and enhances proteasome inhibitors blockade of MM growth and bone destruction.